Contrast ultrasound targeted treatment of gliomas in mice via drug-bearing nanoparticle delivery and microvascular ablation.

PubMed

Burke, Caitlin W; Price, Richard J

2010-12-15

We are developing minimally-invasive contrast agent microbubble based therapeutic approaches in which the permeabilization and/or ablation of the microvasculature are controlled by varying ultrasound pulsing parameters. Specifically, we are testing whether such approaches may be used to treat malignant brain tumors through drug delivery and microvascular ablation. Preliminary studies have been performed to determine whether targeted drug-bearing nanoparticle delivery can be facilitated by the ultrasound mediated destruction of "composite" delivery agents comprised of 100nm poly(lactide-co-glycolide) (PLAGA) nanoparticles that are adhered to albumin shelled microbubbles. We denote these agents as microbubble-nanoparticle composite agents (MNCAs). When targeted to subcutaneous C6 gliomas with ultrasound, we observed an immediate 4.6-fold increase in nanoparticle delivery in MNCA treated tumors over tumors treated with microbubbles co-administered with nanoparticles and a 8.5 fold increase over non-treated tumors. Furthermore, in many cancer applications, we believe it may be desirable to perform targeted drug delivery in conjunction with ablation of the tumor microcirculation, which will lead to tumor hypoxia and apoptosis. To this end, we have tested the efficacy of non-theramal cavitation-induced microvascular ablation, showing that this approach elicits tumor perfusion reduction, apoptosis, significant growth inhibition, and necrosis. Taken together, these results indicate that our ultrasound-targeted approach has the potential to increase therapeutic efficiency by creating tumor necrosis through microvascular ablation and/or simultaneously enhancing the drug payload in gliomas.

Ultrasound mediated transdermal insulin delivery in pigs using a lightweight transducer.

PubMed

Park, E J; Werner, Jacob; Smith, Nadine Barrie

2007-07-01

In previous studies, ultrasound mediated transdermal drug delivery has shown a promising potential as a method for noninvasive drug administration. For prospective future human application, this study was designed to determine the feasibility of lightweight cymbal transducer array as a practical device for noninvasive transdermal insulin delivery in large pigs. Six Yorkshire pigs (100-140 lbs) were divided into two groups. As the control (n = 3), the first group did not receive any ultrasound exposure with the insulin. The second group (n = 3) was treated with ultrasound and insulin at 20 kHz with an I(sptp) = 100 mW/cm(2) at a 20% duty cycle for 60 min. With the pigs in lateral recumbency after anesthesia, the ultrasound transducer with insulin was placed on the axillary area of the pig. At the beginning and every 15 min up to 90 min, the blood glucose level was determined using a glucose monitoring system. To compare the results of individual animals, the change of blood glucose level was normalized to each animal's initial glucose value at the start of the experiment. Although each animal had a different initial glucose level, the mean and standard error for the six animals was 146 +/- 13 mg/dl. For the control group, the blood glucose level increased to 31 +/- 21 mg/dl compared to the initial baseline over the 90 min experiment. However for the ultrasound with insulin treated group, the glucose level decreased to -72 +/- 5 mg/dl at 60 min (p < 0.05) and continued to decrease to -91 +/- 23 mg/dl in 90 min (p < 0.05). The results indicate the feasibility of ultrasound mediated transdermal insulin delivery using the cymbal transducer array in animal with a similar size and weight to a human. Based on these result, the cymbal array has potential as a practical ultrasound system for noninvasive transdermal insulin delivery for diabetes management.

Camptothecin-loaded fusogenic nanodroplets as ultrasound theranostic agent in stem cell-mediated drug-delivery system.

PubMed

Ho, Yi-Ju; Chiang, Yu-Jung; Kang, Shih-Tsung; Fan, Ching-Hsiang; Yeh, Chih-Kuang

2018-05-28

Adipose-derived stem cells (ADSCs) have been utilized in cellular delivery systems to carry therapeutic agents into tumors by migration. Drug-loaded nanodroplets release drugs and form bubbles after acoustic droplet vaporization (ADV) triggered by ultrasound stimulation, providing a system for ultrasound-induced cellular delivery of theranostic agents. In order to improve the efficiency of drug release, fusogenic nanodroplets were designed to go from nano to micron size upon uptake by ADSCs for reducing ADV threshold. The purpose of our study was to demonstrate the utility of camptothecin-loaded fusogenic nanodroplets (CPT-FNDs) as ultrasound theranostic agents in an ADSCs delivery system. CPT-FNDs showed an increase in size from 81.6 ± 3.5 to 1043.5 ± 28.3 nm and improved CPT release from 22.0 ± 1.8% to 37.6 ± 2.1%, demonstrating the fusion ability of CPT-FNDs. CPT-FNDs-loaded ADSCs demonstrated a cell viability of 77 ± 4%, and the in vitro migration ability was 3.2 ± 1.2-fold for the tumor condition compared to the cell growth condition. Ultrasound enhancement imaging showed intratumoral ADV-generated bubble formation (increasing 3.24 ± 0.47 dB) triggered by ultrasound after CPT-FNDs-loaded ADSCs migration into B16F0 tumors. Histological images revealed intratumoral distribution of CPT-FNDs-loaded ADSCs and tissue damage due to the ADV. The CPT-FNDs can be used as theranostic agents in an ADSCs delivery system to provide the ultrasound contrast imaging and deliver combination therapy of drug release and physical damage after ADV. Copyright © 2018 Elsevier B.V. All rights reserved.

Microbubble-mediated ultrasound therapy: a review of its potential in cancer treatment

PubMed Central

Ibsen, Stuart; Schutt, Carolyn E; Esener, Sadik

2013-01-01

The inherently toxic nature of chemotherapy drugs is essential for them to kill cancer cells but is also the source of the detrimental side effects experienced by patients. One strategy to reduce these side effects is to limit the healthy tissue exposure by encapsulating the drugs in a vehicle that demonstrates a very low leak rate in circulation while simultaneously having the potential for rapid release once inside the tumor. Designing a vehicle with these two opposing properties is the major challenge in the field of drug delivery. A triggering event is required to change the vehicle from its stable circulating state to its unstable release state. A unique mechanical actuation type trigger is possible by harnessing the size changes that occur when microbubbles interact with ultrasound. These mechanical actuations can burst liposomes and cell membranes alike allowing for rapid drug release and facilitating delivery into nearby cells. The tight focusing ability of the ultrasound to just a few cubic millimeters allows for precise control over the tissue location where the microbubbles destabilize the vehicles. This allows the ultrasound to highlight the tumor tissue and cause rapid drug release from any carrier present. Different vehicle designs have been demonstrated from carrying drug on just the surface of the microbubble itself to encapsulating the microbubble along with the drug within a liposome. In the future, nanoparticles may extend the circulation half-life of these ultrasound triggerable drug-delivery vehicles by acting as nucleation sites of ultrasound-induced mechanical actuation. In addition to the drug delivery capability, the microbubble size changes can also be used to create imaging contrast agents that could allow the internal chemical environment of a tumor to be studied to help improve the diagnosis and detection of cancer. The ability to attain truly tumor-specific release from circulating drug-delivery vehicles is an exciting future prospect to reduce chemotherapy side effects while increasing drug effectiveness. PMID:23667309

Ultrasound mediated nanoparticle drug delivery

NASA Astrophysics Data System (ADS)

Mullin, Lee B.

Ultrasound is not only a powerful diagnostic tool, but also a promising therapeutic technology that can be used to improve localized drug delivery. Microbubble contrast agents are micron sized encapsulated gas filled bubbles that are administered intravenously. Originally developed to enhance ultrasound images, microbubbles are highly echogenic due to the gas core that provides a detectable impedance difference from the surrounding medium. The core also allows for controlled response of the microbubbles to ultrasound pulses. Microbubbles can be pushed using acoustic radiation force and ruptured using high pressures. Destruction of microbubbles can increase permeability at the cellular and vascular level, which can be advantageous for drug delivery. Advances in drug delivery methods have been seen with the introduction of nanoparticles, nanometer sized objects often carrying a drug payload. In chemotherapy, nanoparticles can deliver drugs to tumors while limiting systemic exposure due to abnormalities in tumor vasculature such large gaps between endothelial cells that allow nanoparticles to enter into the interstitial space; this is referred to as the enhanced permeability and retention (EPR) effect. However, this effect may be overestimated in many tumors. Additionally, only a small percentage of the injected dose accumulates in the tumor, which most the nanoparticles accumulating in the liver and spleen. It is hypothesized that combining the acoustic activity of an ultrasound contrast agent with the high payload and extravasation ability of a nanoparticle, localized delivery to the tumor with reduced systemic toxicity can be achieved. This method can be accomplished by either loading nanoparticles onto the shell of the microbubble or through a coadministration method of both nanoparticles and microbubbles. The work presented in this dissertation utilizes novel and commercial nanoparticle formulations, combined with microbubbles and a variety of ultrasound systems. Ultrasound parameters are optimized to achieve maximum cell internalization of molecules and increased nanoparticle delivery to a cell layer on a coverslip. In-vivo studies demonstrate the possibility of using a lower dose of paclitaxel to slow tumor growth rates, increase doxorubicin concentration in tumor tissue, and enhance tumor delivery of fluorescent molecules through treatments that combine nanoparticles with ultrasound and microbubbles.

Sonoporation, drug delivery, and gene therapy.

PubMed

Liang, H-D; Tang, J; Halliwell, M

2010-01-01

Ultrasound is a very effective modality for drug delivery and gene therapy because energy that is non-invasively transmitted through the skin can be focused deeply into the human body in a specific location and employed to release drugs at that site. Ultrasound cavitation, enhanced by injected microbubbles, perturbs cell membrane structures to cause sonoporation and increases the permeability to bioactive materials. Cavitation events also increase the rate of drug transport in general by augmenting the slow diffusion process with convective transport processes. Drugs and genes can be incorporated into microbubbles, which in turn can target a specific disease site using ligands such as the antibody. Drugs can be released ultrasonically from microbubbles that are sufficiently robust to circulate in the blood and retain their cargo of drugs until they enter an insonated volume of tissue. Local drug delivery ensures sufficient drug concentration at the diseased region while limiting toxicity for healthy tissues. Ultrasound-mediated gene delivery has been applied to heart, blood vessel, lung, kidney, muscle, brain, and tumour with enhanced gene transfection efficiency, which depends on the ultrasonic parameters such as acoustic pressure, pulse length, duty cycle, repetition rate, and exposure duration, as well as microbubble properties such as size, gas species, shell material, interfacial tension, and surface rigidity. Microbubble-augmented sonothrombolysis can be enhanced further by using targeting microbubbles.

The Impact of Bubbles on Measurement of Drug Release from Echogenic Liposomes

PubMed Central

Kopechek, Jonathan A.; Haworth, Kevin J.; Radhakrishnan, Kirthi; Huang, Shaoling; Klegerman, Melvin E.; McPherson, David D.; Holland, Christy K.

2013-01-01

Echogenic liposomes (ELIP) encapsulate gas bubbles and drugs within lipid vesicles, but the mechanisms of ultrasound-mediated drug release from ELIP are not well understood. The effect of cavitation activity on drug release from ELIP was investigated in flowing solutions using two fluorescent molecules: a lipophilic drug (rosiglitazone) and a hydrophilic drug substitute (calcein). ELIP samples were exposed to pulsed Doppler ultrasound from a clinical diagnostic ultrasound scanner at pressures above and below the inertial and stable cavitation thresholds. Control samples were exposed to a surfactant, Triton X-100 (positive control), or to flow alone (negative control). Fluorescence techniques were used to detect release. Encapsulated microbubbles reduced the measured fluorescence intensity and this effect should be considered when assessing drug release from ELIP. The origin of this effect is not specific to ELIP. Release of rosiglitazone or calcein compared to the negative control was only observed with detergent treatment, but not with ultrasound exposure, despite the presence of stable and inertial cavitation activity. Release of rosiglitazone or calcein from ELIP exposed to diagnostic ultrasound was not observed, even in the presence of cavitation activity. Ultrasound-mediated drug delivery strategies with ELIP will thus rely on passage of the drug-loaded liposomes to target tissues. PMID:23357288

Ultrasound-mediated gene delivery of naked plasmid DNA in skeletal muscles: a case for bolus injections.

PubMed

Sanches, Pedro Gomes; Mühlmeister, Mareike; Seip, Ralf; Kaijzel, Eric; Löwik, Clemens; Böhmer, Marcel; Tiemann, Klaus; Grüll, Holger

2014-12-10

Localized gene delivery has many potential clinical applications. However, the nucleic acids (e.g. pDNA and siRNA) are incapable of passively crossing the endothelium, cell membranes and other biological barriers which must be crossed to reach their intracellular targets. A possible solution is the use of ultrasound to burst circulating microbubbles inducing transient permeabilization of surrounding tissues which mediates nucleic acid extravasation and cellular uptake. In this study we report on an optimization of the ultrasound gene delivery technique. Naked pDNA (200 μg) encoding luciferase and SonoVue® microbubbles were co-injected intravenously in mice. The hindlimb skeletal muscles were exposed to ultrasound from a non-focused transducer (1 MHz, 1.25 MPa, PRI 30s) and injection protocols and total amounts as well as ultrasound parameters were systemically varied. Gene expression was quantified relative to a control using a bioluminescence camera system at day 7 after sonication. Bioluminescence ratios in sonicated/control muscles of up to 101× were obtained. In conclusion, we were able to specifically deliver genetic material to the selected skeletal muscles and overall, the use of bolus injections and high microbubble numbers resulted in increased gene expression reflected by stronger bioluminescence signals. Based on our data, bolus injections seem to be required in order to achieve transient highly concentrated levels of nucleic acids and microbubbles at the tissue of interest which upon ultrasound exposure should lead to increased levels of gene delivery. Thus, ultrasound mediated gene delivery is a promising technique for the clinical translation of localized drug delivery. Copyright © 2014 Elsevier B.V. All rights reserved.

The effect of particle density on ultrasound-mediated transport of nanoparticles.

PubMed

Lea-Banks, Harriet; Teo, Boon; Stride, Eleanor; Coussios, Constantin C

2016-11-21

A significant barrier to successful drug delivery is the limited penetration of nanoscale therapeutics beyond the vasculature. Building on recent in vivo findings in the context of cancer drug delivery, the current study investigates whether modification of nanoparticle drug-carriers to increase their density can be used to enhance their penetration into viscoelastic materials under ultrasound exposure. A computational model is first presented to predict the transport of identically sized nanoparticles of different densities in an ultrasonic field in the presence of an oscillating microbubble, by a combination of primary and secondary acoustic radiation forces, acoustic streaming and microstreaming. Experiments are then described in which near monodisperse (polydispersity index  <0.2) nanoparticles of approximate mean diameter 200 nm and densities ranging from 1.01 g cm -3 to 5.58 g cm -3 were fabricated and delivered to a tissue-mimicking material in the presence or absence of a microbubble ultrasound contrast agent, at ultrasound frequencies of 0.5 MHz and 1.6 MHz and a peak negative pressure of 1 MPa. Both the theoretical and experimental results confirm that denser particles exhibit significantly greater ultrasound-mediated transport than their lower density counterparts, indicating that density is a key consideration in the design of nanoscale therapeutics.

Ultrasonic Drug Delivery – A General Review

PubMed Central

Pitt, William G.; Husseini, Ghaleb A.; Staples, Bryant J.

2006-01-01

Ultrasound (US) has an ever-increasing role in the delivery of therapeutic agents including genetic material, proteins, and chemotherapeutic agents. Cavitating gas bodies such as microbubbles are the mediators through which the energy of relatively non-interactive pressure waves is concentrated to produce forces that permeabilize cell membranes and disrupt the vesicles that carry drugs. Thus the presence of microbubbles enormously enhances delivery of genetic material, proteins and smaller chemical agents. Delivery of genetic material is greatly enhanced by ultrasound in the presence of microbubbles. Attaching the DNA directly to the microbubbles or to gas-containing liposomes enhances gene uptake even further. US-enhanced gene delivery has been studied in various tissues including cardiac, vascular, skeletal muscle, tumor and even fetal tissue. US-enhanced delivery of proteins has found most application in transdermal delivery of insulin. Cavitation events reversibly disrupt the structure of the stratus corneum to allow transport of these large molecules. Other hormones and small proteins could also be delivered transdermally. Small chemotherapeutic molecules are delivered in research settings from micelles and liposomes exposed to ultrasound. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; it also makes the cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has upon cells and drug-carrying vesicles. PMID:16296719

Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

PubMed Central

Aryal, Muna; Arvanitis, Costas D.; Alexander, Phillip M.; McDannold, Nathan

2014-01-01

The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB. PMID:24462453

Exploitation of sub-micron cavitation nuclei to enhance ultrasound-mediated transdermal transport and penetration of vaccines.

PubMed

Bhatnagar, Sunali; Kwan, James J; Shah, Apurva R; Coussios, Constantin-C; Carlisle, Robert C

2016-09-28

Inertial cavitation mediated by ultrasound has been previously shown to enable skin permeabilisation for transdermal drug and vaccine delivery, by sequentially applying the ultrasound then the therapeutic in liquid form on the skin surface. Using a novel hydrogel dosage form, we demonstrate that the use of sub-micron gas-stabilising polymeric nanoparticles (nanocups) to sustain and promote cavitation activity during simultaneous application of both drug and vaccine results in a significant enhancement of both the dose and penetration of a model vaccine, Ovalbumin (OVA), to depths of 500μm into porcine skin. The nanocups themselves exceeded the penetration depth of the vaccine (up to 700μm) due to their small size and capacity to 'self-propel'. In vivo murine studies indicated that nanocup-assisted ultrasound transdermal vaccination achieved significantly (p<0.05) higher delivery doses without visible skin damage compared to the use of a chemical penetration enhancer. Transdermal OVA doses of up to 1μg were achieved in a single 90-second treatment, which was sufficient to trigger an antigen-specific immune response. Furthermore, ultrasound-assisted vaccine delivery in the presence of nanocups demonstrated substantially higher specific anti-OVA IgG antibody levels compared to other transdermal methods. Further optimisation can lead to a viable, safe and non-invasive delivery platform for vaccines with potential use in a primary care setting or personalized self-vaccination at home. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

A Disposable Microfluidic Device for Controlled Drug Release from Thermal-Sensitive Liposomes by High Intensity Focused Ultrasound.

PubMed

Meng, Long; Deng, Zhiting; Niu, Lili; Li, Fei; Yan, Fei; Wu, Junru; Cai, Feiyan; Zheng, Hairong

2015-01-01

The drug release triggered thermally by high intensity focused ultrasound (HIFU) has been considered a promising drug delivery strategy due to its localized energy and non-invasive characters. However, the mechanism underlying the HIFU-mediated drug delivery remains unclear due to its complexity at the cellular level. In this paper, micro-HIFU (MHIFU) generated by a microfluidic device is introduced which is able to control the drug release from temperature-sensitive liposomes (TSL) and evaluate the thermal and mechanical effects of ultrasound on the cellular drug uptake and apoptosis. By simply adjusting the input electrical signal to the device, the temperature of sample can be maintained at 37 °C, 42 °C and 50 °C with the deviation of ± 0.3 °C as desired. The flow cytometry results show that the drug delivery under MHIFU sonication leads to a significant increase in apoptosis compared to the drug release by incubation alone at elevated temperature of 42 °C. Furthermore, increased squamous and protruding structures on the surface membrane of cells were detected by atomic force microscopy (AFM) after MHIFU irradiation of TSL. We demonstrate that compared to the routine HIFU treatment, MHIFU enables monitoring of in situ interactions between the ultrasound and cell in real time. Furthermore, it can quantitatively analyze and characterize the alterations of the cell membrane as a function of the treatment time.

Gene therapy for cardiovascular disease mediated by ultrasound and microbubbles

PubMed Central

2013-01-01

Gene therapy provides an efficient approach for treatment of cardiovascular disease. To realize the therapeutic effect, both efficient delivery to the target cells and sustained expression of transgenes are required. Ultrasound targeted microbubble destruction (UTMD) technique has become a potential strategy for target-specific gene and drug delivery. When gene-loaded microbubble is injected, the ultrasound-mediated microbubble destruction may spew the transported gene to the targeted cells or organ. Meanwhile, high amplitude oscillations of microbubbles increase the permeability of capillary and cell membrane, facilitating uptake of the released gene into tissue and cell. Therefore, efficiency of gene therapy can be significantly improved. To date, UTMD has been successfully investigated in many diseases, and it has achieved outstanding progress in the last two decades. Herein, we discuss the current status of gene therapy of cardiovascular diseases, and reviewed the progress of the delivery of genes to cardiovascular system by UTMD. PMID:23594865

Unilateral Opening of Rat Blood-Brain Barrier Assisted by Diagnostic Ultrasound Targeted Microbubbles Destruction.

PubMed

Xu, Yali; Cui, Hai; Zhu, Qiong; Hua, Xing; Xia, Hongmei; Tan, Kaibin; Gao, Yunhua; Zhao, Jing; Liu, Zheng

2016-01-01

Objective. Blood-brain barrier (BBB) is a key obstacle that prevents the medication from blood to the brain. Microbubble-enhanced cavitation by focused ultrasound can open the BBB and proves to be valuable in the brain drug delivery. The study aimed to explore the feasibility, efficacy, and safety of unilateral opening of BBB using diagnostic ultrasound targeted microbubbles destruction in rats. Methods. A transtemporal bone irradiation of diagnostic ultrasound and intravenous injection of lipid-coated microbubbles were performed at unilateral hemisphere. Pathological changes were monitored. Evans Blue extravasation grades, extraction from brain tissue, and fluorescence optical density were quantified. Lanthanum nitrate was traced by transmission electron microscopy. Results. After diagnostic ultrasound mediated microbubbles destruction, Evans Blue extravasation and fluorescence integrated optical density were significantly higher in the irradiated hemisphere than the contralateral side (all p < 0.01). Erythrocytes extravasations were demonstrated in the ultrasound-exposed hemisphere (4 ± 1, grade 2) while being invisible in the control side. Lanthanum nitrate tracers leaked through interendothelial cleft and spread to the nerve fiber existed in the irradiation side. Conclusions. Transtemporal bone irradiation under DUS mediated microbubble destruction provides us with a more accessible, safer, and higher selective BBB opening approach in rats, which is advantageous in brain targeted drugs delivery.

Tracking of cell nuclei for assessment of in vitro uptake kinetics in ultrasound-mediated drug delivery using fibered confocal fluorescence microscopy.

PubMed

Derieppe, Marc; de Senneville, Baudouin Denis; Kuijf, Hugo; Moonen, Chrit; Bos, Clemens

2014-10-01

Previously, we demonstrated the feasibility to monitor ultrasound-mediated uptake of a cell-impermeable model drug in real time with fibered confocal fluorescence microscopy. Here, we present a complete post-processing methodology, which corrects for cell displacements, to improve the accuracy of pharmacokinetic parameter estimation. Nucleus detection was performed based on the radial symmetry transform algorithm. Cell tracking used an iterative closest point approach. Pharmacokinetic parameters were calculated by fitting a two-compartment model to the time-intensity curves of individual cells. Cells were tracked successfully, improving time-intensity curve accuracy and pharmacokinetic parameter estimation. With tracking, 93 % of the 370 nuclei showed a fluorescence signal variation that was well-described by a two-compartment model. In addition, parameter distributions were narrower, thus increasing precision. Dedicated image analysis was implemented and enabled studying ultrasound-mediated model drug uptake kinetics in hundreds of cells per experiment, using fiber-based confocal fluorescence microscopy.

Ultrasound-mediated transdermal drug delivery of fluorescent nanoparticles and hyaluronic acid into porcine skin in vitro

NASA Astrophysics Data System (ADS)

Wang, Huan-Lei; Fan, Peng-Fei; Guo, Xia-Sheng; Tu, Juan; Ma, Yong; Zhang, Dong

2016-12-01

Transdermal drug delivery (TDD) can effectively bypass the first-pass effect. In this paper, ultrasound-facilitated TDD on fresh porcine skin was studied under various acoustic parameters, including frequency, amplitude, and exposure time. The delivery of yellow-green fluorescent nanoparticles and high molecular weight hyaluronic acid (HA) in the skin samples was observed by laser confocal microscopy and ultraviolet spectrometry, respectively. The results showed that, with the application of ultrasound exposures, the permeability of the skin to these markers (e.g., their penetration depth and concentration) could be raised above its passive diffusion permeability. Moreover, ultrasound-facilitated TDD was also tested with/without the presence of ultrasound contrast agents (UCAs). When the ultrasound was applied without UCAs, low ultrasound frequency will give a better drug delivery effect than high frequency, but the penetration depth was less likely to exceed 200 μm. However, with the help of the ultrasound-induced microbubble cavitation effect, both the penetration depth and concentration in the skin were significantly enhanced even more. The best ultrasound-facilitated TDD could be achieved with a drug penetration depth of over 600 μm, and the penetration concentrations of fluorescent nanoparticles and HA increased up to about 4-5 folds. In order to get better understanding of ultrasound-facilitated TDD, scanning electron microscopy was used to examine the surface morphology of skin samples, which showed that the skin structure changed greatly under the treatment of ultrasound and UCA. The present work suggests that, for TDD applications (e.g., nanoparticle drug carriers, transdermal patches and cosmetics), protocols and methods presented in this paper are potentially useful. Project partially supported by the National Natural Science Foundation of China (Grant Nos. 81127901, 81227004, 81473692, 81673995, 11374155, 11574156, 11274170, 11274176, 11474001, 11474161, 11474166, and 11674173), the Natural Science Foundation of Jiangsu Province, China (Grant No. BK2011812), the Fundamental Research Funds for the Central Universities, and the National High-Tech Research and Development Program of China (Grant No. 2012AA022702).

Research of Ultrasound-Mediated Transdermal Drug Delivery System Using Cymbal-Type Piezoelectric Composite Transducer

NASA Astrophysics Data System (ADS)

Huan, Huiting; Gao, Chunming; Liu, Lixian; Sun, Qiming; Zhao, Binxing; Yan, Laijun

2015-06-01

Transdermal drug delivery (TDD) implemented by especially low-frequency ultrasound is generally known as sonophoresis or phonophoresis which has drawn considerable wide attention. However, TDD has not yet achieved its full potential as an alternative to conventional drug delivery methods due to its bulky instruments. In this paper, a cymbal-type piezoelectric composite transducer (CPCT) which has advantages over a traditional ultrasound generator in weight, flexibility, and power consumption, is used as a substitute ultrasonicator to realize TDD. First, theoretical research on a CPCT based on the finite element analysis was carried out according to which a series of applicable CPCTs with bandwidths of 20 kHz to 100 kHz were elaborated. Second, a TDD experimental setup was built with previously fabricated CPCTs aimed at the administration of glucose. Finally, the TDD performance of glucose molecule transport in porcine skin was measured in vitro by quantifying the concentration of glucose, and the time variation curves were subsequently obtained. During the experiment, the driving wave form, frequency, and power consumption of the transducers were selected as the main elements which determined the efficacy of glucose delivery. The results indicate that the effectiveness of the CPCT-based delivery is constrained more by the frequency and intensity of ultrasound rather than the driving waveform. The light-weight, flexibility, and low-power consumption of a CPCT can potentially achieve effective TDD.

Ultrasound-Mediated Transdermal Drug Delivery: Mechanisms, Scope, and Emerging Trends

PubMed Central

Polat, Baris E.; Hart, Douglas; Langer, Robert; Blankschtein, Daniel

2012-01-01

The use of ultrasound for the delivery of drugs to, or through, the skin is commonly known as sonophoresis or phonophoresis. The use of therapeutic and high frequencies of ultrasound (≥ 0.7 MHz) for sonophoresis (HFS) dates back to as early as the 1950s, while low-frequency sonophoresis (LFS, 20 – 100 kHz) has only been investigated significantly during the past two decades. Although HFS and LFS are similar because they both utilize ultrasound to increase the skin penetration of permeants, the mechanisms associated with each physical enhancer are different. Specifically, the location of cavitation and the extent to which each process can increase skin permeability are quite dissimilar. Although the applications of both technologies are different, they each have strengths that could allow them to improve current methods of local, regional, and systemic drug delivery. In this review, we will discuss the mechanisms associated with both HFS and LFS, specifically concentrating on the key mechanistic differences between these two skin treatment methods. Background on the relevant physics associated with ultrasound transmitted through aqueous media will also be discussed, along with implications of these phenomena on sonophoresis. Finally, a thorough review of the literature is included, dating back to the first published reports of sonophoresis, including a discussion of emerging trends in the field. PMID:21238514

Ultrasound enhanced release of therapeutics from drug-releasing implants based on titania nanotube arrays.

PubMed

Aw, Moom Sinn; Losic, Dusan

2013-02-25

A non-invasive and external stimulus-driven local drug delivery system (DDS) based on titania nanotube (TNT) arrays loaded with drug encapsulated polymeric micelles as drug carriers and ultrasound generator is described. Ultrasound waves (USW) generated by a pulsating sonication probe (Sonotrode) in phosphate buffered saline (PBS) at pH 7.2 as the medium for transmitting pressure waves, were used to release drug-loaded nano-carriers from the TNT arrays. It was demonstrated that a very rapid release in pulsatile mode can be achieved, controlled by several parameters on the ultrasonic generator. This includes pulse length, time, amplitude and power intensity. By optimization of these parameters, an immediate drug-micelles release of 100% that spans a desirable time of 5-50 min was achieved. It was shown that stimulated release can be generated and reproduced at any time throughout the TNT-Ti implant life, suggesting considerable potential of this approach as a feasible and tunable ultrasound-mediated drug delivery system in situ via drug-releasing implants. It is expected that this concept can be translated from an in vitro to in vivo regime for therapeutic applications using drug-releasing implants in orthopedic and coronary stents. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Physically facilitating drug-delivery systems

PubMed Central

Rodriguez-Devora, Jorge I; Ambure, Sunny; Shi, Zhi-Dong; Yuan, Yuyu; Sun, Wei; Xu, Tao

2012-01-01

Facilitated/modulated drug-delivery systems have emerged as a possible solution for delivery of drugs of interest to pre-allocated sites at predetermined doses for predefined periods of time. Over the past decade, the use of different physical methods and mechanisms to mediate drug release and delivery has grown significantly. This emerging area of research has important implications for development of new therapeutic drugs for efficient treatments. This review aims to introduce and describe different modalities of physically facilitating drug-delivery systems that are currently in use for cancer and other diseases therapy. In particular, delivery methods based on ultrasound, electrical, magnetic and photo modulations are highlighted. Current uses and areas of improvement for these different physically facilitating drug-delivery systems are discussed. Furthermore, the main advantages and drawbacks of these technologies reviewed are compared. The review ends with a speculative viewpoint of how research is expected to evolve in the upcoming years. PMID:22485192

Ultrasound-triggered drug delivery using acoustic droplet vaporization

NASA Astrophysics Data System (ADS)

Fabiilli, Mario Leonardo

The goal of targeted drug delivery is the spatial and temporal localization of a therapeutic agent and its associated bioeffects. One method of drug localization is acoustic droplet vaporization (ADV), whereby drug-laden perfluorocarbon (PFC) emulsions are vaporized into gas bubbles using ultrasound, thereby releasing drug locally. Transpulmonary droplets are converted into bubbles that occlude capillaries, sequestering the released drug within an organ or tumor. This research investigates the relationship between the ADV and inertial cavitation (IC) thresholds---relevant for drug delivery due to the bioffects generated by IC---and explores the delivery of lipophilic and hydrophilic compounds using PFC double emulsions. IC can positively and negatively affect ultrasound mediated drug delivery. The ADV and IC thresholds were determined for various bulk fluid, droplet, and acoustic parameters. At 3.5 MHz, the ADV threshold occurred at a lower rarefactional pressure than the IC threshold. The results suggest that ADV is a distinct phenomenon from IC, the ADV nucleus is internal to the droplet, and the IC nucleus is the bubble generated by ADV. The ADV triggered release of a lipophilic chemotherapeutic agent, chlorambucil (CHL), from a PFC-in-oil-in-water emulsion was explored using plated cells. Cells exposed to a CHL-loaded emulsion, without ADV, displayed 44% less growth inhibition than cells exposed to an equal concentration of CHL in solution. Upon ADV of the CHL-loaded emulsion, the growth inhibition increased to the same level as cells exposed to CHL in solution. A triblock copolymer was synthesized which enabled the formulation of stable water-in-PFC-in-water (W1/PFC/W2) emulsions. The encapsulation of fluorescein in the W1 phase significantly decreased the mass flux of fluorescein; ADV was shown to completely release the fluorescein from the emulsions. ADV was also shown to release thrombin, dissolved in the W1 phase, which could be used in vivo to extend synergistically the duration of ADV-generated, microbubble-based embolizations. Overall, the results suggest that PFC double emulsions can be used as an ultrasound-triggered drug delivery system. Compared to traditional drug delivery systems, ADV could be used to increase the therapeutic efficacy and decrease the systemic toxicity of drug therapy.

Ultrasound-enhanced drug delivery for cancer.

PubMed

Mo, Steven; Coussios, Constantin-C; Seymour, Len; Carlisle, Robert

2012-12-01

Ultrasound, which has traditionally been used as a diagnostic tool, is increasingly being used in non-invasive therapy and drug delivery. Of particular interest to this review is the rapidly accumulating evidence that ultrasound may have a key role to play both in improving the targeting and the efficacy of drug delivery for cancer. Currently available ultrasound-triggerable vehicles are first described, with particular reference to the ultrasonic mechanism that can activate release and the suitability of the size range of the vehicle used for drug delivery. Further mechanical and thermal effects of ultrasound that can enhance extravasation and drug distribution following release are then critically reviewed. Acoustic cavitation is found to play a potentially key role both in achieving targeted drug release and enhanced extravasation at modest pressure amplitudes and acoustic energies, whilst simultaneously enabling real-time monitoring of the drug delivery process. The next challenge in ultrasound-enhanced drug delivery will thus be to develop a new generation of drug-carrying nanoparticles which are of the right size range for delivery to tumours, yet still capable of achieving initiation of cavitation activity and drug release at modest acoustic pressures and energies that have no safety implications for the patient.

Driving delivery vehicles with ultrasound ☆

PubMed Central

Ferrara, Katherine W.

2009-01-01

Therapeutic applications of ultrasound have been considered for over 40 years, with the mild hyperthermia and associated increases in perfusion produced by ultrasound harnessed in many of the earliest treatments. More recently, new mechanisms for ultrasound-based or ultrasound-enhanced therapies have been described, and there is now great momentum and enthusiasm for the clinical translation of these techniques. This dedicated issue of Advanced Drug Delivery Reviews, entitled “Ultrasound for Drug and Gene Delivery,” addresses the mechanisms by which ultrasound can enhance local drug and gene delivery and the applications that have been demonstrated at this time. In this commentary, the identified mechanisms, delivery vehicles, applications and current bottlenecks for translation of these techniques are summarized. PMID:18479775

New chitosan nanobubbles for ultrasound-mediated gene delivery: preparation and in vitro characterization.

PubMed

Cavalli, Roberta; Bisazza, Agnese; Trotta, Michele; Argenziano, Monica; Civra, Andrea; Donalisio, Manuela; Lembo, David

2012-01-01

The development of nonviral gene delivery systems is one of the most intriguing topics in nanomedicine. However, despite the advances made in recent years, several key issues remain unsettled. One of the main problems relates to the difficulty in designing nanodevices for targeted delivery of genes and other drugs to specific anatomic sites. In this study, we describe the development of a novel chitosan nanobubble-based gene delivery system for ultrasound-triggered release. Chitosan was selected for the nanobubble shell because of its low toxicity, low immunogenicity, and excellent biocompatibility, while the core consisted of perfluoropentane. DNA-loaded chitosan nanobubbles were formed with a mean diameter of less than 300 nm and a positive surface charge. Transmission electron microscopic analysis confirmed composition of the core-shell structure. The ability of the chitosan nanobubbles to complex with and protect DNA was confirmed by agarose gel assay. Chitosan nanobubbles were found to be stable following insonation (2.5 MHz) for up to 3 minutes at 37°C. DNA release was evaluated in vitro in both the presence and absence of ultrasound. The release of chitosan nanobubble-bound plasmid DNA occurred after just one minute of insonation. In vitro transfection experiments were performed by exposing adherent COS7 cells to ultrasound in the presence of different concentrations of plasmid DNA-loaded nanobubbles. In the absence of ultrasound, nanobubbles failed to trigger transfection at all concentrations tested. In contrast, 30 seconds of ultrasound promoted a moderate degree of transfection. Cell viability experiments demonstrated that neither ultrasound nor the nanobubbles affected cell viability under these experimental conditions. Based on these results, chitosan nanobubbles have the potential to be promising tools for ultrasound-mediated DNA delivery.

New chitosan nanobubbles for ultrasound-mediated gene delivery: preparation and in vitro characterization

PubMed Central

Cavalli, Roberta; Bisazza, Agnese; Trotta, Michele; Argenziano, Monica; Civra, Andrea; Donalisio, Manuela; Lembo, David

2012-01-01

Background The development of nonviral gene delivery systems is one of the most intriguing topics in nanomedicine. However, despite the advances made in recent years, several key issues remain unsettled. One of the main problems relates to the difficulty in designing nanodevices for targeted delivery of genes and other drugs to specific anatomic sites. In this study, we describe the development of a novel chitosan nanobubble-based gene delivery system for ultrasound-triggered release. Methods and results Chitosan was selected for the nanobubble shell because of its low toxicity, low immunogenicity, and excellent biocompatibility, while the core consisted of perfluoropentane. DNA-loaded chitosan nanobubbles were formed with a mean diameter of less than 300 nm and a positive surface charge. Transmission electron microscopic analysis confirmed composition of the core-shell structure. The ability of the chitosan nanobubbles to complex with and protect DNA was confirmed by agarose gel assay. Chitosan nanobubbles were found to be stable following insonation (2.5 MHz) for up to 3 minutes at 37°C. DNA release was evaluated in vitro in both the presence and absence of ultrasound. The release of chitosan nanobubble-bound plasmid DNA occurred after just one minute of insonation. In vitro transfection experiments were performed by exposing adherent COS7 cells to ultrasound in the presence of different concentrations of plasmid DNA-loaded nanobubbles. In the absence of ultrasound, nanobubbles failed to trigger transfection at all concentrations tested. In contrast, 30 seconds of ultrasound promoted a moderate degree of transfection. Cell viability experiments demonstrated that neither ultrasound nor the nanobubbles affected cell viability under these experimental conditions. Conclusion Based on these results, chitosan nanobubbles have the potential to be promising tools for ultrasound-mediated DNA delivery. PMID:22802689

Activation of microbubbles by low-intensity pulsed ultrasound enhances the cytotoxicity of curcumin involving apoptosis induction and cell motility inhibition in human breast cancer MDA-MB-231 cells.

PubMed

Li, Yixiang; Wang, Pan; Chen, Xiyang; Hu, Jianmin; Liu, Yichen; Wang, Xiaobing; Liu, Quanhong

2016-11-01

Ultrasound and microbubbles-mediated drug delivery has become a promising strategy to promote drug delivery and its therapeutic efficacy. The aim of this research was to assess the effects of microbubbles (MBs)-combined low-intensity pulsed ultrasound (LPUS) on the delivery and cytotoxicity of curcumin (Cur) to human breast cancer MDA-MB-231 cells. Under the experimental condition, MBs raised the level of acoustic cavitation and enhanced plasma membrane permeability; and cellular uptake of Cur was notably improved by LPUS-MBs treatment, aggravating Cur-induced MDA-MB-231 cells death. The combined treatment markedly caused more obvious changes of cell morphology, F-actin cytoskeleton damage and cell migration inhibition. Our results demonstrated that combination of MBs and LPUS may be an efficient strategy for improving anti-tumor effect of Cur, suggesting a potential effective method for antineoplastic therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

The Role of Acoustic Cavitation in Ultrasound-triggered Drug Release from Echogenic Liposomes

NASA Astrophysics Data System (ADS)

Kopechek, Jonathan A.

Cardiovascular disease (CVD) is the leading cause of death in the United States and globally. CVD-related mortality, including coronary heart disease, heart failure, or stroke, generally occurs due to atherosclerosis, a condition in which plaques build up within arterial walls, potentially causing blockage or rupture. Targeted therapies are needed to achieve more effective treatments. Echogenic liposomes (ELIP), which consist of a lipid membrane surrounding an aqueous core, have been developed to encapsulate a therapeutic agent and/or gas bubbles for targeted delivery and ultrasound image enhancement. Under certain conditions ultrasound can cause nonlinear bubble growth and collapse, known as "cavitation." Cavitation activity has been associated with enhanced drug delivery across cellular membranes. However, the mechanisms of ultrasound-mediated drug release from ELIP have not been previously investigated. Thus, the objective of this dissertation is to elucidate the role of acoustic cavitation in ultrasound-mediated drug release from ELIP. To determine the acoustic and physical properties of ELIP, the frequency-dependent attenuation and backscatter coefficients were measured between 3 and 30 MHz. The results were compared to a theoretical model by measuring the ELIP size distribution in order to determine properties of the lipid membrane. It was found that ELIP have a broad size distribution and can provide enhanced ultrasound image contrast across a broad range of clinically-relevant frequencies. Calcein, a hydrophilic fluorescent dye, and papaverine, a lipophilic vasodilator, were separately encapsulated in ELIP and exposed to color Doppler ultrasound pulses from a clinical diagnostic ultrasound scanner in a flow system. Spectrophotometric techniques (fluorescence and absorbance measurements) were used to detect calcein or papaverine release. As a positive control, Triton X-100 (a non-ionic detergent) was added to ELIP samples not exposed to ultrasound in order to release encapsulated agents completely. Also, sham samples without Triton X-100 or ultrasound exposure were used as negative controls. Color Doppler ultrasound did not release encapsulated calcein or papaverine from ELIP even though there was a complete loss of echogenicity. In subsequent experiments, calcein and rosiglitazone, a hydrophobic anti-diabetic drug, were separately encapsulated in ELIP and exposed to pulsed Doppler ultrasound in a flow system while monitoring cavitation. Samples were exposed to ultrasound pressures above and below cavitation thresholds. In addition, Triton X-100 was used for positive control samples and sham samples were also tested without ultrasound exposure. Adding Triton X-100 resulted in complete release of encapsulated calcein or rosiglitzone. However, Doppler ultrasound exposure did not induce calcein or rosiglitazone release from ELIP in the flow system even when there was persistent cavitation activity and a loss of echogenicity. The results of this dissertation indicate that cavitation of encapsulated bubbles in ELIP solutions is not sufficient to induce drug release. It is possible that ultrasoundmediated thermal processes may have a stronger effect on ELIP permeability than cavitation activity. Perhaps ultrasound-triggered drug release will be possible by improving the ELIP formulation or encapsulating a different gas instead of air. However, cavitation is not a reliable indicator of ultrasound-mediated drug release with the ELIP formulations used in this dissertation.

Ultrasound-Guided Delivery of siRNA and a Chemotherapeutic Drug by Using Microbubble Complexes: In Vitro and In Vivo Evaluations in a Prostate Cancer Model.

PubMed

Bae, Yun Jung; Yoon, Young Il; Yoon, Tae-Jong; Lee, Hak Jong

2016-01-01

To evaluate the effectiveness of ultrasound and microbubble-liposome complex (MLC)-mediated delivery of siRNA and doxorubicin into prostate cancer cells and its therapeutic capabilities both in vitro and in vivo. Microbubble-liposome complexes conjugated with anti-human epidermal growth factor receptor type 2 (Her2) antibodies were developed to target human prostate cancer cell lines PC-3 and LNCaP. Intracellular delivery of MLC was observed by confocal microscopy. We loaded MLC with survivin-targeted small interfering RNA (siRNA) and doxorubicin, and delivered it into prostate cancer cells. The release of these agents was facilitated by ultrasound application. Cell viability was analyzed by MTT assay after the delivery of siRNA and doxorubicin. Survivin-targeted siRNA loaded MLC was delivered into the xenograft mouse tumor model. Western blotting was performed to quantify the expression of survivin in vivo. Confocal microscopy demonstrated substantial intracellular uptake of MLCs in LNCaP, which expresses higher levels of Her2 than PC-3. The viability of LNCaP cells was significantly reduced after the delivery of MLCs loaded with siRNA and doxorubicin (85.0 ± 2.9%), which was further potentiated by application of ultrasound (55.0 ± 3.5%, p = 0.009). Survivin expression was suppressed in vivo in LNCaP tumor xenograft model following the ultrasound and MLC-guided delivery of siRNA (77.4 ± 4.90% to 36.7 ± 1.34%, p = 0.027). Microbubble-liposome complex can effectively target prostate cancer cells, enabling intracellular delivery of the treatment agents with the use of ultrasound. Ultrasound and MLC-mediated delivery of survivin-targeted siRNA and doxorubicin can induce prostate cell apoptosis and block survivin expression in vitro and in vivo.

Lung Surfactant Microbubbles Increase Lipophilic Drug Payload for Ultrasound-Targeted Delivery

PubMed Central

Sirsi, Shashank R.; Fung, Chinpong; Garg, Sumit; Tianning, Mary Y.; Mountford, Paul A.; Borden, Mark A.

2013-01-01

The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials. One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer. In this study, we investigated the use of natural lung surfactant extract (Survanta®, Abbott Nutrition) as a microbubble shell material in order to improve drug payload and delivery. Pulmonary surfactant extracts such as Survanta contain hydrophobic surfactant proteins (SP-B and SP-C) that facilitate lipid folding and retention on lipid monolayers. Here, we show that Survanta-based microbubbles exhibit wrinkles in bright-field microscopy and increased lipid retention on the microbubble surface in the form of surface-associated aggregates observed with fluorescence microscopy. The payload of a model lipophilic drug (DiO), measured by flow cytometry, increased by over 2-fold compared to lipid-coated microbubbles lacking SP-B and SP-C. Lung surfactant microbubbles were highly echogenic to contrast enhanced ultrasound imaging at low acoustic intensities. At higher ultrasound intensity, excess lipid was observed to be acoustically cleaved for localized release. To demonstrate targeting, a biotinylated lipopolymer was incorporated into the shell, and the microbubbles were subjected to a sequence of radiation force and fragmentation pulses as they passed through an avidinated hollow fiber. Lung surfactant microbubbles showed a 3-fold increase in targeted deposition of the model fluorescent drug compared to lipid-only microbubbles. Our results demonstrate that lung surfactant microbubbles maintain the acoustic responsiveness of lipid-coated microbubbles with the added benefit of increased lipophilic drug payload. PMID:23781287

Lung surfactant microbubbles increase lipophilic drug payload for ultrasound-targeted delivery.

PubMed

Sirsi, Shashank R; Fung, Chinpong; Garg, Sumit; Tianning, Mary Y; Mountford, Paul A; Borden, Mark A

2013-01-01

The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials. One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer. In this study, we investigated the use of natural lung surfactant extract (Survanta(®), Abbott Nutrition) as a microbubble shell material in order to improve drug payload and delivery. Pulmonary surfactant extracts such as Survanta contain hydrophobic surfactant proteins (SP-B and SP-C) that facilitate lipid folding and retention on lipid monolayers. Here, we show that Survanta-based microbubbles exhibit wrinkles in bright-field microscopy and increased lipid retention on the microbubble surface in the form of surface-associated aggregates observed with fluorescence microscopy. The payload of a model lipophilic drug (DiO), measured by flow cytometry, increased by over 2-fold compared to lipid-coated microbubbles lacking SP-B and SP-C. Lung surfactant microbubbles were highly echogenic to contrast enhanced ultrasound imaging at low acoustic intensities. At higher ultrasound intensity, excess lipid was observed to be acoustically cleaved for localized release. To demonstrate targeting, a biotinylated lipopolymer was incorporated into the shell, and the microbubbles were subjected to a sequence of radiation force and fragmentation pulses as they passed through an avidinated hollow fiber. Lung surfactant microbubbles showed a 3-fold increase in targeted deposition of the model fluorescent drug compared to lipid-only microbubbles. Our results demonstrate that lung surfactant microbubbles maintain the acoustic responsiveness of lipid-coated microbubbles with the added benefit of increased lipophilic drug payload.

Trans-Stent B-Mode Ultrasound and Passive Cavitation Imaging

PubMed Central

Haworth, Kevin J.; Raymond, Jason L.; Radhakrishnan, Kirthi; Moody, Melanie R.; Huang, Shao-Ling; Peng, Tao; Shekhar, Himanshu; Klegerman, Melvin E.; Kim, Hyunggun; Mcpherson, David D.; Holland, Christy K.

2015-01-01

Angioplasty and stenting of a stenosed artery enable acute restoration of blood flow. However, restenosis or a lack of re-endothelization can subsequently occur depending on the stent type. Cavitation-mediated drug delivery is a potential therapy for these conditions, but requires that particular types of cavitation be induced by ultrasound insonation. Because of the heterogeneity of tissue and stochastic nature of cavitation, feedback mechanisms are needed to determine whether the sustained bubble activity is induced. The objective of this study was to determine the feasibility of passive cavitation imaging through a metal stent in a flow phantom and an animal model. In this study, an endovascular stent was deployed in a flow phantom and in porcine femoral arteries. Fluorophore-labeled echogenic liposomes, a theragnostic ultrasound contrast agent, were injected proximal to the stent. Cavitation images were obtained by passively recording and beamforming the acoustic emissions from echogenic liposomes insonified with a low-frequency (500 kHz) transducer. In vitro experiments revealed that the signal-to-noise ratio for detecting stable cavitation activity through the stent was greater than 8 dB. The stent did not significantly reduce the signal-to-noise ratio. Trans-stent cavitation activity was also detected in vivo via passive cavitation imaging when echogenic liposomes were insonified by the 500-kHz transducer. When stable cavitation was detected, delivery of the fluorophore into the arterial wall was observed. Increased echogenicity within the stent was also observed when echogenic liposomes were administered. Thus, both B-mode ultrasound imaging and cavitation imaging are feasible in the presence of an endovascular stent in vivo. Demonstration of this capability supports future studies to monitor restenosis with contrast-enhanced ultrasound and pursue image-guided ultrasound-mediated drug delivery to inhibit restenosis. PMID:26547633

Acoustically active liposome-nanobubble complexes for enhanced ultrasonic imaging and ultrasound-triggered drug delivery.

PubMed

Nguyen, An T; Wrenn, Steven P

2014-01-01

Ultrasound is well known as a safe, reliable imaging modality. A historical limitation of ultrasound, however, was its inability to resolve structures at length scales less than nominally 20 µm, which meant that classical ultrasound could not be used in applications such as echocardiography and angiogenesis where one requires the ability to image small blood vessels. The advent of ultrasound contrast agents, or microbubbles, removed this limitation and ushered in a new wave of enhanced ultrasound applications. In recent years, the microbubbles have been designed to achieve yet another application, namely ultrasound-triggered drug delivery. Ultrasound contrast agents are thus tantamount to 'theranostic' vehicles, meaning they can do both therapy (drug delivery) and imaging (diagnostics). The use of ultrasound contrast agents as drug delivery vehicles, however, is perhaps less than ideal when compared to traditional drug delivery vehicles (e.g., polymeric microcapsules and liposomes) which have greater drug carrying capacities. The drawback of the traditional drug delivery vehicles is that they are not naturally acoustically active and cannot be used for imaging. The notion of a theranostic vehicle is sufficiently intriguing that many attempts have been made in recent years to achieve a vehicle that combines the echogenicity of microbubbles with the drug carrying capacity of liposomes. The attempts can be classified into three categories, namely entrapping, tethering, and nesting. Of these, nesting is the newest-and perhaps the most promising. © 2014 Wiley Periodicals, Inc.

Development of a custom biological scaffold for investigating ultrasound-mediated intracellular delivery.

PubMed

Bui, Loan; Aleid, Adham; Alassaf, Ahmad; Wilson, Otto C; Raub, Christopher B; Frenkel, Victor

2017-01-01

In vitro investigations of ultrasound mediated, intracellular drug and gene delivery (i.e. sonoporation) are typically carried out in cells cultured in standard plastic well plates. This creates conditions that poorly resemble in vivo conditions, as well as generating unwanted ultrasound phenomena that may confound the interpretation of results. Here, we present our results in the development of a biological scaffold for sonoporation studies. The scaffolds were comprised of cellulose fibers coated with chitosan and gelatin. Scaffold formulation was optimized for adherence and proliferation of mouse fibroblasts in terms of the ratio and relative concentration of the two constituents. The scaffolds were also shown to significantly reduce ultrasound reflections compared to the plastic well plates. A custom treatment chamber was designed and built, and the occurrence of acoustic cavitation in the chamber during the ultrasound treatments was detected; a requirement for the process of sonoporation. Finally, experiments were carried out to optimize the ultrasound exposures to minimize cellular damage. Ultrasound exposure was then shown to enable the uptake of 100nm fluorescently labeled polystyrene nanoparticles in suspension into the cells seeded on scaffolds, compared to incubation of cell-seeded scaffolds with nanoparticles alone. These preliminary results set the basis for further development of this platform. They also provide motivation for the development of similar platforms for the controlled investigation of other ultrasound mediated cell and tissue therapies. Copyright © 2016 Elsevier B.V. All rights reserved.

State-of-the-Art Materials for Ultrasound-Triggered Drug Delivery

PubMed Central

Sirsi, Shashank; Borden, Mark

2014-01-01

Ultrasound is a unique and exciting theranostic modality that can be used to track drug carriers, trigger drug release and improve drug deposition with high spatial precision. In this review, we briefly describe the mechanisms of interaction between drug carriers and ultrasound waves, including cavitation, streaming and hyperthermia, and how those interactions can promote drug release and tissue uptake. We then discuss the rational design of some state-of-the-art materials for ultrasound-triggered drug delivery and review recent progress for each drug carrier, focusing on the delivery of chemotherapeutic agents such as doxorubicin. These materials include nanocarrier formulations, such as liposomes and micelles, designed specifically for ultrasound-triggered drug release, as well as microbubbles, microbubble-nanocarrier hybrids, microbubble-seeded hydrogels and phase-change agents. PMID:24389162

Two-photon microscopy for real-time monitoring of focused ultrasound-mediated drug delivery to the brain in a mouse model of Alzheimer's disease

NASA Astrophysics Data System (ADS)

Burgess, Alison; Eterman, Naomi; Aubert, Isabelle; Hynynen, Kullervo

2013-02-01

There is substantial evidence that focused ultrasound (FUS) in combination with microbubble contrast agent can cause disruption of the blood-brain barrier (BBB) to aid in drug delivery to the brain. We have previously demonstrated that FUS efficiently delivers antibodies against amyloid-β peptides (Aβ) through the BBB, leading to a reduction in amyloid pathology at 4 days in a mouse model of Alzheimer's disease. In the current study, we used two-photon microscopy to characterize the effect of FUS in real time on amyloid pathology in the mouse brain. Mice were anesthetized and a cranial window was made in the skull. A custom-built ultrasound transducer was fixed to a coverslip and attached to the skull, covering the cranial window. Methoxy-X04 [2-5mg/kg] delivered intravenously 1 hr prior to the experiment clearly labelled the Aβ surrounding the vessels and the amyloid plaques in the cortex. Dextran conjugated Texas Red (70kDa) administered intravenously, confirmed BBB disruption. BBB disruption occurred in transgenic and non-transgenic animals at similar ultrasound pressures tested. However, the time required for BBB closure following FUS was longer in the Tg mice. We have conjugated Aβ antibodies to the fluorescent molecule FITC for real time monitoring of the antibody distribution in the brain. Our current experiments are aimed at optimizing the parameters to achieve maximal fluorescent intensity of the BAM10 antibody at the plaque surface. Two-photon microscopy has proven to be a valuable tool for evaluating the efficacy of FUS mediated drug delivery, including antibodies, to the Alzheimer brain.

Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration.

PubMed

Park, Donghee; Song, Gillsoo; Jo, Yongjun; Won, Jongho; Son, Taeyoon; Cha, Ohrum; Kim, Jinho; Jung, Byungjo; Park, Hyunjin; Kim, Chul-Woo; Seo, Jongbum

2016-01-01

Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa) causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with microbubbles depends on the concentration of microbubbles in case stable cavitation is predominant.

Trans-Stent B-Mode Ultrasound and Passive Cavitation Imaging.

PubMed

Haworth, Kevin J; Raymond, Jason L; Radhakrishnan, Kirthi; Moody, Melanie R; Huang, Shao-Ling; Peng, Tao; Shekhar, Himanshu; Klegerman, Melvin E; Kim, Hyunggun; McPherson, David D; Holland, Christy K

2016-02-01

Angioplasty and stenting of a stenosed artery enable acute restoration of blood flow. However, restenosis or a lack of re-endothelization can subsequently occur depending on the stent type. Cavitation-mediated drug delivery is a potential therapy for these conditions, but requires that particular types of cavitation be induced by ultrasound insonation. Because of the heterogeneity of tissue and stochastic nature of cavitation, feedback mechanisms are needed to determine whether the sustained bubble activity is induced. The objective of this study was to determine the feasibility of passive cavitation imaging through a metal stent in a flow phantom and an animal model. In this study, an endovascular stent was deployed in a flow phantom and in porcine femoral arteries. Fluorophore-labeled echogenic liposomes, a theragnostic ultrasound contrast agent, were injected proximal to the stent. Cavitation images were obtained by passively recording and beamforming the acoustic emissions from echogenic liposomes insonified with a low-frequency (500 kHz) transducer. In vitro experiments revealed that the signal-to-noise ratio for detecting stable cavitation activity through the stent was greater than 8 dB. The stent did not significantly reduce the signal-to-noise ratio. Trans-stent cavitation activity was also detected in vivo via passive cavitation imaging when echogenic liposomes were insonified by the 500-kHz transducer. When stable cavitation was detected, delivery of the fluorophore into the arterial wall was observed. Increased echogenicity within the stent was also observed when echogenic liposomes were administered. Thus, both B-mode ultrasound imaging and cavitation imaging are feasible in the presence of an endovascular stent in vivo. Demonstration of this capability supports future studies to monitor restenosis with contrast-enhanced ultrasound and pursue image-guided ultrasound-mediated drug delivery to inhibit restenosis. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Ultrasound-assisted drug delivery for treatment of venous thrombosis: a case study.

PubMed

Marchiondo, Kathleen; Frink, Amber

2008-01-01

Ultrasound-assisted drug delivery is a relatively new medical intervention that combines low-intensity ultrasound waves with infusion of a thrombolytic agent directly into a thrombosed vein. Studies have demonstrated that clots are eradicated faster, more completely, and with fewer bleeding events with the use of ultrasound-assisted drug delivery for treatment of deep vein thrombosis compared to that of traditional therapies. Critical care nurses are responsible for preprocedure assessment and teaching and continuous monitoring of the patient during therapy for effectiveness and potential complications. An advantage of this technology from a nursing perspective is the minimal amount of time required for monitoring the drug delivery system, allowing greater focus on patient assessment and care.

Effects of the microbubble shell physicochemical properties on ultrasound-mediated drug delivery to the brain.

PubMed

Wu, Shih-Ying; Chen, Cherry C; Tung, Yao-Sheng; Olumolade, Oluyemi O; Konofagou, Elisa E

2015-08-28

Lipid-shelled microbubbles have been used in ultrasound-mediated drug delivery. The physicochemical properties of the microbubble shell could affect the delivery efficiency since they determine the microbubble mechanical properties, circulation persistence, and dissolution behavior during cavitation. Therefore, the aim of this study was to investigate the shell effects on drug delivery efficiency in the brain via blood-brain barrier (BBB) opening in vivo using monodisperse microbubbles with different phospholipid shell components. The physicochemical properties of the monolayer were varied by using phospholipids with different hydrophobic chain lengths (C16, C18, and C24). The dependence on the molecular size and acoustic energy (both pressure and pulse length) were investigated. Our results showed that a relatively small increase in the microbubble shell rigidity resulted in a significant increase in the delivery of 40-kDa dextran, especially at higher pressures. Smaller (3kDa) dextran did not show significant difference in the delivery amount, suggesting that the observed shell effect was molecular size-dependent. In studying the impact of acoustic energy on the shell effects, it was found that they occurred most significantly at pressures causing microbubble destruction (450kPa and 600kPa); by increasing the pulse length to deliver the 40-kDa dextran, the difference between C16 and C18 disappeared while C24 still achieved the highest delivery efficiency. These indicated that the acoustic energy could be used to modulate the shell effects. The acoustic cavitation emission revealed the physical mechanisms associated with different shells. Overall, lipid-shelled microbubbles with long hydrophobic chain length could achieve high delivery efficiency for larger molecules especially with high acoustic energy. Our study, for the first time, offered evidence directly linking the microbubble monolayer shell with their efficacy for drug delivery in vivo. Copyright © 2015 Elsevier B.V. All rights reserved.

Ultrasound-enhanced ocular delivery of dexamethasone sodium phosphate: an in vivo study

PubMed Central

2014-01-01

Background The eye's unique anatomy and its physiological and anatomical barriers can limit effective drug delivery into the eye. Methods An in vivo study was designed to determine the effectiveness and safety of ultrasound application in enhancing drug delivery in a rabbit model. Permeability of a steroid ophthalmic drug, dexamethasone sodium phosphate, was investigated in ultrasound- and sham-treated cases. For this study, an eye cup filled with dexamethasone sodium phosphate was placed on the cornea. Ultrasound was applied at intensity of 0.8 W/cm2 and frequency of 400 or 600 kHz for 5 min. The drug concentration in aqueous humor samples, collected 90 min after the treatment, was determined using chromatography methods. Light microscopy observations were done to determine the structural changes in the cornea as a result of ultrasound application. Results An increase in drug concentration in aqueous humor samples of 2.8 times (p < 0.05) with ultrasound application at 400 kHz and 2.4 times (p < 0.01) with ultrasound application at 600 kHz was observed as compared to sham-treated samples. Histological analysis showed that the structural changes in the corneas exposed to ultrasound predominantly consisted of minor epithelial disorganization. Conclusions Ultrasound application enhanced the delivery of an anti-inflammatory ocular drug, dexamethasone sodium phosphate, through the cornea in vivo. Ultrasound-enhanced ocular drug delivery appears to be a promising area of research with a potential future application in a clinical setting. PMID:24921047

TU-EF-210-01: HIFU, Drug Delivery, and Immunotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferrara, K.

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

Microbubbles in Ultrasound-Triggered Drug and Gene Delivery

PubMed Central

Hernot, Sophie; Klibanov, Alexander L.

2008-01-01

Ultrasound contrast agents, in the form of gas-filled microbubbles, are becoming popular in perfusion monitoring; they are employed as molecular imaging agents. Microbubbles are manufactured from biocompatible materials, they can be injected intravenously, and some are approved for clinical use. Microbubbles can be destroyed by ultrasound irradiation. This destruction phenomenon can be applied to targeted drug delivery and enhancement of drug action. The ultrasonic field can be focused at the target tissues and organs; thus, selectivity of the treatment can be improved, reducing undesirable side effects. Microbubbles enhance ultrasound energy deposition in the tissues and serve as cavitation nuclei, increasing intracellular drug delivery. DNA delivery and successful tissue transfection is observed in the areas of the body where ultrasound is applied after intravascular administration of microbubbles and plasmid DNA. Accelerated blood clot dissolution in the areas of insonation by cooperative action of thrombolytic agents and microbubbles is demonstrated in several clinical trials. PMID:18486268

Application of Ultrasound Energy as a New Drug Delivery System

NASA Astrophysics Data System (ADS)

Tachibana, Katsuro; Tachibana, Shunro

1999-05-01

Ultrasound has been in use for the last three decades as amodality for diagnostic imaging in medicine. Recently, there have beennumerous reports on the application of nonthermal ultrasound energyfor targeting or controlling drug release. This new concept oftherapeutic ultrasound combined with drugs has led to much excitementin various medical fields. Ultrasound energy can enhance the effectsof thrombolytic agents such as urokinase. Therapeutic ultrasoundcatheters are currently being developed for treatment ofcardiovascular diseases. Devices with ultrasound transducers implantedin transdermal drug patches are also being evaluated for possibledelivery of insulin through the skin. Chemical activation of drugs byultrasound energy for treatment of cancers is another new fieldrecently termed “Sonodynamic Therapy”. Various examples of ultrasoundapplication are under investigation which could lead to revolutionarydrug delivery systems in the future.

Ultrasound-Targeted Microbubble Destruction to Deliver siRNA Cancer Therapy

PubMed Central

Carson, Andrew R; McTiernan, Charles F; Lavery, Linda; Grata, Michelle; Leng, Xiaoping; Wang, Jianjun; Chen, Xucai; Villanueva, Flordeliza S

2012-01-01

Microbubble contrast agents can specifically deliver nucleic acids to target tissues when exposed to ultrasound treatment parameters that mediate microbubble destruction. In this study, we evaluated whether microbubbles and ultrasound targeted microbubble destruction (UTMD) could be used to enhance delivery of EGFR-directed small inhibitory RNA (siRNA) to murine squamous cell carcinomas. Custom designed microbubbles efficiently bound siRNA and mediated RNAse protection. UTMD-mediated delivery of microbubbles loaded with EGFR-directed siRNA to murine squamous carcinoma cells in vitro reduced EGFR expression and EGF-dependent growth, relative to delivery of control siRNA. Similarly, serial UTMD-mediated delivery of EGFR siRNA to squamous cell carcinoma in vivo decreased EGFR expression and increased tumor doubling times, relative to controls receiving EGFR siRNA loaded microbubbles but not ultrasound or control siRNA loaded microbubbles and UTMD. Taken together, our results offer a preclinical proof of concept for customized microbubbles and UTMD to deliver gene-targeted siRNA for cancer therapy. PMID:23010078

TU-EF-210-04: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farahani, K.

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

Ultrasound-mediated structural changes in cells revealed by FTIR spectroscopy: A contribution to the optimization of gene and drug delivery

NASA Astrophysics Data System (ADS)

Grimaldi, Paola; Di Giambattista, Lucia; Giordani, Serena; Udroiu, Ion; Pozzi, Deleana; Gaudenzi, Silvia; Bedini, Angelico; Giliberti, Claudia; Palomba, Raffaele; Congiu Castellano, Agostina

2011-12-01

Ultrasound effects on biological samples are gaining a growing interest concerning in particular, the intracellular delivery of drugs and genes in a safe and in a efficient way. Future progress in this field will require a better understanding of how ultrasound and acoustic cavitation affect the biological system properties. The morphological changes of cells due to ultrasound (US) exposure have been extensively studied, while little attention has been given to the cells structural changes. We have exposed two different cell lines to 1 MHz frequency ultrasound currently used in therapy, Jurkat T-lymphocytes and NIH-3T3 fibroblasts, both employed as models respectively in the apoptosis and in the gene therapy studies. The Fourier Transform Infrared (FTIR) Spectroscopy was used as probe to reveal the structural changes in particular molecular groups belonging to the main biological systems. The genotoxic damage of cells exposed to ultrasound was ascertained by the Cytokinesis-Block Micronucleus (CBMN) assay. The FTIR spectroscopy results, combined with multivariate statistical analysis, regarding all cellular components (lipids, proteins, nucleic acids) of the two cell lines, show that Jurkat cells are more sensitive to therapeutic ultrasound in the lipid and protein regions, whereas the NIH-3T3 cells are more sensitive in the nucleic acids region; a meaningful genotoxic effect is present in both cell lines only for long sonication times while in the Jurkat cells also a significant cytotoxic effect is revealed for long times of exposure to ultrasound.

WE-G-12A-01: High Intensity Focused Ultrasound Surgery and Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farahani, K; O'Neill, B

More and more emphasis is being made on alternatives to invasive surgery and the use of ionizing radiation to treat various diseases including cancer. Novel screening, diagnosis, treatment and monitoring of response to treatment are also hot areas of research and new clinical technologies. Ultrasound(US) has gained traction in all of the aforementioned areas of focus. Especially with recent advances in the use of ultrasound to noninvasively treat various diseases/organ systems. This session will focus on covering MR-guided focused ultrasound and the state of the art clinical applications, and the second speaker will survey the more cutting edge technologies e.g.more » Focused Ultrasound (FUS) mediated drug delivery, principles of cavitation and US guided FUS. Learning Objectives: Fundamental physics and physical limitations of US interaction with tissue and nanoparticles The alteration of tissue transport using focused ultrasound US control of nanoparticle drug carriers for targeted release The basic principles of MRI-guided focused ultrasound (MRgFUS) surgery and therapy the current state of the art clinical applications of MRgFUS requirements for quality assurance and treatment planning.« less

PMO Delivery System Using Bubble Liposomes and Ultrasound Exposure for Duchenne Muscular Dystrophy Treatment.

PubMed

Negishi, Yoichi; Ishii, Yuko; Nirasawa, Kei; Sasaki, Eri; Endo-Takahashi, Yoko; Suzuki, Ryo; Maruyama, Kazuo

2018-01-01

Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration, caused by nonsense or frameshift mutations in the dystrophin (DMD) gene. Antisense oligonucleotides can be used to induce specific exon skipping; recently, a phosphorodiamidate morpholino oligomer (PMO) has been approved for clinical use in DMD. However, an efficient PMO delivery strategy is required to improve the therapeutic efficacy in DMD patients. We previously developed polyethylene glycol (PEG)-modified liposomes containing ultrasound contrast gas, "Bubble liposomes" (BLs), and found that the combination of BLs with ultrasound exposure is a useful gene delivery tool. Here, we describe an efficient PMO delivery strategy using the combination of BLs and ultrasound exposure to treat muscles in a DMD mouse model (mdx). This ultrasound-mediated BL technique can increase the PMO-mediated exon-skipping efficiency, leading to significantly increased dystrophin expression. Thus, the combination of BLs and ultrasound exposure may be a feasible PMO delivery method to improve therapeutic efficacy and reduce the PMO dosage for DMD treatment.

Noninvasive Ultrasound Transdermal Insulin Delivery and Glucose Monitoring Using a Low-Profile Cymbal Array

NASA Astrophysics Data System (ADS)

Park, E.-J.; Luis, J.; Meyer, R. J.; Pishko, M. V.; Smith, N. B.

2006-05-01

Recent studies have shown that ultrasound mediated transdermal drug delivery offers promising results for noninvasive drug administration. The purpose of this study was to demonstrate ultrasonic transdermal insulin delivery and in vivo sensing glucose with a novel, low-profile ultrasound array based on the cymbal transducer. As a practical device, the array composed of circular cymbal transducers was thin (< 7mm) and weighed less than 22g. Using this array on hyperglycemic rats, our previous experiments demonstrated that blood glucose would decrease by 296.7 mg/dL from 60 minutes of ultrasound exposure. With a similar intensity, our goal was to evaluate the feasibility of insulin delivery with large animals (rabbits and pigs) and noninvasively determine the glucose level of hyperglycemic rats with the array system. Ultrasound was exposed for 60 minutes at Isptp=100 mW/cm2. With the same procedure, a preliminary experiment of large animal was performed on a pig (12 kg) at Isptp=50 mW/cm2. For the control experiments in insulin delivery, the blood glucose level varied little from the initial baseline. However, for the ultrasound and insulin exposure experiment, the glucose level was found to decrease by 132.6 mg/dL in 60 minutes and continued to decrease by 208.1 mg/dL in 90 minutes. From the preliminary pig experiment, the blood glucose level decreased by 120 mg/dL in 90 minutes. To noninvasively determine the glucose level, ultrasound exposure experiments with an electrochemical glucose biosensor were performed on hyperglycemic rats. After 20 minutes ultrasound exposure, the biosensor was placed at the exposure area to determine the concentration of glucose diffused through the skin. The glucose level of rats determined by the biosensor was 408 mg/dL which was very similar to the results of conventional glucose meter reading 396.7 mg/dL. Recently, a rectangular cymbal transducer was developed to obtain a larger sonication area without an increase in array size. Preliminary experiments were performed on hyperglycemic rabbits to evaluate the new transducer design. The results showed that the rectangular array has enhanced performance compared to the circular array. All results of ultrasound application indicate the feasibility of using a low-cost, light-weight cymbal array for enhanced noninvasive transdermal insulin delivery and glucose monitoring.

TU-EF-210-03: Real-Time Ablation Monitoring and Lesion Quantification Using Harmonic Motion Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Konofagou, E.

2015-06-15

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

TU-EF-210-00: Therapeutic Strategies and Image Guidance

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

2015-06-15

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

TU-EF-210-02: MRg Hyperthermia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chopra, R.

2015-06-15

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets.

PubMed

Chen, Cherry C; Sheeran, Paul S; Wu, Shih-Ying; Olumolade, Oluyemi O; Dayton, Paul A; Konofagou, Elisa E

2013-12-28

Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood-brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature. © 2013.

Drug-Loaded Nanoemulsions/Microbubbles for Combined Tumor Imaging and Therapy

NASA Astrophysics Data System (ADS)

Rapoport, Natalya; Gao, Zhonggao; Kennedy, Ann

2007-05-01

A new class of multifunctional nanoparticles that combine properties of polymeric drug carriers, ultrasound imaging contrast agents, and enhancers of ultrasound-mediated intracellular drug delivery was developed. At room temperature, the developed systems comprise perfluorocarbon nanodroplets stabilized by the walls made of biodegradable block copolymers. The nanodroplets convert into microbubbles upon heating to physiological temperatures. The phase state of the systems and nanodroplet size may be controlled by the copolymer/perfluorocarbon volume ratio. Three areas observed in phase diagrams correspond to micelles; micelle/microbubble coexistence; and nano/microbubble coexistence. These systems manifest a relatively high drug loading capacity (about 15 % wt/wt). As indicated by biodistribution measurements and ultrasound imaging, the micelles and nanobubbles extravasate selectively into the tumor interstitia. Microbubble cavitate and collapse under the action of tumor-directed ultrasound, resulting in a dramatically enhanced intracellular drug uptake by the tumor cells. Upon intravenous injections, a long-lasting, strong and selective ultrasound contrast is observed in the tumor volume confirming nanobubble extravasation through the defected tumor microvasculature and suggesting their coalescence into larger, highly echogenic microbubbles in the tumor tissue. This effect is tumor-selective; no accumulation of echogenic microbubbles is observed in other organs. Tumor contrast increases in time confirming gradual accumulation of echogenic microbubbles in the tumor tissue, presumably via the enhanced penetration and retention (EPR) effect.

Acoustic characterization of ultrasound contrast microbubbles and echogenic liposomes: Applications to imaging and drug-delivery

NASA Astrophysics Data System (ADS)

Paul, Shirshendu

Micron- to nanometer - sized ultrasound agents, like encapsulated microbubbles and echogenic liposomes (ELIPs), are being actively developed for possible clinical implementations in diagnostic imaging and ultrasound mediated drug/gene delivery. The primary objective of this thesis is to characterize the acoustic behavior of and the ultrasound-mediated contents release from these contrast agents for developing multi-functional ultrasound contrast agents. Subharmonic imaging using contrast microbubbles can improve image quality by providing a higher signal to noise ratio. However, the design and development of contrast microbubbles with favorable subharmonic behavior requires accurate mathematical models capable of predicting their nonlinear dynamics. To this goal, 'strain-softening' viscoelastic interfacial models of the encapsulation were developed and subsequently utilized to simulate the dynamics of encapsulated microbubbles. A hierarchical two-pronged approach of modeling --- a model is applied to one set of experimental data to obtain the model parameters (material characterization), and then the model is validated against a second independent experiment --- is demonstrated in this thesis for two lipid coated (SonazoidRTM and DefinityRTM) and a few polymer (polylactide) encapsulated microbubbles. The proposed models were successful in predicting several experimentally observed behaviors e.g., low subharmonic thresholds and "compression-only" radial oscillations. Results indicate that neglecting the polydisperse size distribution of contrast agent suspensions, a common practice in the literature, can lead to inaccurate results. In vitro experimental investigation of the dependence of subharmonic response from these microbubbles on the ambient pressure is also in conformity with the recent numerical investigations, showing both increase or decrease under appropriate excitation conditions. Experimental characterization of the ELIPs and polymersomes was performed with the goal of demonstrating their potential as ultrasound agents with simultaneous imaging and drug/gene delivery applications --- 'dual-purpose' contrast agents. Both in vitro acoustic studies and ultrasound imaging (performed in NDSU by our collaborators) showed the echogenicity of the various formulations studied. We believe that this echogenicity results from the larger diameter liposomes present in the polydisperse suspension obtained after reconstitution of the lyophilized powders. Although, ultrasound excitation (< 5 MHz) alone was incapable of causing optimal release of contents, a dual-triggering strategy (with enzymes or redox) proved successful, resulting in a total release of up to 80-90%. Considering these experimental results, it can be concluded that these novel formulations hold the potential of providing powerful treatment strategies for many diseases, including cardiovascular ones and various cancers.

In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs.

PubMed

Bez, Maxim; Sheyn, Dmitriy; Tawackoli, Wafa; Avalos, Pablo; Shapiro, Galina; Giaconi, Joseph C; Da, Xiaoyu; David, Shiran Ben; Gavrity, Jayne; Awad, Hani A; Bae, Hyun W; Ley, Eric J; Kremen, Thomas J; Gazit, Zulma; Ferrara, Katherine W; Pelled, Gadi; Gazit, Dan

2017-05-17

More than 2 million bone-grafting procedures are performed each year using autografts or allografts. However, both options carry disadvantages, and there remains a clear medical need for the development of new therapies for massive bone loss and fracture nonunions. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would induce efficient bone regeneration and fracture repair. To test this hypothesis, we surgically created a critical-sized bone fracture in the tibiae of Yucatán mini-pigs, a clinically relevant large animal model. A collagen scaffold was implanted in the fracture to facilitate recruitment of endogenous mesenchymal stem/progenitor cells (MSCs) into the fracture site. Two weeks later, transcutaneous ultrasound-mediated reporter gene delivery successfully transfected 40% of cells at the fracture site, and flow cytometry showed that 80% of the transfected cells expressed MSC markers. Human bone morphogenetic protein-6 ( BMP - 6 ) plasmid DNA was delivered using ultrasound in the same animal model, leading to transient expression and secretion of BMP-6 localized to the fracture area. Micro-computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to complete radiographic and functional fracture healing in all animals 6 weeks after treatment, whereas nonunion was evident in control animals. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchymal progenitor cells can effectively treat nonhealing bone fractures in large animals, thereby addressing a major orthopedic unmet need and offering new possibilities for clinical translation. Copyright © 2017, American Association for the Advancement of Science.

In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs

PubMed Central

Bez, Maxim; Sheyn, Dmitriy; Tawackoli, Wafa; Avalos, Pablo; Shapiro, Galina; Giaconi, Joseph C.; Da, Xiaoyu; Ben David, Shiran; Gavrity, Jayne; Awad, Hani A.; Bae, Hyun W.; Ley, Eric J.; Kremen, Thomas J.; Gazit, Zulma; Ferrara, Katherine W.; Pelled, Gadi; Gazit, Dan

2017-01-01

More than 2 million bone-grafting procedures are performed each year using autografts or allografts. However, both options carry disadvantages, and there remains a clear medical need for the development of new therapies for massive bone loss and fracture nonunions. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would induce efficient bone regeneration and fracture repair. To test this hypothesis, we surgically created a critical-sized bone fracture in the tibiae of Yucatán mini-pigs, a clinically relevant large animal model. A collagen scaffold was implanted in the fracture to facilitate recruitment of endogenous mesenchymal stem/progenitor cells (MSCs) into the fracture site. Two weeks later, transcutaneous ultrasound-mediated reporter gene delivery successfully transfected 40% of cells at the fracture site, and flow cytometry showed that 80% of the transfected cells expressed MSC markers. Human bone morphogenetic protein-6 (BMP-6) plasmid DNA was delivered using ultrasound in the same animal model, leading to transient expression and secretion of BMP-6 localized to the fracture area. Micro–computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to complete radiographic and functional fracture healing in all animals 6 weeks after treatment, whereas nonunion was evident in control animals. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchy-mal progenitor cells can effectively treat nonhealing bone fractures in large animals, thereby addressing a major orthopedic unmet need and offering new possibilities for clinical translation. PMID:28515335

Model for Porosity Changes Occurring during Ultrasound-Enhanced Transcorneal Drug Delivery.

PubMed

Hariharan, Prasanna; Nabili, Marjan; Guan, Allan; Zderic, Vesna; Myers, Matthew

2017-06-01

Ultrasound-enhanced drug delivery through the cornea has considerable therapeutic potential. However, our understanding of how ultrasound enhances drug transport is poor, as is our ability to predict the increased level of transport for given ultrasound parameters. Described here is a computational model for quantifying changes in corneal porosity during ultrasound exposure. The model is calibrated through experiments involving sodium fluorescein transport through rabbit cornea. Validation was performed using nylon filters, for which the properties are known. It was found that exposure to 800-kHz ultrasound at an intensity 2 W/cm 2 for 5 min increased the porosity of the epithelium by a factor of 5. The model can be useful for determining the extent to which ultrasound enhances the amount of drug transported through biological barriers, and the time at which a therapeutic dose is achieved at a given location, for different drugs and exposure strategies. Published by Elsevier Inc.

Correction for photobleaching in dynamic fluorescence microscopy: application in the assessment of pharmacokinetic parameters in ultrasound-mediated drug delivery

NASA Astrophysics Data System (ADS)

Derieppe, M.; Bos, C.; de Greef, M.; Moonen, C.; de Senneville, B. Denis

2016-01-01

We have previously demonstrated the feasibility of monitoring ultrasound-mediated uptake of a hydrophilic model drug in real time with dynamic confocal fluorescence microscopy. In this study, we evaluate and correct the impact of photobleaching to improve the accuracy of pharmacokinetic parameter estimates. To model photobleaching of the fluorescent model drug SYTOX Green, a photobleaching process was added to the current two-compartment model describing cell uptake. After collection of the uptake profile, a second acquisition was performed when SYTOX Green was equilibrated, to evaluate the photobleaching rate experimentally. Photobleaching rates up to 5.0 10-3 s-1 were measured when applying power densities up to 0.2 W.cm-2. By applying the three-compartment model, the model drug uptake rate of 6.0 10-3 s-1 was measured independent of the applied laser power. The impact of photobleaching on uptake rate estimates measured by dynamic fluorescence microscopy was evaluated. Subsequent compensation improved the accuracy of pharmacokinetic parameter estimates in the cell population subjected to sonopermeabilization.

Drug Delivery Systems, CNS Protection, and the Blood Brain Barrier

PubMed Central

Upadhyay, Ravi Kant

2014-01-01

Present review highlights various drug delivery systems used for delivery of pharmaceutical agents mainly antibiotics, antineoplastic agents, neuropeptides, and other therapeutic substances through the endothelial capillaries (BBB) for CNS therapeutics. In addition, the use of ultrasound in delivery of therapeutic agents/biomolecules such as proline rich peptides, prodrugs, radiopharmaceuticals, proteins, immunoglobulins, and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has been explained. In addition, therapeutic applications of various types of nanoparticles such as chitosan based nanomers, dendrimers, carbon nanotubes, niosomes, beta cyclodextrin carriers, cholesterol mediated cationic solid lipid nanoparticles, colloidal drug carriers, liposomes, and micelles have been discussed with their recent advancements. Emphasis has been given on the need of physiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount of drug into the brain for treatment of various neurological diseases and disorders. Further, strong recommendations are being made to develop nanosized drug carriers/vehicles and noninvasive therapeutic alternatives of conventional methods for better therapeutics of CNS related diseases. Hence, there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive delivery methods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs and treatment methods. PMID:25136634

Ultrasound-mediated structural changes in cells revealed by FTIR spectroscopy: a contribution to the optimization of gene and drug delivery.

PubMed

Grimaldi, Paola; Di Giambattista, Lucia; Giordani, Serena; Udroiu, Ion; Pozzi, Deleana; Gaudenzi, Silvia; Bedini, Angelico; Giliberti, Claudia; Palomba, Raffaele; Castellano, Agostina Congiu

2011-12-15

Ultrasound effects on biological samples are gaining a growing interest concerning in particular, the intracellular delivery of drugs and genes in a safe and in a efficient way. Future progress in this field will require a better understanding of how ultrasound and acoustic cavitation affect the biological system properties. The morphological changes of cells due to ultrasound (US) exposure have been extensively studied, while little attention has been given to the cells structural changes. We have exposed two different cell lines to 1 MHz frequency ultrasound currently used in therapy, Jurkat T-lymphocytes and NIH-3T3 fibroblasts, both employed as models respectively in the apoptosis and in the gene therapy studies. The Fourier Transform Infrared (FTIR) Spectroscopy was used as probe to reveal the structural changes in particular molecular groups belonging to the main biological systems. The genotoxic damage of cells exposed to ultrasound was ascertained by the Cytokinesis-Block Micronucleus (CBMN) assay. The FTIR spectroscopy results, combined with multivariate statistical analysis, regarding all cellular components (lipids, proteins, nucleic acids) of the two cell lines, show that Jurkat cells are more sensitive to therapeutic ultrasound in the lipid and protein regions, whereas the NIH-3T3 cells are more sensitive in the nucleic acids region; a meaningful genotoxic effect is present in both cell lines only for long sonication times while in the Jurkat cells also a significant cytotoxic effect is revealed for long times of exposure to ultrasound. Copyright © 2011 Elsevier B.V. All rights reserved.

Low-intensity focused ultrasound mediated localized drug delivery for liver tumors in rabbits.

PubMed

Gong, Yuping; Wang, Zhigang; Dong, Guifang; Sun, Yang; Wang, Xi; Rong, Yue; Li, Maoping; Wang, Dong; Ran, Haitao

2016-09-01

To explore the antitumor effects of low-intensity focused ultrasound (LIFU) mediated localized drug delivery of adriamycin-microbubble-PLGA nanoparticle complexes on rabbits VX2 liver tumor. ADM-NMCs were prepared by covalent linking of ADM-PLGA nanoparticles (ADM-NPs) to the shell of the microbubbles. A fixed water bag filled with microbubbles was subjected to LIFU and non-focused ultrasound respectively, and the ultrasound images of which were recorded before and after ultrasonication. A total of 54 VX2 liver tumor-burdened rabbits were divided into six groups randomly, including control, ADM-NPs combined with LIFU, microbubbles combined with LIFU, ADM-NPs and microbubbles combined with LIFU, ADM-NMCs combined with LIFU and ADM-NMCs combined with Non-FUS. The tumor volume and volume inhibition rate (VIR) of tumor progression were calculated and compared. Apoptotic cells were labeled by terminal deoxyuridine nick end. Proliferating cell nuclear antigen was detected by immunohistochemistry. The median survival time of the animals were recorded and compared. ADM-NMCs were successfully prepared with an average diameter of 1721 nm. The highest VIR and apoptotic index (AI) were found in the group of ADM-NMCs combined with LIFU while the lowest proliferating index (PI) was simultaneously observed in this group. The median survival time of the rabbits in the ADM-NMCs combined with LIFU group was the longest (71days) among all groups. ADM-NMCs combined with LIFU could inhibit the rabbits VX2 liver tumor progress by delaying the tumor proliferation and accelerating apoptosis, which presents a novel process for liver tumor targeting chemotherapy.

Improving performance of nanoscale ultrasound contrast agents using N,N-diethylacrylamide stabilization.

PubMed

Perera, Reshani H; Wu, Hanping; Peiris, Pubudu; Hernandez, Christopher; Burke, Alan; Zhang, Helen; Exner, Agata A

2017-01-01

The design of nanoscale yet highly echogenic agents for imaging outside of the vasculature and for ultrasound-mediated drug delivery remains a formidable challenge. We have previously reported on formulation of echogenic perfluoropropane gas nanobubbles stabilized by a lipid-pluronic surfactant shell. In the current work we describe the development of a new generation of these nanoparticles which consist of perfluoropropane gas stabilized by a surfactant and lipid membrane and a crosslinked network of N,N-diethylacrylamide. The resulting crosslinked nanobubbles (CL-PEG-NB) were 95.2±25.2nm in diameter and showed significant improvement in stability and retention of echogenic signal over 24h. In vivo analysis via ultrasound and fluorescence mediated tomography showed greater tumor extravasation and accumulation with CL-PEG-NB compared to microbubbles. Together these results demonstrate the capabilities and advantages of a new, more stable, nanometer-scale ultrasound contrast agent that can be utilized in future work for diagnostic scans and molecular imaging. Copyright © 2016 Elsevier Inc. All rights reserved.

Potential and problems in ultrasound-responsive drug delivery systems

PubMed Central

Zhao, Ying-Zheng; Du, Li-Na; Lu, Cui-Tao; Jin, Yi-Guang; Ge, Shu-Ping

2013-01-01

Ultrasound is an important local stimulus for triggering drug release at the target tissue. Ultrasound-responsive drug delivery systems (URDDS) have become an important research focus in targeted therapy. URDDS include many different formulations, such as microbubbles, nanobubbles, nanodroplets, liposomes, emulsions, and micelles. Drugs that can be loaded into URDDS include small molecules, biomacromolecules, and inorganic substances. Fields of clinical application include anticancer therapy, treatment of ischemic myocardium, induction of an immune response, cartilage tissue engineering, transdermal drug delivery, treatment of Huntington’s disease, thrombolysis, and disruption of the blood–brain barrier. This review focuses on recent advances in URDDS, and discusses their formulations, clinical application, and problems, as well as a perspective on their potential use in the future. PMID:23637531

Sonochemotherapy: from bench to bedside

PubMed Central

Lammertink, Bart H. A.; Bos, Clemens; Deckers, Roel; Storm, Gert; Moonen, Chrit T. W.; Escoffre, Jean-Michel

2015-01-01

The combination of microbubbles and ultrasound has emerged as a promising method for local drug delivery. Microbubbles can be locally activated by a targeted ultrasound beam, which can result in several bio-effects. For drug delivery, microbubble-assisted ultrasound is used to increase vascular- and plasma membrane permeability for facilitating drug extravasation and the cellular uptake of drugs in the treated region, respectively. In the case of drug-loaded microbubbles, these two mechanisms can be combined with local release of the drug following destruction of the microbubble. The use of microbubble-assisted ultrasound to deliver chemotherapeutic agents is also referred to as sonochemotherapy. In this review, the basic principles of sonochemotherapy are discussed, including aspects such as the type of (drug-loaded) microbubbles used, the routes of administration used in vivo, ultrasound devices and parameters, treatment schedules and safety issues. Finally, the clinical translation of sonochemotherapy is discussed, including the first clinical study using sonochemotherapy. PMID:26217226

Ultrasonically targeted delivery into endothelial and smooth muscle cells in ex vivo arteries

PubMed Central

Hallow, Daniel M.; Mahajan, Anuj D.; Prausnitz, Mark R.

2007-01-01

This study tested the hypothesis that ultrasound can target intracellular uptake of drugs into vascular endothelial cells (ECs) at low to intermediate energy and into smooth muscle cells (SMCs) at high energy. Ultrasound-enhanced delivery has been shown to enhance and target intracellular drug and gene delivery in the vasculature to treat cardiovascular disease, but quantitative studies of the delivery process are lacking. Viable ex vivo porcine carotid arteries were placed in a solution containing a model drug, TO-PRO®-1, and Optison® microbubbles. Arteries were exposed to ultrasound at 1.1 MHz and acoustic energies of 5.0, 66, or 630 J/cm2. Using confocal microscopy and fluorescent labeling of cells, the artery endothelium and media were imaged to determine the localization and to quantify intracellular uptake and cell death. At low to intermediate ultrasound energy, ultrasound was shown to target intracellular delivery into viable cells that represented 9 – 24% of exposed ECs. These conditions also typically caused 7 – 25% EC death. At high energy, intracellular delivery was targeted to SMCs, which was associated with denuding or death of proximal ECs. This work represents the first known in-depth study to evaluate intracellular uptake into cells in tissue. We conclude that significant intracellular uptake of molecules can be targeted into ECs and SMCs by ultrasound-enhanced delivery suggesting possible applications for treatment of cardivascular diseases and dysfunctions. PMID:17291619

Gene delivery systems by the combination of lipid bubbles and ultrasound.

PubMed

Negishi, Yoichi; Endo-Takahashi, Yoko; Maruyama, Kazuo

2016-11-28

Gene therapy is promising for the treatment of many diseases including cancers and genetic diseases. From the viewpoint of safety, ultrasound (US)-mediated gene delivery with nano/ microbubbles was recently developed as a novel non-viral vector system. US-mediated gene delivery using nano/microbubbles are able to produce transient changes in the permeability of the cell membrane after US-induced cavitation while reducing cellular damage and enables the tissue-specific or the site-specific intracellular delivery of gene both in vitro and in vivo. We have recently developed novel lipid nanobubbles (Lipid Bubbles). These nanobubbles can also be used to enhance the efficacy of the US-mediated genes (plasmid DNA, siRNA, and miRNA etc.) delivery. In this review, we describe US-mediated delivery systems combined with nano/microbubbles and discuss their feasibility as non-viral vector systems.

Gas-Stabilizing Gold Nanocones for Acoustically Mediated Drug Delivery.

PubMed

Mannaris, Christophoros; Teo, Boon M; Seth, Anjali; Bau, Luca; Coussios, Constantin; Stride, Eleanor

2018-06-01

The efficient penetration of drugs into tumors is a major challenge that remains unmet. Reported herein is a strategy to promote extravasation and enhanced penetration using inertial cavitation initiated by focused ultrasound and cone-shaped gold nanoparticles that entrap gas nanobubbles. The cones are capable of initiating inertial cavitation under pressures and frequencies achievable with existing clinical ultrasound systems and of promoting extravasation and delivery of a model large therapeutic molecule in an in vitro tissue mimicking flow phantom, achieving penetration depths in excess of 2 mm. Ease of functionalization and intrinsic imaging capabilities provide gold with significant advantages as a material for biomedical applications. The cones show neither cytotoxicity in Michigan Cancer Foundation (MCF)-7 cells nor hemolytic activity in human blood at clinically relevant concentrations and are found to be colloidally stable for at least 5 d at 37 °C and several months at 4 °C. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Micelles and Nanoparticles for Ultrasonic Drug and Gene Delivery

PubMed Central

Husseini, Ghaleb A.; Pitt, William G.

2008-01-01

Drug delivery research employing micelles and nanoparticles has expanded in recent years. Of particular interest is the use of these nanovehicles that deliver high concentrations of cytotoxic drugs to diseased tissues selectively, thus reducing the agent’s side effects on the rest of the body. Ultrasound, traditionally used in diagnostic medicine, is finding a place in drug delivery in connection with these nanoparticles. In addition to their non-invasive nature and the fact that they can be focused on targeted tissues, acoustic waves have been credited with releasing pharmacological agents from nanocarriers, as well as rendering cell membranes more permeable. In this article, we summarize new technologies that combine the use of nanoparticles with acoustic power both in drug and gene delivery. Ultrasonic drug delivery from micelles usually employs polyether block copolymers, and has been found effective in vivo for treating tumors. Ultrasound releases drug from micelles, most probably via shear stress and shock waves from collapse of cavitation bubbles. Liquid emulsions and solid nanoparticles are used with ultrasound to deliver genes in vitro and in vivo. The small packaging allows nanoparticles to extravasate into tumor tissues. Ultrasonic drug and gene delivery from nano-carriers has tremendous potential because of the wide variety of drugs and genes that could be delivered to targeted tissues by fairly non-invasive means. PMID:18486269

Current Status and Prospects for Microbubbles in Ultrasound Theranostics

PubMed Central

Martin, K. Heath

2013-01-01

Encapsulated microbubbles have been developed over the past two decades to provide both improvements in imaging as well as new therapeutic applications. Microbubble contrast agents are used currently for clinical imaging where increased sensitivity to blood flow is required, such as echocardiography. These compressible spheres oscillate in an acoustic field, producing nonlinear responses which can be uniquely distinguished from surrounding tissue, resulting in substantial enhancements in imaging signal-to-noise ratio. Furthermore, with sufficient acoustic energy the oscillation of microbubbles can mediate localized biological effects in tissue including the enhancement of membrane permeability or increased thermal energy deposition. Structurally, microbubbles are comprised of two principal components – an encapsulating shell and an inner gas core. This configuration enables microbubbles to be loaded with drugs or genes for additional therapeutic effect. Application of sufficient ultrasound energy can release this payload, resulting in site-specific delivery. Extensive pre-clinical studies illustrate that combining microbubbles and ultrasound can result in enhanced drug delivery or gene expression at spatially selective sites. Thus, microbbubles can be used for imaging, for therapy, or for both simultaneously. In this sense, microbubbles combined with acoustics may be one of the most universal theranostic tools. PMID:23504911

Hyperthermia in bone generated with MR imaging-controlled focused ultrasound: control strategies and drug delivery.

PubMed

Staruch, Robert; Chopra, Rajiv; Hynynen, Kullervo

2012-04-01

To evaluate the feasibility of achieving image-guided drug delivery in bone by using magnetic resonance (MR) imaging-controlled focused ultrasound hyperthermia and temperature-sensitive liposomes. Experiments were approved by the institutional animal care committee. Hyperthermia (43°C, 20 minutes) was generated in 10-mm-diameter regions at a muscle-bone interface in nine rabbit thighs by using focused ultrasound under closed-loop temperature control with MR thermometry. Thermosensitive liposomal doxorubicin was administered systemically during heating. Heating uniformity and drug delivery were evaluated for control strategies with the temperature control image centered 10 mm (four rabbits) or 0 mm (five rabbits) from the bone. Simulations estimated temperature elevations in bone. Drug delivery was quantified by using the fluorescence of doxorubicin extracted from bone marrow and muscle and was compared between treated and untreated thighs by using the one-sided Wilcoxon signed rank test. With ultrasound focus and MR temperature control plane 0 mm and 10 mm from the bone interface, average target region temperatures were 43.1°C and 43.3°C, respectively; numerically estimated bone temperatures were 46.8°C and 78.1°C. The 10-mm offset resulted in thermal ablation; numerically estimated muscle temperature was 66.1°C at the bone interface. Significant increases in doxorubicin concentration occurred in heated versus unheated marrow (8.2-fold, P = .002) and muscle (16.8-fold, P = .002). Enhancement occurred for 0- and 10-mm offsets, which suggests localized drug delivery in bone is possible with both hyperthermia and thermal ablation. MR imaging-controlled focused ultrasound can achieve localized hyperthermia in bone for image-guided drug delivery in bone with temperature-sensitive drug carriers. © RSNA, 2012.

Investigation of microbubble response to long pulses used in ultrasound-enhanced drug delivery.

PubMed

Mannaris, Christophoros; Averkiou, Michalakis A

2012-04-01

In current drug delivery approaches, microbubbles and drugs can be co-administered while ultrasound is applied. The mechanism of microbubble interaction with ultrasound, the drug and the cells is not fully understood. The aim of this study was to investigate microbubble response to long ultrasonic pulses used in drug delivery approaches. Two different in vitro set-ups were considered: with the microbubbles diluted in an enclosure and with the microbubbles flowing in a capillary tube. Acoustic streaming, which influences the observed bubble response, was observed in "typical" drug delivery conditions in the first set-up. With the capillary set-up, streaming effects were avoided and accurate bubble responses were recorded. The diffraction pattern of the source greatly influences the bubble response and in different locations of the field different bubble responses are observed. At low nondestructive pressures, microbubbles can oscillate for thousands of cycles repeatedly. At high acoustic pressures (at 1 MHz), most bubble activity disappeared within about 100 μs despite the length of the pulse, mainly due to violent bubble destruction and subsequent accelerated diffusion. Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Ultrasound-stimulated drug delivery for treatment of residual disease after incomplete resection of head and neck cancer.

PubMed

Sorace, Anna G; Korb, Melissa; Warram, Jason M; Umphrey, Heidi; Zinn, Kurt R; Rosenthal, Eben; Hoyt, Kenneth

2014-04-01

Microbubbles triggered with localized ultrasound (US) can improve tumor drug delivery and retention. Termed US-stimulated drug delivery, this strategy was applied to head and neck cancer (HNC) in a post-surgical tumor resection model. Luciferase-positive HNC squamous cell carcinoma (SCC) was implanted in the flanks of nude athymic mice (N = 24) that underwent various degrees of surgical tumor resection (0%, 50% or 100%). After surgery, animals received adjuvant therapy with cetuximab-IRDye alone, or cetuximab-IRDye in combination with US-stimulated drug delivery or saline injections (control) on days 4, 7 and 10. Tumor drug delivery was assessed on days 0, 4, 7, 10, 14 and 17 with an in vivo fluorescence imaging system, and tumor viability was evaluated at the same times with in vivo bioluminescence imaging. Tumor caliper measurements occurred two times per week for 24 d. Optical imaging revealed that in the 50% tumor resection group, US-stimulated drug delivery resulted in a significant increase in cetuximab delivery compared with administration of drug alone on day 10 (day of peak fluorescence) (p = 0.03). Tumor viability decreased in all groups that received cetuximab-IRDye in combination with US-stimulated drug delivery, compared with the group that received only the drug. After various degrees of surgical resection, this novel study reports positive improvements in drug uptake in the residual cancer cells when drug delivery is stimulated with US. Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Ultrasound Microbubble Treatment Enhances Clathrin-Mediated Endocytosis and Fluid-Phase Uptake through Distinct Mechanisms.

PubMed

Fekri, Farnaz; Delos Santos, Ralph Christian; Karshafian, Raffi; Antonescu, Costin N

2016-01-01

Drug delivery to tumors is limited by several factors, including drug permeability of the target cell plasma membrane. Ultrasound in combination with microbubbles (USMB) is a promising strategy to overcome these limitations. USMB treatment elicits enhanced cellular uptake of materials such as drugs, in part as a result of sheer stress and formation of transient membrane pores. Pores formed upon USMB treatment are rapidly resealed, suggesting that other processes such as enhanced endocytosis may contribute to the enhanced material uptake by cells upon USMB treatment. How USMB regulates endocytic processes remains incompletely understood. Cells constitutively utilize several distinct mechanisms of endocytosis, including clathrin-mediated endocytosis (CME) for the internalization of receptor-bound macromolecules such as Transferrin Receptor (TfR), and distinct mechanism(s) that mediate the majority of fluid-phase endocytosis. Tracking the abundance of TfR on the cell surface and the internalization of its ligand transferrin revealed that USMB acutely enhances the rate of CME. Total internal reflection fluorescence microscopy experiments revealed that USMB treatment altered the assembly of clathrin-coated pits, the basic structural units of CME. In addition, the rate of fluid-phase endocytosis was enhanced, but with delayed onset upon USMB treatment relative to the enhancement of CME, suggesting that the two processes are distinctly regulated by USMB. Indeed, vacuolin-1 or desipramine treatment prevented the enhancement of CME but not of fluid phase endocytosis upon USMB, suggesting that lysosome exocytosis and acid sphingomyelinase, respectively, are required for the regulation of CME but not fluid phase endocytosis upon USMB treatment. These results indicate that USMB enhances both CME and fluid phase endocytosis through distinct signaling mechanisms, and suggest that strategies for potentiating the enhancement of endocytosis upon USMB treatment may improve targeted drug delivery.

Novel ultrasound-responsive chitosan/perfluorohexane nanodroplets for image-guided smart delivery of an anticancer agent: Curcumin.

PubMed

Baghbani, Fatemeh; Chegeni, Mahdieh; Moztarzadeh, Fathollah; Hadian-Ghazvini, Samaneh; Raz, Majid

2017-05-01

Ultrasound-responsive nanodroplets are a class of new emerging smart drug delivery systems which provide image-guided nano-therapy of various diseases, especially cancers. Here, we developed multifunctional smart curcumin-loaded chitosan/perfluorohexane nanodroplets for contrast-ultrasound imaging and on-demand drug delivery. The nanodroplets were synthesized via nanoemulsion process. The optimal formulation with the size of 101.2nm and 77.8% curcumin entrapment was chosen for release study and cytotoxicity evaluation. Sonication at the frequency of 1MHz, 2W/cm 2 for 4min triggered the release of 63.5% of curcumin from optimal formulation (Cur-NDs-2). Ultrasound aided release study indicated that the concentration of perfluorohexane and the degree of acoustic droplet vaporization play important role in ultrasound-active drug release. B-mode ultrasound imaging confirmed strong ultrasound contrast of chitosan nanodroplets even at low concentrations via droplet to bubble transition. Finally, cytotoxicity of the ultrasound-responsive nanodroplets in the presence of ultrasound was evaluated in-vitro on 4T1 human breast cancer cells. Cell growth inhibitory effects of curcumin-loaded nanodroplets significantly increased by ultrasound exposure. According to the obtained results, these ultrasound responsive curcumin-loaded chitosan/perfluorohexane nanodroplets have a great potential for imaged-guided cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Optical Fluorescent Imaging to Monitor Temporal Effects of Microbubble-Mediated Ultrasound Therapy

PubMed Central

Sorace, Anna G.; Saini, Reshu; Rosenthal, Eben; Warram, Jason M.; Zinn, Kurt R.; Hoyt, Kenneth

2013-01-01

Microbubble-mediated ultrasound therapy can noninvasively enhance drug delivery to localized regions in the body. This technique can be beneficial in cancer therapy, but currently there are limitations to tracking the therapeutic effects. The purpose of this experiment was to investigate the potential of fluorescent imaging for monitoring the temporal effects of microbubble-mediated ultrasound therapy. Mice were implanted with 2LMP breast cancer cells. The animals underwent microbubble-mediated ultrasound therapy in the presence of Cy5.5 fluorescent-labeled IgG antibody (large molecule) or Cy5.5 dye (small molecule) and microbubble contrast agents. Control animals were administered fluorescent molecules only. Animals were transiently imaged in vivo at 1, 10, 30, and 60 min post therapy using a small animal optical imaging system. Tumors were excised and analyzed ex vivo. Tumors were homogenized and emulsion imaged for Cy5.5 fluorescence. Monitoring in vivo results showed significant influx of dye into the tumor (p < 0.05) using the small molecule, but not in the large molecule group (p > 0.05). However, after tumor emulsion, significantly higher dye concentration was detected in therapy group tumors for both small and large molecule groups in comparison to their control counterparts (p < 0.01). This paper explores a noninvasive optical imaging method for monitoring the effects of microbubble-mediated ultrasound therapy in a cancer model. It provides temporal information following the process of increasing extravasation of molecules into target tumors. PMID:23357902

Optical fluorescent imaging to monitor temporal effects of microbubble-mediated ultrasound therapy.

PubMed

Sorace, Anna G; Saini, Reshu; Rosenthal, Eben; Warram, Jason M; Zinn, Kurt R; Hoyt, Kenneth

2013-02-01

Microbubble-mediated ultrasound therapy can noninvasively enhance drug delivery to localized regions in the body. This technique can be beneficial in cancer therapy, but currently there are limitations to tracking the therapeutic effects. The purpose of this experiment was to investigate the potential of fluorescent imaging for monitoring the temporal effects of microbubble-mediated ultrasound therapy. Mice were implanted with 2LMP breast cancer cells. The animals underwent microbubble-mediated ultrasound therapy in the presence of Cy5.5 fluorescent-labeled IgG antibody (large molecule) or Cy5.5 dye (small molecule) and microbubble contrast agents. Control animals were administered fluorescent molecules only. Animals were transiently imaged in vivo at 1, 10, 30, and 60 min post therapy using a small animal optical imaging system. Tumors were excised and analyzed ex vivo. Tumors were homogenized and emulsion imaged for Cy5.5 fluorescence. Monitoring in vivo results showed significant influx of dye into the tumor (p < 0.05) using the small molecule, but not in the large molecule group (p > 0.05). However, after tumor emulsion, significantly higher dye concentration was detected in therapy group tumors for both small and large molecule groups in comparison to their control counterparts (p <0.01). This paper explores a noninvasive optical imaging method for monitoring the effects of microbubble-mediated ultrasound therapy in a cancer model. It provides temporal information following the process of increasing extravasation of molecules into target tumors.

Ultrasound-Enhanced Delivery of Antibiotics and Anti-Inflammatory Drugs into the Eye

PubMed Central

Nabili, Marjan; Patel, Hetal; Mahesh, Sankaranarayana P.; Liu, Ji; Geist, Craig; Zderic, Vesna

2013-01-01

Delivery of sufficient amounts of therapeutic drugs into the eye is often a challenging task. In this study, ultrasound application (frequencies of 400 KHz to 1 MHz, intensities of 0.3–1.0 W/cm2 and exposure duration of 5 min) was investigated to overcome the barrier properties of cornea, which is a typical route for topical administration of ophthalmic drugs. Permeability of ophthalmic drugs, tobramycin and dexamethasone and sodium fluorescein, a drug-mimicking compound, was studied in ultrasound- and sham-treated rabbit corneas in vitro using a standard diffusion cell setup. Light microscopy observations were used to determine ultrasound-induced structural changes in the cornea. For tobramycin, an increase in permeability for ultrasound- and sham-treated corneas was not statistically significant. Increase of 46%–126% and 32%–109% in corneal permeability was observed for sodium fluorescein and dexamethasone, respectively, with statistical significance (p < 0.05) achieved at all treatment parameter combinations (compared with sham treatments) except for 1-MHz ultrasound applications for dexamethasone experiments. This permeability increase was highest at 400 kHz and appeared to be higher at higher intensities applied. Histologic analysis showed structural changes that were limited to epithelial layers of cornea. In summary, ultrasound application provided enhancement of drug delivery, increasing the permeability of the cornea for the anti-inflammatory ocular drug dexamethasone. Future investigations are needed to determine the effectiveness and safety of this application in in vivo long-term survival studies. (E-mail: mnabili@gwu.edu) PMID:23415283

Fluorescent Microscope System to Monitor Real-Time Interactions between Focused Ultrasound, Echogenic Drug Delivery Vehicles, and Live Cell Membranes

PubMed Central

Ibsen, Stuart; Benchimol, Michael; Esener, Sadik

2012-01-01

Rapid development in the field of ultrasound triggered drug delivery has made it essential to study the real-time interaction between the membranes of live cells and the membranes of echogenic delivery vehicles under exposure to focused ultrasound. The objective of this work was to design an analysis system that combined fluorescent imagining, high speed videography, and definable pulse sequences of focused ultrasound to allow for real time observations of both cell and vehicle membranes. Documenting the behavior of the membranes themselves has not previously been possible due to limitations with existing optical systems used to understand the basic physics of microbubble/ultrasound interaction and the basic interaction between microbubbles and cells. The performance of this new system to monitor membrane behavior was demonstrated by documenting the modes of vehicle fragmentation at different ultrasound intensity levels. At 1.5 MPa the membranes were shown to completely fragment while at intensities below 1 MPa there is a popping and slow unfolding. The interaction between these vehicles and cell membranes was also documented by the removal of fluorescent particles from the surfaces of live cells out to 20 μm from the microbubble location. The fluid flow created by microstreaming around ensonated microbubbles was documented at video recording speeds from 60 to 18,000 frames per second. This information about membrane behavior allows the chemical and physical properties of the drug delivery vehicle to be designed along with the ultrasound pulse sequence to cause the most efficient drug delivery. PMID:22749476

Fluorescent microscope system to monitor real-time interactions between focused ultrasound, echogenic drug delivery vehicles, and live cell membranes.

PubMed

Ibsen, Stuart; Benchimol, Michael; Esener, Sadik

2013-01-01

Rapid development in the field of ultrasound triggered drug delivery has made it essential to study the real-time interaction between the membranes of live cells and the membranes of echogenic delivery vehicles under exposure to focused ultrasound. The objective of this work was to design an analysis system that combined fluorescent imagining, high speed videography, and definable pulse sequences of focused ultrasound to allow for real time observations of both cell and vehicle membranes. Documenting the behavior of the membranes themselves has not previously been possible due to limitations with existing optical systems used to understand the basic physics of microbubble/ultrasound interaction and the basic interaction between microbubbles and cells. The performance of this new system to monitor membrane behavior was demonstrated by documenting the modes of vehicle fragmentation at different ultrasound intensity levels. At 1.5MPa the membranes were shown to completely fragment while at intensities below 1MPa the membranes pop open and slowly unfold. The interaction between these vehicles and cell membranes was also documented by the removal of fluorescent particles from the surfaces of live cells out to 20μm from the microbubble location. The fluid flow created by microstreaming around ensonated microbubbles was documented at video recording speeds from 60 to 18,000 frames per second. This information about membrane behavior allows the chemical and physical properties of the drug delivery vehicle to be designed along with the ultrasound pulse sequence to cause the most efficient drug delivery. Copyright © 2012 Elsevier B.V. All rights reserved.

Impact of Focused Ultrasound-enhanced Drug Delivery on Survival in Rats with Glioma

NASA Astrophysics Data System (ADS)

Treat, Lisa Hsu; Zhang, Yongzhi; McDannold, Nathan; Hynynen, Kullervo

2009-04-01

Malignancies of the brain remain difficult to treat with chemotherapy because the selective permeability of the blood-brain barrier (BBB) blocks many potent agents from reaching their target. Previous studies have illustrated the feasibility of drug and antibody delivery across the BBB using MRI-guided focused ultrasound. In this study, we investigated the impact of focused ultrasound-enhanced delivery of doxorubicin on survival in rats with aggressive glioma. Sprague-Dawley rats were implanted with 9 L gliosarcoma cells in the brain. Eight days after implantation, each rat received one of the following: (1) no treatment (control), (2) a single treatment with microbubble-enhanced MRI-guided focused ultrasound (FUS only), (3) a single treatment with i.v. liposomal doxorubicin (DOX only), or (4) a single treatment with microbubble-enhanced MRI-guided focused ultrasound and concurrent i.v. injections of liposomal doxorubicin (FUS+DOX). The survival time from implantation to death or euthanasia was recorded. We observed a modest but significant increase in median survival time in rats treated with combined MRI-guided focused ultrasound chemotherapy, compared to chemotherapy alone (p<0.001). There was no significant improvement in survival between those who received stand-alone chemotherapy and those who did not receive any treatment (p>0.10). Our study demonstrates for the first time a therapeutic benefit achieved with ultrasound-enhanced drug delivery across the blood-brain barrier. This confirmation of efficacy in an in vivo tumor model indicates that targeted drug delivery using MRI-guided focused ultrasound has the potential to have a major impact on the treatment of patients with brain tumors and other neurological disorders.

Ultrasound-enhanced delivery of antibiotics and anti-inflammatory drugs into the eye.

PubMed

Nabili, Marjan; Patel, Hetal; Mahesh, Sankaranarayana P; Liu, Ji; Geist, Craig; Zderic, Vesna

2013-04-01

Delivery of sufficient amounts of therapeutic drugs into the eye is often a challenging task. In this study, ultrasound application (frequencies of 400 KHz to 1 MHz, intensities of 0.3-1.0 W/cm(2) and exposure duration of 5 min) was investigated to overcome the barrier properties of cornea, which is a typical route for topical administration of ophthalmic drugs. Permeability of ophthalmic drugs, tobramycin and dexamethasone and sodium fluorescein, a drug-mimicking compound, was studied in ultrasound- and sham-treated rabbit corneas in vitro using a standard diffusion cell setup. Light microscopy observations were used to determine ultrasound-induced structural changes in the cornea. For tobramycin, an increase in permeability for ultrasound- and sham-treated corneas was not statistically significant. Increase of 46%-126% and 32%-109% in corneal permeability was observed for sodium fluorescein and dexamethasone, respectively, with statistical significance (p < 0.05) achieved at all treatment parameter combinations (compared with sham treatments) except for 1-MHz ultrasound applications for dexamethasone experiments. This permeability increase was highest at 400 kHz and appeared to be higher at higher intensities applied. Histologic analysis showed structural changes that were limited to epithelial layers of cornea. In summary, ultrasound application provided enhancement of drug delivery, increasing the permeability of the cornea for the anti-inflammatory ocular drug dexamethasone. Future investigations are needed to determine the effectiveness and safety of this application in in vivo long-term survival studies. Copyright © 2013 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Advanced Ultrasound Technologies for Diagnosis and Therapy.

PubMed

Rix, Anne; Lederle, Wiltrud; Theek, Benjamin; Lammers, Twan; Moonen, Chrit; Schmitz, Georg; Kiessling, Fabian

2018-05-01

Ultrasound is among the most rapidly advancing imaging techniques. Functional methods such as elastography have been clinically introduced, and tissue characterization is improved by contrast-enhanced scans. Here, novel superresolution techniques provide unique morphologic and functional insights into tissue vascularization. Functional analyses are complemented by molecular ultrasound imaging, to visualize markers of inflammation and angiogenesis. The full potential of diagnostic ultrasound may become apparent by integrating these multiple imaging features in radiomics approaches. Emerging interest in ultrasound also results from its therapeutic potential. Various applications of tumor ablation with high-intensity focused ultrasound are being clinically evaluated, and its performance strongly benefits from the integration into MRI. Additionally, oscillating microbubbles mediate sonoporation to open biologic barriers, thus improving the delivery of drugs or nucleic acids that are coadministered or coformulated with microbubbles. This article provides an overview of recent developments in diagnostic and therapeutic ultrasound, highlighting multiple innovation tracks and their translational potential. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

Development of therapeutic microbubbles for enhancing ultrasound-mediated gene delivery.

PubMed

Sun, Ryan R; Noble, Misty L; Sun, Samuel S; Song, Shuxian; Miao, Carol H

2014-05-28

Ultrasound (US)-mediated gene delivery has emerged as a promising non-viral method for safe and selective gene delivery. When enhanced by the cavitation of microbubbles (MBs), US exposure can induce sonoporation that transiently increases cell membrane permeability for localized delivery of DNA. The present study explores the effect of generalizable MB customizations on MB facilitation of gene transfer compared to Definity®, a clinically available contrast agent. These modifications are 1) increased MB shell acyl chain length (RN18) for elevated stability and 2) addition of positive charge on MB (RC5K) for greater DNA associability. The MB types were compared in their ability to facilitate transfection of luciferase and GFP reporter plasmid DNA in vitro and in vivo under various conditions of US intensity, MB dosage, and pretreatment MB-DNA incubation. The results indicated that both RN18 and RC5K were more efficient than Definity®, and that the cationic RC5K can induce even greater transgene expression by increasing payload capacity with prior DNA incubation without compromising cell viability. These findings could be applied to enhance MB functions in a wide range of therapeutic US/MB gene and drug delivery approach. With further designs, MB customizations have the potential to advance this technology closer to clinical application. Copyright © 2014 Elsevier B.V. All rights reserved.

[Application of ultrasound-enhanced gene and drug delivery to the ocular tissue].

PubMed

Sonoda, Shozo; Yamashita, Toshifumi; Suzuki, Ryo; Maruyama, Kazuo; Sakamoto, Taiji

2013-01-01

Visual images provide an immensely rich source of information about the external world. Eye has characteristic structure sensory cells are arranged along the eye wall, and is filled inside with vitreous body. In recent years, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent had widely spread, and numerous number of patients who suffered ocular angiogenic disease such as diabetic retinopathy, age-related macular degeneration and retinal vascular occlusion for the disease, were treated and spared the blindness. Vitreous cavity was regarded as reservoir of drug, intravitreal injection is thought a sort of drug delivery. However, with regard to the administration of a selective drug deliver, it has not yet been solved. Our aim is to establish a new method of gene transfer, drug delivery using low-energy ultrasound to the eye, to date, we confirmed drug and gene deliver to the ocular tissue such as cornea, conjunctiva and retina with high efficiency. In addition, tissue damage was minimal. We have also shown that ultrasound irradiation with combination of a microbubbles or bubble liposome could be introduced drug and gene more effectively. Based on these knowledge, we will focus on development of a new device for intraocular ultrasound exposure and potential for therapeutic application of ultrasound to humans retinal disease such as retinal artery obstruction.

Dynamic Behavior of Microbubbles during Long Ultrasound Tone-Burst Excitation: Mechanistic Insights into Ultrasound-Microbubble Mediated Therapeutics Using High-Speed Imaging and Cavitation Detection.

PubMed

Chen, Xucai; Wang, Jianjun; Pacella, John J; Villanueva, Flordeliza S

2016-02-01

Ultrasound (US)-microbubble (MB)-mediated therapies have been found to restore perfusion and enhance drug/gene delivery. On the presumption that MBs do not persist during long US exposure under high acoustic pressures, most schemes use short US pulses when a high US pressure is employed. However, we recently observed an enhanced thrombolytic effect using long US pulses at high acoustic pressures. Therefore, we explored the fate of MBs during long tone-burst exposures (5 ms) at various acoustic pressures and MB concentrations via direct high-speed optical observation and passive cavitation detection. MBs first underwent stable or inertial cavitation depending on the acoustic pressure and then formed gas-filled clusters that continued to oscillate, break up and form new clusters. Cavitation detection confirmed continued, albeit diminishing, acoustic activity throughout the 5-ms US excitation. These data suggest that persisting cavitation activity during long tone bursts may confer additional therapeutic effects. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Preparation of nanobubbles for ultrasound imaging and intracelluar drug delivery.

PubMed

Wang, Ye; Li, Xiang; Zhou, Yan; Huang, Pengyu; Xu, Yuhong

2010-01-15

Echogenic bubble formulations have wide applications in both disease diagnosis and therapy. In the current study, nanobubbles were prepared and the contrast agent function was evaluated in order to study the nanosized bubble's property for ultrasonic imaging. Coumarin-6 as a model drug was loaded into nanobubbles to investigate the drug delivery potential to cells. The results showed that the nanobubbles composed of 1% of Tween 80, and 3 mg/ml of lipid worked well as an ultrasonic contrast agent by presenting a contrast effect in the liver region in vivo. The drug-loaded nanobubbles could enhance drug delivery to cells significantly, and the process was analyzed by sigmoidally fitting the pharmacokinetic curve. It can be concluded that the nanobubble formulation is a promising approach for both ultrasound imaging and drug delivery enhancing.

Nanoparticle Delivery Enhancement With Acoustically Activated Microbubbles

PubMed Central

Mullin, Lee B; Phillips, Linsey C; Dayton, Paul A

2013-01-01

The application of microbubbles and ultrasound to deliver nanoparticle carriers for drug and gene delivery is an area that has expanded greatly in recent years. Under ultrasound exposure, microbubbles can enhance nanoparticle delivery by increasing cellular and vascular permeability. In this review, the underlying mechanisms of enhanced nanoparticle delivery with ultrasound and microbubbles and various proposed delivery techniques are discussed. Additionally, types of nanoparticles currently being investigated in preclinical studies, as well as the general limitations and benefits of a microbubble-based approach to nanoparticle delivery are reviewed. PMID:23287914

Nanobubbles: a promising efficient tool for therapeutic delivery.

PubMed

Cavalli, Roberta; Soster, Marco; Argenziano, Monica

2016-01-01

In recent decades ultrasound-guided delivery of drugs loaded on nanocarriers has been the focus of increasing attention to improve therapeutic treatments. Ultrasound has often been used in combination with microbubbles, micron-sized spherical gas-filled structures stabilized by a shell, to amplify the biophysical effects of the ultrasonic field. Nanometer size bubbles are defined nanobubbles. They were designed to obtain more efficient drug delivery systems. Indeed, their small sizes allow extravasation from blood vessels into surrounding tissues and ultrasound-targeted site-specific release with minimal invasiveness. Additionally, nanobubbles might be endowed with improved stability and longer residence time in systemic circulation. This review will describe the physico-chemical properties of nanobubbles, the formulation parameters and the drug loading approaches, besides potential applications as a therapeutic tool.

Ultrasound-responsive nanobubbles contained with peptide-camptothecin conjugates for targeted drug delivery.

PubMed

Xie, Xiangyang; Lin, Wen; Liu, Hui; Deng, Jianping; Chen, Ying; Liu, Hong; Fu, Xudong; Yang, Yang

2016-10-01

To improve the targeting delivery efficiency of anticancer drug to tumor sites, a new strategy combining cell-permeable peptide (CPP) and ultrasound was reported in this article. In this study, we devised and tested a strategy for functional payload delivery to cells by loading CPP-camptothecin conjugate (CPP-CPT) into nanobubble (CPP-CPT NB). Here, CPP existing in the conjugation form of CPP and CPT was hidden in nanobubble to cloak the penetration activity of CPP. Meanwhile, local tumor ultrasound was utilized to achieve specific targeting of CPP-CPT to the tumor cells. The mean particle size of the prepared CPP-CPT NB was ∼200 nm, and the drug entrapment efficiency was >80%. Stimulated by ultrasound, over 90% of the entrapped CPP-CPTs would release from the nanobubbles. Subsequent research demonstrated that the CPP-CPT NB showed effective cellular uptake and significant cytotoxic activity in HeLa cells in vitro. Additionally, after systemic administration in mice, CPP-CPT NB with ultrasound showed a higher tumor inhibition effect in nude mice xenografted HeLa cells tumors and excellent body safety when compared with normal CPT injection group. In conclusion, the carrier constructed in this study would be a safe and efficiently drug delivery system for specific cancer treatment.

Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood-brain barrier opening.

PubMed

Sierra, Carlos; Acosta, Camilo; Chen, Cherry; Wu, Shih-Ying; Karakatsani, Maria E; Bernal, Manuel; Konofagou, Elisa E

2017-04-01

Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood-brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood-brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo.

Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood–brain barrier opening

PubMed Central

Sierra, Carlos; Acosta, Camilo; Chen, Cherry; Wu, Shih-Ying; Karakatsani, Maria E; Bernal, Manuel

2016-01-01

Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood–brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood–brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo. PMID:27278929

Localised drug release using MRI-controlled focused ultrasound hyperthermia.

PubMed

Staruch, Robert; Chopra, Rajiv; Hynynen, Kullervo

2011-01-01

Thermosensitive liposomes provide a mechanism for triggering the local release of anticancer drugs, but this technology requires precise temperature control in targeted regions with minimal heating of surrounding tissue. The objective of this study was to evaluate the feasibility of using MRI-controlled focused ultrasound (FUS) and thermosensitive liposomes to achieve thermally mediated localised drug delivery in vivo. Results are reported from ten rabbits, where a FUS beam was scanned in a circular trajectory to heat 10-15 mm diameter regions in normal thigh to 43°C for 20-30 min. MRI thermometry was used for closed-loop feedback control to achieve temporally and spatially uniform heating. Lyso-thermosensitive liposomal doxorubicin was infused intravenously during hyperthermia. Unabsorbed liposomes were flushed from the vasculature by saline perfusion 2 h later, and tissue samples were harvested from heated and unheated thigh regions. The fluorescence intensity of the homogenised samples was used to calculate the concentration of doxorubicin in tissue. Closed-loop control of FUS heating using MRI thermometry achieved temperature distributions with mean, T90 and T10 of 42.9°C, 41.0°C and 44.8°C, respectively, over a period of 20 min. Doxorubicin concentrations were significantly higher in tissues sampled from heated than unheated regions of normal thigh muscle (8.3 versus 0.5 ng/mg, mean per-animal difference = 7.8 ng/mg, P < 0.05, Wilcoxon matched pairs signed rank test). The results show the potential of MRI-controlled focused ultrasound hyperthermia for enhanced local drug delivery with temperature-sensitive drug carriers.

The dynamic behavior of microbubbles during long ultrasound tone-burst excitation: mechanistic insights into ultrasound-microbubble mediated therapeutics using high-speed imaging and cavitation detection

PubMed Central

Pacella, John J.; Villanueva, Flordeliza S.

2015-01-01

Ultrasound (US)-microbubble (MB) mediated therapies have been shown to restore perfusion and enhance drug/gene delivery. Due to the presumption that MBs do not persist during long US exposure under high acoustic pressures, most schemes utilize short US pulses when a high US pressure is employed. However, we recently observed an enhanced thrombolytic effect using long US pulses at high acoustic pressures. Therefore we explored the fate of MBs during long tone-burst exposures (5 ms) at various acoustic pressures and MB concentrations via direct high-speed optical observation and passive cavitation detection. MBs first underwent stable or inertial cavitation depending on the acoustic pressure, and then formed gas-filled clusters that continued to oscillate, break up, and form new clusters. Cavitation detection confirmed continued, albeit diminishing acoustic activity throughout the 5-ms US excitation. These data suggest that persisting cavitation activity during long tone-bursts may confer additional therapeutic effects. PMID:26603628

In vivo evaluation of drug delivery after ultrasound application: A new use for the photoacoustic technique

NASA Astrophysics Data System (ADS)

Barja, P. R.; Acosta-Avalos, D.; Rompe, P. C. B.; Dos Anjos, F. H.; Marciano, F. R.; da Silva, M. D.

2005-06-01

Ultrasound application is a therapeutical resource widely employed in physiotherapy. One of its applications is the phonophoresis, a technique in which the ultrasound radiation is utilized to deliver drugs through the skin to soft tissues. The proposal of our study was to employ the Photoacoustic Technique to evaluate the efficacy of such treatment, analyzing if phonophoresis could enhance drug delivery through skin when compared to the more traditional method of manual massage. The configuration of the system employed was such that it was possible to perform in vivo measurements, which is a pre-requisite for this kind of study. The changes observed in the photoacoustic signal amplitude after each form of drug application were attributed to changes in the thermal effusivity of the system, due to penetration of the drug. The technique was able to detect differences in drug delivery between the specified physiotherapy treatments, indicating that phonophoresis enhances drug absorption by tissue.

Drug Release from Phase-Changeable Nanodroplets Triggered by Low-Intensity Focused Ultrasound

PubMed Central

Cao, Yang; Chen, Yuli; Yu, Tao; Guo, Yuan; Liu, Fengqiu; Yao, Yuanzhi; Li, Pan; Wang, Dong; Wang, Zhigang; Chen, Yu; Ran, Haitao

2018-01-01

Background: As one of the most effective triggers with high tissue-penetrating capability and non-invasive feature, ultrasound shows great potential for controlling the drug release and enhancing the chemotherapeutic efficacy. In this study, we report, for the first time, construction of a phase-changeable drug-delivery nanosystem with programmable low-intensity focused ultrasound (LIFU) that could trigger drug-release and significantly enhance anticancer drug delivery. Methods: Liquid-gas phase-changeable perfluorocarbon (perfluoropentane) and an anticancer drug (doxorubicin) were simultaneously encapsulated in two kinds of nanodroplets. By triggering LIFU, the nanodroplets could be converted into microbubbles locally in tumor tissues for acoustic imaging and the loaded anticancer drug (doxorubicin) was released after the microbubble collapse. Based on the acoustic property of shell materials, such as shell stiffness, two types of nanodroplets (lipid-based nanodroplets and PLGA-based nanodroplets) were activated by different acoustic pressure levels. Ultrasound irradiation duration and power of LIFU were tested and selected to monitor and control the drug release from nanodroplets. Various ultrasound energies were introduced to induce the phase transition and microbubble collapse of nanodroplets in vitro (3 W/3 min for lipid nanodroplets; 8 W/3 min for PLGA nanodroplets). Results: We detected three steps in the drug-releasing profiles exhibiting the programmable patterns. Importantly, the intratumoral accumulation and distribution of the drug with LIFU exposure were significantly enhanced, and tumor proliferation was substantially inhibited. Co-delivery of two drug-loaded nanodroplets could overcome the physical barriers of tumor tissues during chemotherapy. Conclusion: Our study provides a new strategy for the efficient ultrasound-triggered chemotherapy by nanocarriers with programmable LIFU capable of achieving the on-demand drug release. PMID:29507623

Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer

PubMed Central

Papademetriou, Iason T; Porter, Tyrone

2015-01-01

Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood–brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future. PMID:26488496

Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer.

PubMed

Papademetriou, Iason T; Porter, Tyrone

2015-01-01

Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood-brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future.

Transdermal drug delivery

PubMed Central

Prausnitz, Mark R.; Langer, Robert

2009-01-01

Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin’s barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase impact on medicine. PMID:18997767

Bypassing multidrug resistant ovarian cancer using ultrasound responsive doxorubicin/curcumin co-deliver alginate nanodroplets.

PubMed

Baghbani, Fatemeh; Moztarzadeh, Fathollah

2017-05-01

Ultrasound-responsive perfluorocarbon nanoemulsions are a class of new multifunctional smart nanocarriers which combine diagnostic properties with therapeutic properties and release their drug payload in a controlled manner in response to ultrasound. Therefore, combination therapy using chemotherapeutic and chemosensitizing agents co-entrapped in these nanocarriers seems beneficial for cancer treatment. In the present study, multifunctional smart alginate/perfluorohexane nanodroplets were developed for co-delivery of doxorubicin and curcumin (a strong chemosensitizer). The nanodroplets with the average particle size of 55.1nm were synthesized via nanoemulsion process. The entrapment efficiency of doxorubicin was 92.3%. To improve curcumin entrapment into the alginate shell, Span 60 was added to the formulation as a co-surfactant and finally curcumin entrapment of about 40% was achieved. Ultrasound-mediated drug release kinetic was evaluated at two different frequencies of 28kHz (low frequency) and 1MHz (high frequency). Low frequency ultrasound resulted in higher triggered drug release from nanodroplets. The nanodroplets showed strong ultrasound contrast via droplet to bubble transition as confirmed via B-mode ultrasound imaging. Enhanced cytotoxicity in adriamycin-resistant A2780 ovarian cancer cells was observed for Dox-Cur-NDs compared to Dox-NDs because of the synergistic effects of doxorubicin and curcumin. However, ultrasound irradiation significantly increased the cytotoxicity of Dox-Cur-NDs. Finally, in vivo ovarian cancer treatment using Dox/Cur-NDs combined with ultrasound irradiation resulted in efficient tumor regression. According to the present study, nanotherapy of multidrug resistant human ovarian cancer using ultrasound responsive doxorubicin/curcumin co-loaded alginate-shelled nanodroplets combined with ultrasound irradiation could be a promising modality for the future of cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Novel delivery approaches for cancer therapeutics.

PubMed

Mitra, Ashim K; Agrahari, Vibhuti; Mandal, Abhirup; Cholkar, Kishore; Natarajan, Chandramouli; Shah, Sujay; Joseph, Mary; Trinh, Hoang M; Vaishya, Ravi; Yang, Xiaoyan; Hao, Yi; Khurana, Varun; Pal, Dhananjay

2015-12-10

Currently, a majority of cancer treatment strategies are based on the removal of tumor mass mainly by surgery. Chemical and physical treatments such as chemo- and radiotherapies have also made a major contribution in inhibiting rapid growth of malignant cells. Furthermore, these approaches are often combined to enhance therapeutic indices. It is widely known that surgery, chemo- and radiotherapy also inhibit normal cells growth. In addition, these treatment modalities are associated with severe side effects and high toxicity which in turn lead to low quality of life. This review encompasses novel strategies for more effective chemotherapeutic delivery aiming to generate better prognosis. Currently, cancer treatment is a highly dynamic field and significant advances are being made in the development of novel cancer treatment strategies. In contrast to conventional cancer therapeutics, novel approaches such as ligand or receptor based targeting, triggered release, intracellular drug targeting, gene delivery, cancer stem cell therapy, magnetic drug targeting and ultrasound-mediated drug delivery, have added new modalities for cancer treatment. These approaches have led to selective detection of malignant cells leading to their eradication with minimal side effects. Lowering multi-drug resistance and involving influx transportation in targeted drug delivery to cancer cells can also contribute significantly in the therapeutic interventions in cancer. Copyright © 2015 Elsevier B.V. All rights reserved.

Ultrasound mediates the release of curcumin from microemulsions.

PubMed

Lee, Mei-Hwa; Lin, Hung-Yin; Chen, Hsu-Chih; Thomas, James L

2008-03-04

Ultrasound is a powerful noninvasive modality for biomedical imaging, and holds much promise for noninvasive drug delivery enhancement and targeting. However, the optimal design of sound sensitive carriers is still poorly understood. In this study, curcumin, an important natural antioxidant and anticancer compound, was stably entrapped into microemulsion droplets with average size 20-35 nm. To release curcumin, low frequency (40 kHz) ultrasound at an intensity of 3.8 or 9.8 W/cm2 was applied to the microemulsions, using a probe sonicator. On insonation, much of the curcumin was released from the microemulsions and formed insoluble aggregates, as evidenced by decreased UV-vis absorption at 420 nm. The initial release rate (assayed by the rate of change of absorption) was as high as 0.11 microg/s (1.87%/sec) in phosphate buffered saline solution at neutral pH, but decreased at acidic pH. Interestingly, lower curcumin loading led to a more rapid release under insonation. Measurements of emulsion droplet size implicate droplet reorganization (fusion or fission) as an important contributing mechanism for the ultrasonic release of this compound. Although cargo in microemulsions is partitioned, rather than encapsulated (as in, for example, liposomes), these new results demonstrate that microemulsion carriers are feasible for some ultrasonic drug delivery applications.

A novel technology using transscleral ultrasound to deliver protein loaded nanoparticles.

PubMed

Huang, Di; Wang, Lili; Dong, Yixuan; Pan, Xin; Li, Ge; Wu, Chuanbin

2014-09-01

This study was designed to investigate the feasibility of silk fibroin nanoparticles (SFNs) for sustained drug delivery in transscleral ultrasound. Fluorescein isothiocynate labeled bovine serum albumin (FITC-BSA, MW 66.45 kDa) was chosen as a model macromolecular protein drug and SFNs were used as nano-carrier systems suitable for ocular drug delivery. Drug loaded nanoparticles (FITC-BSA-SFNs) were first prepared and characterized. In vitro transscleral study under ultrasound exposure (1MHz, 0.5 W/cm(2), 5 min continuous wave) using isolated sclera of rabbit was performed. The posterior eye segment of rabbit was examined for adverse effect by slit-lamp and histology. It was found that FITC-BSA-SFNs possessed sustained release, bioadhesive, and co-permeation characteristics. The ultrasound application significantly improved the penetration efficiency of FITC-BSA-SFNs as compared with passive delivery, meanwhile caused no damages to the ocular tissue and particles themselves. The distribution profile of SFNs revealed rapid and lasting adhesion on the outer scleral tissues, followed by migration into the interior up to one week after treatment. This research suggested a novel non-invasive transscleral administration of macromolecular protein drugs using SFN carriers combining with ultrasound technology. Copyright © 2014 Elsevier B.V. All rights reserved.

Time-reversal acoustics and ultrasound-assisted convection-enhanced drug delivery to the brain.

PubMed

Olbricht, William; Sistla, Manjari; Ghandi, Gaurav; Lewis, George; Sarvazyan, Armen

2013-08-01

Time-reversal acoustics is an effective way of focusing ultrasound deep inside heterogeneous media such as biological tissues. Convection-enhanced delivery is a method of delivering drugs into the brain by infusing them directly into the brain interstitium. These two technologies are combined in a focusing system that uses a "smart needle" to simultaneously infuse fluid into the brain and provide the necessary feedback for focusing ultrasound using time-reversal acoustics. The effects of time-reversal acoustics-focused ultrasound on the spatial distribution of infused low- and high-molecular weight tracer molecules are examined in live, anesthetized rats. Results show that exposing the rat brain to focused ultrasound significantly increases the penetration of infused compounds into the brain. The addition of stabilized microbubbles enhances the effect of ultrasound exposure.

Enhanced cytotoxic effect of cisplatin using diagnostic ultrasound and microbubbles in vitro

NASA Astrophysics Data System (ADS)

Sasaki, Noboru; Nakamura, Kensuke; Murakami, Masahiro; Lim, Sue Yee; Ohta, Hiroshi; Yamasaki, Masahiro; Takiguchi, Mitsuyoshi

2012-10-01

Diagnostic ultrasound has accomplished drug and gene delivery by ultrasound targeted microbubble destruction (UTMD). However, the efficacy of delivery is still relatively low. Therefore, we optimized conditions of UTMD using diagnostic ultrasound and ultrasound contrast agent microbubbles. Canine thyroid adenocarcinoma cells were cultured in a 96-well plate. After addition of cisplatin and Sonazoid®, the plate was inverted to raise microbubbles near cells and incubated. Cells were exposed to diagnostic ultrasound using a linear probe operated in the contrast harmonic imaging mode. The center frequency was 2.5 MHz with a mechanical index of 1.33 and a frame rate of 48 frames/sec. Cytotoxic effect of cisplatin was evaluated 24h after exposure using trypan blue dye exclusion test. We optimized incubation duration, cisplatin concentration, and the relationship between microbubble concentration and exposure duration. The optimum enhancement was observed at incubation duration of 5min, cisplatin concentration of 1 μg/ml, and microbubble concentration of 2.4 × 105 microbubbles/ml. Exposure duration did not influence the enhancement at the microbubble concentration of 2.4 × 105 microbubbles/ml. Our results suggest that relative low concentrations of drug and microbubbles with short exposure duration might be sufficient for drug delivery by UTMD using diagnostic ultrasound.

Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging.

PubMed

Theek, Benjamin; Gremse, Felix; Kunjachan, Sijumon; Fokong, Stanley; Pola, Robert; Pechar, Michal; Deckers, Roel; Storm, Gert; Ehling, Josef; Kiessling, Fabian; Lammers, Twan

2014-05-28

The Enhanced Permeability and Retention (EPR) effect is extensively used in drug delivery research. Taking into account that EPR is a highly variable phenomenon, we have here set out to evaluate if contrast-enhanced functional ultrasound (ceUS) imaging can be employed to characterize EPR-mediated passive drug targeting to tumors. Using standard fluorescence molecular tomography (FMT) and two different protocols for hybrid computed tomography-fluorescence molecular tomography (CT-FMT), the tumor accumulation of a ~10 nm-sized near-infrared-fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) was evaluated in CT26 tumor-bearing mice. In the same set of animals, two different ceUS techniques (2D MIOT and 3D B-mode imaging) were employed to assess tumor vascularization. Subsequently, the degree of tumor vascularization was correlated with the degree of EPR-mediated drug targeting. Depending on the optical imaging protocol used, the tumor accumulation of the polymeric drug carrier ranged from 5 to 12% of the injected dose. The degree of tumor vascularization, determined using ceUS, varied from 4 to 11%. For both hybrid CT-FMT protocols, a good correlation between the degree of tumor vascularization and the degree of tumor accumulation was observed, within the case of reconstructed CT-FMT, correlation coefficients of ~0.8 and p-values of <0.02. These findings indicate that ceUS can be used to characterize and predict EPR, and potentially also to pre-select patients likely to respond to passively tumor-targeted nanomedicine treatments. Copyright © 2014 Elsevier B.V. All rights reserved.

In vivo monitoring of liposomal release in tumours following ultrasound stimulation.

PubMed

Evjen, Tove J; Hagtvet, Eirik; Moussatov, Alexei; Røgnvaldsson, Sibylla; Mestas, Jean-Louis; Fowler, R Andrew; Lafon, Cyril; Nilssen, Esben A

2013-08-01

Dioeleoylphosphatidylethanolamine (DOPE)-based liposomes were recently reported as a new class of liposomes for ultrasound (US)-mediated drug delivery. The liposomes showed both high stability and in vitro US-mediated drug release (sonosensitivity). In the current study, in vivo proof-of-principle of US triggered release in tumoured mice was demonstrated using optical imaging. Confocal non-thermal US was used to deliver cavitation to tumours in a well-controlled manner. To detect in vivo release, the near infrared fluorochrome Al (III) Phthalocyanine Chloride Tetrasulphonic acid (AlPcS₄) was encapsulated into both DOPE-based liposomes and control liposomes based on hydrogenated soy phosphatidylcholine (HSPC). Encapsulation causes concentration dependent quenching of fluorescence that is recovered upon AlPcS₄ release from the liposomes. Exposure of tumours to US resulted in a significant increase in fluorescence in mice administered with DOPE-based liposomes, but no change in the mice treated with HSPC-based liposomes. Thus, DOPE-based liposomes showed superior sonosensitivity compared to HSPC-based liposomes in vivo. Copyright © 2012 Elsevier B.V. All rights reserved.

Characterizing Focused-Ultrasound Mediated Drug Delivery to the Heterogeneous Primate Brain In Vivo with Acoustic Monitoring

NASA Astrophysics Data System (ADS)

Wu, Shih-Ying; Sanchez, Carlos Sierra; Samiotaki, Gesthimani; Buch, Amanda; Ferrera, Vincent P.; Konofagou, Elisa E.

2016-11-01

Focused ultrasound with microbubbles has been used to noninvasively and selectively deliver pharmacological agents across the blood-brain barrier (BBB) for treating brain diseases. Acoustic cavitation monitoring could serve as an on-line tool to assess and control the treatment. While it demonstrated a strong correlation in small animals, its translation to primates remains in question due to the anatomically different and highly heterogeneous brain structures with gray and white matteras well as dense vasculature. In addition, the drug delivery efficiency and the BBB opening volume have never been shown to be predictable through cavitation monitoring in primates. This study aimed at determining how cavitation activity is correlated with the amount and concentration of gadolinium delivered through the BBB and its associated delivery efficiency as well as the BBB opening volume in non-human primates. Another important finding entails the effect of heterogeneous brain anatomy and vasculature of a primate brain, i.e., presence of large cerebral vessels, gray and white matter that will also affect the cavitation activity associated with variation of BBB opening in different tissue types, which is not typically observed in small animals. Both these new findings are critical in the primate brain and provide essential information for clinical applications.

Characterizing Focused-Ultrasound Mediated Drug Delivery to the Heterogeneous Primate Brain In Vivo with Acoustic Monitoring

PubMed Central

Wu, Shih-Ying; Sanchez, Carlos Sierra; Samiotaki, Gesthimani; Buch, Amanda; Ferrera, Vincent P.; Konofagou, Elisa E.

2016-01-01

Focused ultrasound with microbubbles has been used to noninvasively and selectively deliver pharmacological agents across the blood-brain barrier (BBB) for treating brain diseases. Acoustic cavitation monitoring could serve as an on-line tool to assess and control the treatment. While it demonstrated a strong correlation in small animals, its translation to primates remains in question due to the anatomically different and highly heterogeneous brain structures with gray and white matteras well as dense vasculature. In addition, the drug delivery efficiency and the BBB opening volume have never been shown to be predictable through cavitation monitoring in primates. This study aimed at determining how cavitation activity is correlated with the amount and concentration of gadolinium delivered through the BBB and its associated delivery efficiency as well as the BBB opening volume in non-human primates. Another important finding entails the effect of heterogeneous brain anatomy and vasculature of a primate brain, i.e., presence of large cerebral vessels, gray and white matter that will also affect the cavitation activity associated with variation of BBB opening in different tissue types, which is not typically observed in small animals. Both these new findings are critical in the primate brain and provide essential information for clinical applications. PMID:27853267

Dose comparison of ultrasonic transdermal insulin delivery to subcutaneous insulin injection

NASA Astrophysics Data System (ADS)

Park, Eun-Joo; Dodds, Jeff; Barrie Smith, Nadine

2010-03-01

Prior studies have demonstrated the effectiveness of noninvasive transdermal insulin delivery using a cymbal transducer array. In this study the physiologic response to ultrasound mediated transdermal insulin delivery is compared to that of subcutaneously administered insulin. Anesthetized rats (350-550 g) were divided into four groups of four animals; one group representing ultrasound mediated insulin delivery and three representing subcutaneously administered insulin (0.15, 0.20, and 0.25 U/kg). The cymbal array was operated for 60 minutes at 20 kHz with 100 mW/cm2 spatial-peak temporal-peak intensity and a 20% duty cycle. The blood glucose level was determined at the beginning of the experiment and, following insulin administration, every 15 minutes for 90 minutes for both the ultrasound and injection groups. The change in blood glucose from baseline was compared between groups. When administered by subcutaneous injection at insulin doses of 0.15 and 0.20 U/kg, there was little change in the blood glucose levels over the 90 minute experiment. Following subcutaneous administration of insulin at a dose of 0.25 U/kg, blood glucose decreased by 190±96 mg/dl (mean±SD) at 90 minutes. The change in blood glucose following ultrasound mediated insulin delivery was -262±40 mg/dl at 90 minutes. As expected, the magnitude of change in blood glucose between the three injection groups was dependant on the dose of insulin administered. The change in blood glucose in the ultrasound group was greater than that observed in the injection groups suggesting that a higher effective dose of insulin was delivered.

Time-reversal Techniques in Ultrasound-assisted Convection-enhanced Drug Delivery to the Brain: Technology Development and In Vivo Evaluation

PubMed Central

Lewis, George K.; Guarino, Sabrina; Gandhi, Gaurav; Filinger, Laurent; Lewis, George K.; Olbricht, Willam L.; Sarvazyan, Armen

2011-01-01

We describe a drug delivery method that combines Time-Reversal Acoustics (TRA) with Convection-Enhanced Delivery (CED) to improve the delivery of therapeutics to the interstitium of the brain. The Ultrasound-assisted CED approach (UCED) circumvents the blood-brain barrier by infusing compounds through a cannula that is inserted into the brain while simultaneously delivering ultrasound to improve the penetration of pharmaceuticals. CED without ultrasound-assistance has been used to treat a variety of neural disorders, including glioblastoma multiforme, a malignancy that presents a very poor prognosis for patients. We describe a novel system that is used to infuse fluids into the brain parenchyma while simultaneously exposing the tissue to safe levels of 1-MHz, low intensity, ultrasound energy. The system includes a combined infusion needle-hydrophone, a 10-channel ultralow-output impedance amplifier, a broad-band ultrasound resonator, and MatLab®-based TRA control and user-interface. TRA allows easy coupling of ultrasound therapy through the skull without complex phase-correction and array design. The smart targeting UCED system has been tested in vivo and results show it provides 1.5-mm spatial resolution for UCED and improves tracer distribution in the brain over CED alone. PMID:21881622

Ultrasound beam steering of oxygen nanobubbles for enhanced bladder cancer therapy.

PubMed

Bhandari, Pushpak; Novikova, Gloriia; Goergen, Craig J; Irudayaraj, Joseph

2018-02-15

New intravesical treatment approaches for bladder cancer are needed as currently approved treatments show several side effects and high tumor recurrence rate. Our study used MB49 murine urothelial carcinoma model to evaluate oxygen encapsulated cellulosic nanobubbles as a novel agent for imaging and ultrasound guided drug delivery. In this study, we show that oxygen nanobubbles (ONB) can be propelled (up to 40 mm/s) and precisely guided in vivo to the tumor by an ultrasound beam. Nanobubble velocity can be controlled by altering the power of the ultrasound Doppler beam, while nanobubble direction can be adjusted to different desired angles by altering the angle of the beam. Precise ultrasound beam steering of oxygen nanobubbles was shown to enhance the efficacy of mitomycin-C, resulting in significantly lower tumor progression rates while using a 50% lower concentration of chemotherapeutic drug. Further, dark field imaging was utilized to visualize and quantify the ONB ex vivo. ONBs were found to localize up to 500 µm inside the tumor using beam steering. These results demonstrate the potential of an oxygen nanobubble drug encapsulated system to become a promising strategy for targeted drug delivery because of its multimodal (imaging and oxygen delivery) and multifunctional (targeting and hypoxia programming) properties.

Time-reversal acoustics and ultrasound-assisted convection-enhanced drug delivery to the brain

PubMed Central

Olbricht, William; Sistla, Manjari; Ghandi, Gaurav; Lewis, George; Sarvazyan, Armen

2013-01-01

Time-reversal acoustics is an effective way of focusing ultrasound deep inside heterogeneous media such as biological tissues. Convection-enhanced delivery is a method of delivering drugs into the brain by infusing them directly into the brain interstitium. These two technologies are combined in a focusing system that uses a “smart needle” to simultaneously infuse fluid into the brain and provide the necessary feedback for focusing ultrasound using time-reversal acoustics. The effects of time-reversal acoustics-focused ultrasound on the spatial distribution of infused low- and high-molecular weight tracer molecules are examined in live, anesthetized rats. Results show that exposing the rat brain to focused ultrasound significantly increases the penetration of infused compounds into the brain. The addition of stabilized microbubbles enhances the effect of ultrasound exposure. PMID:23927197

Efficacy of Combined Ultrasound-and-Microbubbles-Mediated Diclofenac Gel Delivery to Enhance Transdermal Permeation in Adjuvant-Induced Rheumatoid Arthritis in the Rat.

PubMed

Liao, Ai-Ho; Chung, Huan-Yu; Chen, Wen-Shiang; Yeh, Ming-Kung

2016-08-01

A previous study that investigated the effect of ultrasound (US) on the transdermal permeation of the non-steroidal anti-inflammatory drug diclofenac found that therapeutic US can increase circulation in an inflamed joint and decrease arthritic pain. Transdermal drug delivery has recently been demonstrated by US combined with microbubbles (MB) contrast agent (henceforth referred to as "US-MB"). The present study evaluated the efficacy of US-MB-mediated diclofenac delivery for treating adjuvant-induced rheumatoid arthritis (RA) in rats. RA was induced by injecting 100 μL of complete Freund's adjuvant into the ankle joint of male Sprague-Dawley rats (250-300 g) that were randomly divided into five treatment groups: (i) carbopol gel alone (the control [group C]), (ii) diclofenac-carbopol gel (group D), (iii) US plus carbopol gel (group U), (iv) US plus diclofenac-carbopol gel (group DU) and (v) US-MB plus diclofenac-carbopol gel (group DUB). The ankle width was measured over 10 d using high-frequency (40-MHz) US B-mode and color Doppler-mode imaging, covering the period before and after treatment. Longitudinal US images of the induced RA showed synovitis and neovascularity. Only a small amount of neovascularity was observed after treatment. The recovery rate on day 10 was significantly higher in group DUB (97.7% ± 2.7%, mean ± standard deviation [SD]) than in groups C (1.0% ± 2.7%), D (37.5% ± 4.6%), U (75.5% ± 4.2%) and DU (87.3% ± 5.2%) (p < 0.05). The results obtained indicate that combining US and MB can increase the skin permeability and thereby enhance the delivery of diclofenac sodium gel and thereby inhibit inflammation of the tissues surrounding the arthritic ankle. Color Doppler-mode imaging revealed that US-MB treatment induced a rapid reduction in synovial neoangiogenesis in the arthritic area. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Nanostructured ultra-thin patches for ultrasound-modulated delivery of anti-restenotic drug

PubMed Central

Vannozzi, Lorenzo; Ricotti, Leonardo; Filippeschi, Carlo; Sartini, Stefania; Coviello, Vito; Piazza, Vincenzo; Pingue, Pasqualantonio; La Motta, Concettina; Dario, Paolo; Menciassi, Arianna

2016-01-01

This work aims to demonstrate the possibility to fabricate ultra-thin polymeric films loaded with an anti-restenotic drug and capable of tunable drug release kinetics for the local treatment of restenosis. Vascular nanopatches are composed of a poly(lactic acid) supporting membrane (thickness: ~250 nm) on which 20 polyelectrolyte bilayers (overall thickness: ~70 nm) are alternatively deposited. The anti-restenotic drug is embedded in the middle of the polyelectrolyte structure, and released by diffusion mechanisms. Nanofilm fabrication procedure and detailed morphological characterization are reported here. Barium titanate nanoparticles (showing piezoelectric properties) are included in the polymeric support and their role is investigated in terms of influence on nanofilm morphology, drug release kinetics, and cell response. Results show an efficient drug release from the polyelectrolyte structure in phosphate-buffered saline, and a clear antiproliferative effect on human smooth muscle cells, which are responsible for restenosis. In addition, preliminary evidences of ultrasound-mediated modulation of drug release kinetics are reported, thus evaluating the influence of barium titanate nanoparticles on the release mechanism. Such data were integrated with quantitative piezoelectric and thermal measurements. These results open new avenues for a fine control of local therapies based on smart responsive materials. PMID:26730191

Drug delivery monitoring by photoacoustic tomography with an ICG encapsulated double emulsion

NASA Astrophysics Data System (ADS)

Wang, Xueding; Rajian, Justin R.; Fabiilli, Mario L.; Fowlkes, J. Brian; Carson, Paul L.

2012-02-01

We successfully encapsulated ICG in an ultrasound-triggerable perfluorocarbon double emulsion that prevents ICG from binding with plasma proteins. Photoacoustic spectral measurements on point target as well as 2-D photoacoustic images of blood vessels revealed that the photoacoustic spectrum changes significantly in blood when the ICG-loaded emulsion undergoes acoustic droplet vaporization (ADV), which is the conversion of liquid droplets into gas bubbles using ultrasound. Other than providing a new photoacoustic contrast agent, the ICG encapsulated double emulsion, when imaged with photoacoustic tomography, could facilitate spatial and quantitative monitoring of ultrasound initiated drug delivery.

Magnetic nanobubbles with potential for targeted drug delivery and trimodal imaging in breast cancer: an in vitro study.

PubMed

Song, Weixiang; Luo, Yindeng; Zhao, Yajing; Liu, Xinjie; Zhao, Jiannong; Luo, Jie; Zhang, Qunxia; Ran, Haitao; Wang, Zhigang; Guo, Dajing

2017-05-01

The aim of this study was to improve tumor-targeted therapy for breast cancer by designing magnetic nanobubbles with the potential for targeted drug delivery and multimodal imaging. Herceptin-decorated and ultrasmall superparamagnetic iron oxide (USPIO)/paclitaxel (PTX)-embedded nanobubbles (PTX-USPIO-HER-NBs) were manufactured by combining a modified double-emulsion evaporation process with carbodiimide technique. PTX-USPIO-HER-NBs were examined for characterization, specific cell-targeting ability and multimodal imaging. PTX-USPIO-HER-NBs exhibited excellent entrapment efficiency of Herceptin/PTX/USPIO and showed greater cytotoxic effects than other delivery platforms. Low-frequency ultrasound triggered accelerated PTX release. Moreover, the magnetic nanobubbles were able to enhance ultrasound, magnetic resonance and photoacoustics trimodal imaging. These results suggest that PTX-USPIO-HER-NBs have potential as a multimodal contrast agent and as a system for ultrasound-triggered drug release in breast cancer.

Facilitation of Drug Transport across the Blood-Brain Barrier with Ultrasound and Microbubbles.

PubMed

Meairs, Stephen

2015-08-31

Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood-brain barrier (BBB). Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This technique offers a unique non-invasive avenue to deliver a wide range of drugs to the brain and promises to provide treatments for CNS disorders with the advantage of being able to target specific brain regions without unnecessary drug exposure. If this method could be applied for a range of different drugs, new CNS therapeutic strategies could emerge at an accelerated pace that is not currently possible in the field of drug discovery and development. This article reviews both the merits and potential risks of this new approach. It assesses methods used to verify disruption of the BBB with MRI and examines the results of studies aimed at elucidating the mechanisms of opening the BBB with ultrasound and microbubbles. Possible interactions of this novel delivery method with brain disease, as well as safety aspects of BBB disruption with ultrasound and microbubbles are addressed. Initial translational research for treatment of brain tumors and Alzheimer's disease is presented.

Randomized, Double-Blind, Split-Face Study Evaluating Fractional Ablative Erbium:YAG Laser-Mediated Trans-Epidermal Delivery of Cosmetic Actives and a Novel Acoustic Pressure Wave Ultrasound Technology for the Treatment of Skin Aging, Melasma, and Acne Scars.

PubMed

Alexiades, Macrene

2015-11-01

Fractional laser resurfacing enhances trans-epidermal delivery (TED), however laser penetration depths >250- μm fail to substantively increase drug delivery. Evaluate the safety and efficacy of a novel acoustic pressure wave ultrasound device following fractional ablative Er:YAG 2940-nm laser (FELR) and topical agents for rhytids, melasma, and acne scars. Randomized, blinded, parallel group split-face side-by-side, controlled study evaluating FELR and topical anti-aging and anti-pigment agents to entire face succeeded by ultrasound to randomized side. Fifteen subjects were enrolled to three treatment arms:rhytids, melasma, and acne scars. Two monthly treatments were administered with 1, 3, and 6 month follow-up. Efficacy was assessed by Comprehensive Grading Scale of Rhytids, Laxity, and Photoaging by Investigator and two blinded physician evaluators. Subject assessments, digital photographs, and reflectance spectroscopic analyses were obtained. Rhytid severity was reduced from a mean of 3.25 to 2.60 on the 4-point grading scale. Spectrophotometric analysis demonstrated increases in lightness (L*) and reductions in redness (a*) and pigment (b*), with greater improvements on the ultrasound side as compared to FELR and topicals alone. Moderate erythema post-treatment resolved in 7 days and no serious adverse events were observed. In this randomized, paired split-face clinical study, FELR-facilitated TED of topical anti-aging actives with ultrasound treatment is safe and effective with improvement in rhytids, melasma, and acne scars. Statistically significant greater improvement in pigment levels was observed on the ultrasound side as compared to FELR-TED and topical agents alone.

Ultrasound-mediated oxygen delivery from chitosan nanobubbles.

PubMed

Cavalli, Roberta; Bisazza, Agnese; Rolfo, Alessandro; Balbis, Sonia; Madonnaripa, Daniele; Caniggia, Isabella; Guiot, Caterina

2009-08-13

Ultrasound (US) energy combined with gas-filled microbubbles has been used for several years in medical imaging. This study investigated the ability of oxygen-loaded chitosan bubbles to exchange oxygen in the presence or in the absence of US. Oxygen delivery is enhanced by sonication and both frequency and time duration of US affected the exchange kinetics.

Therapeutic Ultrasound Enhancement of Drug Delivery to Soft Tissues

NASA Astrophysics Data System (ADS)

Lewis, George; Wang, Peng; Lewis, George; Olbricht, William

2009-04-01

Effects of exposure to 1.58 MHz focused ultrasound on transport of Evans Blue Dye (EBD) in soft tissues are investigated when an external pressure gradient is applied to induce convective flow through the tissue. The magnitude of the external pressure gradient is chosen to simulate conditions in brain parenchyma during convection-enhanced drug delivery (CED) to the brain. EBD uptake and transport are measured in equine brain, avian muscle and agarose brain-mimicking phantoms. Results show that ultrasound enhances EBD uptake and transport, and the greatest enhancement occurs when the external pressure gradient is applied. The results suggest that exposure of the brain parenchyma to ultrasound could enhance penetration of material infused into the brain during CED therapy.

Ultrasound-enhanced localized chemotherapy of drug-sensitive and multidrug resistant tumors

NASA Astrophysics Data System (ADS)

Rapoport, Natalya Y.; Gao, Zhonggao; Kamaev, Pavel; Christensen, Douglas A.

2006-05-01

A new modality of targeted tumor chemotherapy is based on the drug encapsulation in polymeric nanoparticles followed by a localized release at the tumor site triggered by focused ultrasound. Effect of 1 MHz and 3 MHz unfocused ultrasound applied locally to the tumor on the Doxorubicin (DOX) biodistribution and tumor growth rates was measured for ovarian carcinoma tumors in nu/nu mice. The bioeffects of ultrasound were investigated on the systemic and cellular levels. Growth rates of A2780 ovarian carcinoma tumors were substantially reduced by combining micellar drug delivery with tumor irradiation. Ultrasound effect was not thermal as manifested by intratumoral temperature measurements during sonication. Biodistribution studies showed that ultrasound did not enhance micelle extravasation. Main mechanisms of the ultrasound-enhanced chemotherapy included (i) passive targeting of drug-loaded micelles to the tumor interstitium; (ii) ultrasound-triggered localized drug release from micelles in the tumor volume; (iii) enhanced micelle and drug diffusion through the tumor interstitium; and (iv) ultrasound-triggered cell membrane damage resulting in the enhanced micelle and drug uptake by tumor cells.

Advances in ultrasound-targeted microbubble-mediated gene therapy for liver fibrosis.

PubMed

Huang, Cuiyuan; Zhang, Hong; Bai, Ruidan

2017-07-01

Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix (ECM) and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications. However, fibrosis can be reversed before developing into cirrhosis and has thus been the subject of extensive researches particularly at the gene level. Currently, therapeutic genes are imported into the damaged liver to delay or prevent the development of liver fibrosis by regulating the expression of exogenous genes. One technique of gene delivery uses ultrasound targeting of microbubbles combined with therapeutic genes where the time and intensity of the ultrasound can control the release process. Ultrasound irradiation of microbubbles in the vicinity of cells changes the permeability of the cell membrane by its cavitation effect and enhances gene transfection. In this paper, recent progress in the field is reviewed with emphasis on the following aspects: the types of ultrasound microbubbles, the construction of an ultrasound-mediated gene delivery system, the mechanism of ultrasound microbubble-mediated gene transfer and the application of ultrasound microbubbles in the treatment of liver fibrosis.

Cell-penetrating peptide-doxorubicin conjugate loaded NGR-modified nanobubbles for ultrasound triggered drug delivery.

PubMed

Lin, Wen; Xie, Xiangyang; Deng, Jianping; Liu, Hui; Chen, Ying; Fu, Xudong; Liu, Hong; Yang, Yang

2016-01-01

A new drug-targeting system for CD13(+) tumors has been developed, based on ultrasound-sensitive nanobubbles (NBs) and cell-permeable peptides (CPPs). Here, the CPP-doxorubicin conjugate (CPP-DOX) was entrapped in the asparagine-glycine-arginine (NGR) peptide modified NB (CPP-DOX/NGR-NB) and the penetration of CPP-DOX was temporally masked; local ultrasound stimulation could trigger the CPP-DOX release from NB and activate its penetration. The CPP-DOX/NGR-NBs had particle sizes of about 200 nm and drug entrapment efficiency larger than 90%. In vitro release results showed that over 85% of the encapsulated DOX or CPP-DOX would release from NBs in the presence of ultrasound, while less than 1.5% of that (30 min) without ultrasound. Cell experiments showed the higher cellular CPP-DOX uptake of CPP-DOX/NGR-NB among the various NB formulations in Human fibrosarcoma cells (HT-1080, CD13(+)). The CPP-DOX/NGR-NB with ultrasound treatment exhibited an increased cytotoxic activity than the one without ultrasound. In nude mice xenograft of HT-1080 cells, CPP-DOX/NGR-NB with ultrasound showed a higher tumor inhibition effect (3.1% of T/C%, day 24), longer median survival time (50 days) and excellent body safety compared with the normal DOX injection group. These results indicate that the constructed vesicle would be a promising drug delivery system for specific cancer treatment.

[Novel dianostics and therapeutics with ultrasound technologies and nanotechnologies].

PubMed

Suzuki, Ryo; Oda, Yusuke; Omata, Daiki; Sawaguchi, Yoshikazu; Negishi, Yoichi; Maruyama, Kazuo

2013-01-01

Ultrasound is a good tool for theranostics due to have multi-potency both of diagnostics with sonography and therapeutics with high intensity focused ultrasound (HIFU). In addition, microbubbles and nanobubbles are utilized as not only contrast imaging agent but also enhancer of drug and gene delivery by combination of ultrasound. Recently, we developed novel liposomal nanobubbles (Bubble liposomes) which were containing perfluoropropane. Bubble liposomes induced jet stream by low intensity ultrasound exposure and resulted in enhancing permeability of cell membrane. This phenomenon has been utilized as driving force for drug and gene delivery. On the other hand, the combination of Bubble liposomes and high intensity ultrasound induces strong jet stream and increase temperature. This condition can directly damage to tumor cells, we are applying this for cancer therapy. Therefore, their combination has potency for various cancer therapies such as gene therapy, immunotherapy and hyperthermia. In this review, we discuss about cancer therapy by the combination of Bubble liposomes and ultrasound.

Focused Ultrasound Hyperthermia Mediated Drug Delivery Using Thermosensitive Liposomes and Visualized With in vivo Two-Photon Microscopy.

PubMed

Santos, Marc A; Goertz, David E; Hynynen, Kullervo

2017-01-01

The future of nanomedicines in oncology requires leveraging more than just the passive drug accumulation in tumors through the enhanced permeability and retention effect. Promising results combining mild hyperthermia (HT) with lyso-thermosensitive liposomal doxorubicin (LTSL-DOX) has led to improved drug delivery and potent antitumor effects in pre-clinical studies. The ultimate patient benefit from these treatments can only be realized when robust methods of HT can be achieved clinically. One of the most promising methods of non-invasive HT is the use of focused ultrasound (FUS) with MRI thermometry for anatomical targeting and feedback. MRI-guided focused ultrasound (MRgFUS) is limited by respiratory motion and large blood vessel cooling. In order to translate exciting pre-clinical results to the clinic, novel heating approaches capable of overcoming the limitations on clinical MRgFUS+HT must be tested and evaluated on their ability to locally release drug from LTSL-DOX. Methods: In this work, a new system is described to integrate focused ultrasound (FUS) into a two-photon microscopy (2PM) setting to image the release of drug from LTSL-DOX in real-time during FUS+HT in vivo . A candidate scheme for overcoming the limitations of respiratory motion and large blood vessel cooling during MRgFUS+HT involves applying FUS+HT to 42°C in short ~30s bursts. The spatiotemporal drug release pattern from LTSL-DOX as a result is quantified using 2PM and compared against continuous (3.5min and 20min at 42°C) FUS+HT schemes and unheated controls. Results: It was observed for the first time in vivo that these short duration temperature elevations could produce substantial drug release from LTSL-DOX. Ten 30s bursts of FUS+HT was able to achieve almost half of the interstitial drug concentration as 20min of continuous FUS+HT. There was no significant difference between the intravascular area under the concentration-time curve for ten 30s bursts of FUS+HT and 3.5min of continuous FUS+HT. Conclusion: We have successfully combined 2PM with FUS+HT for imaging the release of DOX from LTSL-DOX in vivo in real-time, which will permit the investigation of FUS+HT heating schemes to improve drug delivery from LTSL-DOX. We have evaluated the ability to release DOX in short 30s FUS+HT bursts to 42°C as a method to overcome limitations on clinical MRgFUS+HT and have found that such exposures are capable of releasing measurable amounts of drug. Such an exposure has the potential to overcome limitations that hamper conventional MRgFUS+HT treatments in targets that are associated with substantial tissue motion.

Transcranial cavitation-mediated ultrasound therapy at sub-MHz frequency via temporal interference modulation

NASA Astrophysics Data System (ADS)

Sun, Tao; Sutton, Jonathan T.; Power, Chanikarn; Zhang, Yongzhi; Miller, Eric L.; McDannold, Nathan J.

2017-10-01

Sub-megahertz transmission is not usually adopted in pre-clinical small animal experiments for focused ultrasound (FUS) brain therapy due to the large focal size. However, low frequency FUS is vital for preclinical evaluations due to the frequency-dependence of cavitation behavior. To maximize clinical relevance, a dual-aperture FUS system was designed for low-frequency (274.3 kHz) cavitation-mediated FUS therapy. Combining two spherically curved transducers provides significantly improved focusing in the axial direction while yielding an interference pattern with strong side lobes, leading to inhomogeneously distributed cavitation activities. By operating the two transducers at slightly offset frequencies to modulate this interference pattern over the period of sonication, the acoustic energy was redistributed and resulted in a spatially homogenous treatment profile. Simulation and pressure field measurements in water were performed to assess the beam profiles. In addition, the system performance was demonstrated in vivo in rats via drug delivery through microbubble-mediated blood-brain barrier disruption. This design resulted in a homogenous treatment profile that was fully contained within the rat brain at a clinically relevant acoustic frequency.

Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

NASA Astrophysics Data System (ADS)

Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E.

2016-06-01

The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound.

PubMed

Bazan-Peregrino, Miriam; Rifai, Bassel; Carlisle, Robert C; Choi, James; Arvanitis, Costas D; Seymour, Leonard W; Coussios, Constantin C

2013-07-10

Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

Recent advances in ultrasound-triggered therapy.

PubMed

Yang, Chaopin; Li, Yue; Du, Meng; Chen, Zhiyi

2018-04-27

As a non-invasive and real-time diagnostic technique, ultrasound has provided a novel strategy for targeted treatment. With the rapid development of ultrasonic technique and ultrasound contrast agents (UCAs), spatiotemporally controllable application of ultrasound with or without UCAs makes it possible for site-specific delivery of therapeutic agents and targeted modulation with minimal side effects, which indicated a promising therapy in clinical use. This review will describe the main mechanism of targeted therapy induced by ultrasound briefly, then focus on the current application of ultrasound mediated targeted therapy in various fields including tumour, cardiovascular disease, central nervous system, skeletal muscle system diseases and stem cells therapy. In addition, ongoing challenges of ultrasound-mediated targeted therapy for further research and its clinical use are reviewed.

Multimodal targeted high relaxivity thermosensitive liposome for in vivo imaging

NASA Astrophysics Data System (ADS)

Kuijten, Maayke M. P.; Hannah Degeling, M.; Chen, John W.; Wojtkiewicz, Gregory; Waterman, Peter; Weissleder, Ralph; Azzi, Jamil; Nicolay, Klaas; Tannous, Bakhos A.

2015-11-01

Liposomes are spherical, self-closed structures formed by lipid bilayers that can encapsulate drugs and/or imaging agents in their hydrophilic core or within their membrane moiety, making them suitable delivery vehicles. We have synthesized a new liposome containing gadolinium-DOTA lipid bilayer, as a targeting multimodal molecular imaging agent for magnetic resonance and optical imaging. We showed that this liposome has a much higher molar relaxivities r1 and r2 compared to a more conventional liposome containing gadolinium-DTPA-BSA lipid. By incorporating both gadolinium and rhodamine in the lipid bilayer as well as biotin on its surface, we used this agent for multimodal imaging and targeting of tumors through the strong biotin-streptavidin interaction. Since this new liposome is thermosensitive, it can be used for ultrasound-mediated drug delivery at specific sites, such as tumors, and can be guided by magnetic resonance imaging.

Ultrasound-enhanced delivery of targeted echogenic liposomes in a novel ex vivo mouse aorta model.

PubMed

Hitchcock, Kathryn E; Caudell, Danielle N; Sutton, Jonathan T; Klegerman, Melvin E; Vela, Deborah; Pyne-Geithman, Gail J; Abruzzo, Todd; Cyr, Peppar E P; Geng, Yong-Jian; McPherson, David D; Holland, Christy K

2010-06-15

The goal of this study was to determine whether targeted, Rhodamine-labeled echogenic liposomes (Rh-ELIP) containing nanobubbles could be delivered to the arterial wall, and whether 1-MHz continuous wave ultrasound would enhance this delivery profile. Aortae excised from apolipoprotein-E-deficient (n=8) and wild-type (n=8) mice were mounted in a pulsatile flow system through which Rh-ELIP were delivered in a stream of bovine serum albumin. Half the aortae from each group were treated with 1-MHz continuous wave ultrasound at 0.49 MPa peak-to-peak pressure, and half underwent sham exposure. Ultrasound parameters were chosen to promote stable cavitation and avoid inertial cavitation. A broadband hydrophone was used to monitor cavitation activity. After treatment, aortic sections were prepared for histology and analyzed by an individual blinded to treatment conditions. Delivery of Rh-ELIP to the vascular endothelium was observed, and sub-endothelial penetration of Rh-ELIP was present in five of five ultrasound-treated aortae and was absent in those not exposed to ultrasound. However, the degree of penetration in the ultrasound-exposed aortae was variable. There was no evidence of ultrasound-mediated tissue damage in any specimen. Ultrasound-enhanced delivery within the arterial wall was demonstrated in this novel model, which allows quantitative evaluation of therapeutic delivery. Copyright (c) 2010 Elsevier B.V. All rights reserved.

New mechanisms for non-porative ultrasound stimulation of cargo delivery to cell cytosol with targeted perfluorocarbon nanoparticles

NASA Astrophysics Data System (ADS)

Soman, N. R.; Marsh, J. N.; Lanza, G. M.; Wickline, S. A.

2008-05-01

The cell membrane constitutes a major barrier for non-endocytotic intracellular delivery of therapeutic molecules from drug delivery vehicles. Existing approaches to breaching the cell membrane include cavitational ultrasound (with microbubbles), electroporation and cell-penetrating peptides. We report the use of diagnostic ultrasound for intracellular delivery of therapeutic bulky cargo with the use of molecularly targeted liquid perfluorocarbon (PFC) nanoparticles. To demonstrate the concept, we used a lipid with a surrogate polar head group, nanogold-DPPE, incorporated into the nanoparticle lipid monolayer. Melanoma cells were incubated with nanogold particles and this was followed by insonication with continuous wave ultrasound (2.25 MHz, 5 min, 0.6 MPa). Cells not exposed to ultrasound showed gold particles partitioned only in the outer bilayer of the cell membrane with no evidence of the intracellular transit of nanogold. However, the cells exposed to ultrasound exhibited numerous nanogold-DPPE components inside the cell that appeared polarized inside intracellular vesicles demonstrating cellular uptake and trafficking. Further, ultrasound-exposed cells manifested no incorporation of calcein or the release of lactate dehydrogenase. These observations are consistent with a mechanism that suggests that ultrasound is capable of stimulating the intracellular delivery of therapeutic molecules via non-porative mechanisms. Therefore, non-cavitational adjunctive ultrasound offers a novel paradigm in intracellular cargo delivery from PFC nanoparticles.

Effect of high intensity focused ultrasound (HIFU) in conjunction with a nanomedicines-microbubble complex for enhanced drug delivery.

PubMed

Han, Hyounkoo; Lee, Hohyeon; Kim, Kwangmeyung; Kim, Hyuncheol

2017-11-28

Although nanomedicines have been intensively investigated for cancer therapy in the past, poor accumulation of nanomedicines in tumor sites remains a serious problem. Therefore, a novel drug delivery system is required to enhance accumulation and penetration of nanomedicines at the tumor site. Recently, high-intensity focused ultrasound (HIFU) has been highlighted as a non-invasive therapeutic modality, and showed enhanced therapeutic efficacy in combination with nanomedicines. Cavitation effect induced by the combination of HIFU and microbubbles results in transiently enhanced cell membrane permeability, facilitating improved drug delivery efficiency into tumor sites. Therefore, we introduce the acoustic cavitation and thermal/mechanical effects of HIFU in conjunction with microbubble to overcome the limitation of conventional drug delivery. The cavitation effect maximized by the strong acoustic energy of HIFU induced the preferential accumulation of nanomedicine locally released from the nanomedicines-microbubble complex in the tumor. In addition, the mechanical effect of HIFU allowed the accumulated nanomedicines to penetrate into deeper tumor region. The preferential accumulation and deeper penetration of nanomedicines by HIFU showed enhanced therapeutic efficacy, compared to low frequency ultrasound (US). These overall results demonstrate that the strategy combined nanomedicines-microbubble complex with HIFU is a promising tools for cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Optically generated ultrasound for enhanced drug delivery

DOEpatents

Visuri, Steven R.; Campbell, Heather L.; Da Silva, Luiz

2002-01-01

High frequency acoustic waves, analogous to ultrasound, can enhance the delivery of therapeutic compounds into cells. The compounds delivered may be chemotherapeutic drugs, antibiotics, photodynamic drugs or gene therapies. The therapeutic compounds are administered systemically, or preferably locally to the targeted site. Local delivery can be accomplished through a needle, cannula, or through a variety of vascular catheters, depending on the location of routes of access. To enhance the systemic or local delivery of the therapeutic compounds, high frequency acoustic waves are generated locally near the target site, and preferably near the site of compound administration. The acoustic waves are produced via laser radiation interaction with an absorbing media and can be produced via thermoelastic expansion, thermodynamic vaporization, material ablation, or plasma formation. Acoustic waves have the effect of temporarily permeabilizing the membranes of local cells, increasing the diffusion of the therapeutic compound into the cells, allowing for decreased total body dosages, decreased side effects, and enabling new therapies.

Design strategies and applications of circulating cell-mediated drug delivery systems.

PubMed

Su, Yixue; Xie, Zhiwei; Kim, Gloria B; Dong, Cheng; Yang, Jian

2015-01-01

Drug delivery systems, particularly nanomaterial-based drug delivery systems, possess a tremendous amount of potential to improve diagnostic and therapeutic effects of drugs. Controlled drug delivery targeted to a specific disease is designed to significantly improve the pharmaceutical effects of drugs and reduce their side effects. Unfortunately, only a few targeted drug delivery systems can achieve high targeting efficiency after intravenous injection, even with the development of numerous surface markers and targeting modalities. Thus, alternative drug and nanomedicine targeting approaches are desired. Circulating cells, such as erythrocytes, leukocytes, and stem cells, present innate disease sensing and homing properties. Hence, using living cells as drug delivery carriers has gained increasing interest in recent years. This review highlights the recent advances in the design of cell-mediated drug delivery systems and targeting mechanisms. The approaches of drug encapsulation/conjugation to cell-carriers, cell-mediated targeting mechanisms, and the methods of controlled drug release are elaborated here. Cell-based "live" targeting and delivery could be used to facilitate a more specific, robust, and smart payload distribution for the next-generation drug delivery systems.

Enhanced therapeutic anti-inflammatory effect of betamethasone on topical administration with low-frequency, low-intensity (20 kHz, 100 mW/cm(2)) ultrasound exposure on carrageenan-induced arthritis in a mouse model.

PubMed

Cohen, Gadi; Natsheh, Hiba; Sunny, Youhan; Bawiec, Christopher R; Touitou, Elka; Lerman, Melissa A; Lazarovici, Philip; Lewin, Peter A

2015-09-01

The purpose of this work was to investigate whether low-frequency, low-intensity (20 kHz, <100 mW/cm(2), spatial-peak, temporal-peak intensity) ultrasound, delivered with a lightweight (<100 g), tether-free, fully wearable, battery-powered applicator, is capable of reducing inflammation in a mouse model of rheumatoid arthritis. The therapeutic, acute, anti-inflammatory effect was estimated from the relative swelling induced in mice hindlimb paws. In an independent, indirect approach, the inflammation was bio-imaged by measuring glycolytic activity with near-infrared labeled 2-deoxyglucose. The outcome of the experiments indicated that the combination of ultrasound exposure and topical application of 0.1% (w/w) betamethasone gel resulted in statistically significantly (p < 0.05) enhanced anti-inflammatory activity in comparison with drug or ultrasound treatment alone. The present study underscores the potential benefits of low-frequency, low-intensity ultrasound-assisted drug delivery. However, the proof of concept presented indicates the need for additional experiments to systematically evaluate and optimize the potential of, and the conditions for, tolerable low-frequency, low-intensity ultrasound-promoted non-invasive drug delivery. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Ultrasound in Radiology: from Anatomic, Functional, Molecular Imaging to Drug Delivery and Image-Guided Therapy

PubMed Central

Klibanov, Alexander L.; Hossack, John A.

2015-01-01

During the past decade, ultrasound has expanded medical imaging well beyond the “traditional” radiology setting - a combination of portability, low cost and ease of use makes ultrasound imaging an indispensable tool for radiologists as well as for other medical professionals who need to obtain imaging diagnosis or guide a therapeutic intervention quickly and efficiently. Ultrasound combines excellent ability for deep penetration into soft tissues with very good spatial resolution, with only a few exceptions (i.e. those involving overlying bone or gas). Real-time imaging (up to hundreds and thousands frames per second) enables guidance of therapeutic procedures and biopsies; characterization of the mechanical properties of the tissues greatly aids with the accuracy of the procedures. The ability of ultrasound to deposit energy locally brings about the potential for localized intervention encompassing: tissue ablation, enhancing penetration through the natural barriers to drug delivery in the body and triggering drug release from carrier micro- and nanoparticles. The use of microbubble contrast agents brings the ability to monitor and quantify tissue perfusion, and microbubble targeting with ligand-decorated microbubbles brings the ability to obtain molecular biomarker information, i.e., ultrasound molecular imaging. Overall, ultrasound has become the most widely used imaging modality in modern medicine; it will continue to grow and expand. PMID:26200224

Nano carriers for drug transport across the blood-brain barrier.

PubMed

Li, Xinming; Tsibouklis, John; Weng, Tingting; Zhang, Buning; Yin, Guoqiang; Feng, Guangzhu; Cui, Yingde; Savina, Irina N; Mikhalovska, Lyuba I; Sandeman, Susan R; Howel, Carol A; Mikhalovsky, Sergey V

2017-01-01

Effective therapy lies in achieving a therapeutic amount of drug to the proper site in the body and then maintaining the desired drug concentration for a sufficient time interval to be clinically effective for treatment. The blood-brain barrier (BBB) hinders most drugs from entering the central nervous system (CNS) from the blood stream, leading to the difficulty of delivering drugs to the brain via the circulatory system for the treatment, diagnosis and prevention of brain diseases. Several brain drug delivery approaches have been developed, such as intracerebral and intracerebroventricular administration, intranasal delivery and blood-to-brain delivery, as a result of transient BBB disruption induced by biological, chemical or physical stimuli such as zonula occludens toxin, mannitol, magnetic heating and ultrasound, but these approaches showed disadvantages of being dangerous, high cost and unsuitability for most brain diseases and drugs. The strategy of vector-mediated blood-to-brain delivery, which involves improving BBB permeability of the drug-carrier conjugate, can minimize side effects, such as being submicrometre objects that behave as a whole unit in terms of their transport and properties, nanomaterials, are promising carrier vehicles for direct drug transport across the intact BBB as a result of their potential to enter the brain capillary endothelial cells by means of normal endocytosis and transcytosis due to their small size, as well as their possibility of being functionalized with multiple copies of the drug molecule of interest. This review provids a concise discussion of nano carriers for drug transport across the intact BBB, various forms of nanomaterials including inorganic/solid lipid/polymeric nanoparticles, nanoemulsions, quantum dots, nanogels, liposomes, micelles, dendrimers, polymersomes and exosomes are critically evaluated, their mechanisms for drug transport across the BBB are reviewed, and the future directions of this area are fully discussed.

Acoustic Sensing and Ultrasonic Drug Delivery in Multimodal Theranostic Capsule Endoscopy

PubMed Central

Stewart, Fraser R.; Qiu, Yongqiang; Newton, Ian P.; Cox, Benjamin F.; Al-Rawhani, Mohammed A.; Beeley, James; Liu, Yangminghao; Huang, Zhihong; Cumming, David R. S.; Näthke, Inke

2017-01-01

Video capsule endoscopy (VCE) is now a clinically accepted diagnostic modality in which miniaturized technology, an on-board power supply and wireless telemetry stand as technological foundations for other capsule endoscopy (CE) devices. However, VCE does not provide therapeutic functionality, and research towards therapeutic CE (TCE) has been limited. In this paper, a route towards viable TCE is proposed, based on multiple CE devices including important acoustic sensing and drug delivery components. In this approach, an initial multimodal diagnostic device with high-frequency quantitative microultrasound that complements video imaging allows surface and subsurface visualization and computer-assisted diagnosis. Using focused ultrasound (US) to mark sites of pathology with exogenous fluorescent agents permits follow-up with another device to provide therapy. This is based on an US-mediated targeted drug delivery system with fluorescence imaging guidance. An additional device may then be utilized for treatment verification and monitoring, exploiting the minimally invasive nature of CE. While such a theranostic patient pathway for gastrointestinal treatment is presently incomplete, the description in this paper of previous research and work under way to realize further components for the proposed pathway suggests it is feasible and provides a framework around which to structure further work. PMID:28671642

Thermal safety of ultrasound-enhanced ocular drug delivery: A modeling study

PubMed Central

Nabili, Marjan; Geist, Craig; Zderic, Vesna

2015-01-01

Purpose: Delivery of sufficient amounts of therapeutic drugs into the eye for treatment of various ocular diseases is often a challenging task. Ultrasound was shown to be effective in enhancing ocular drug delivery in the authors’ previous in vitro and in vivo studies. Methods: The study reported here was designed to investigate the safety of ultrasound application and its potential thermal effects in the eye using PZFlex modeling software. The safety limit in this study was set as a temperature increase of no more than 1.5 °C based on regulatory recommendations and previous experimental safety studies. Acoustic and thermal specifications of different human eye tissues were obtained from the published literature. The tissues of particular interest in this modeling safety study were cornea, lens, and the location of optic nerve in the posterior eye. Ultrasound application was modeled at frequencies of 400 kHz–1 MHz, intensities of 0.3–1 W/cm2, and exposure duration of 5 min, which were the parameters used in the authors’ previous drug delivery experiments. The baseline eye temperature was 37 °C. Results: The authors’ results showed that the maximal tissue temperatures after 5 min of ultrasound application were 38, 39, 39.5, and 40 °C in the cornea, 39.5, 40, 42, and 43 °C in the center of the lens, and 37.5, 38.5, and 39 °C in the back of the eye (at the optic nerve location) at frequencies of 400, 600, 800 kHz, and 1 MHz, respectively. Conclusions: The ocular temperatures reached at higher frequencies were considered unsafe based on current recommendations. At a frequency of 400 kHz and intensity of 0.8 W/cm2 (parameters shown in the authors’ previous in vivo studies to be optimal for ocular drug delivery), the temperature increase was small enough to be considered safe inside different ocular tissues. However, the impact of orbital bone and tissue perfusion should be included in future modeling efforts to determine the safety of this method in the whole orbit especially regarding potential adverse optic nerve heating at the location of the bone. PMID:26429235

Pulsed high intensity focused ultrasound (pHIFU) enhances delivery of doxorubicin in a preclinical model of pancreatic cancer

PubMed Central

Li, Tong; Wang, Yak-Nam; Khokhlova, Tatiana D.; D’Andrea, Samantha; Starr, Frank; Chen, Hong; McCune, Jeannine S.; Risler, Linda J.; Mashadi-Hossein, Afshin; Hwang, Joo Ha

2015-01-01

Pancreatic cancer is characterized by extensive stromal desmoplasia which decreases blood perfusion and impedes chemotherapy delivery. Breaking the stromal barrier could both increase perfusion and permeabilize the tumor, enhancing chemotherapy penetration. Mechanical disruption of the stroma can be achieved using ultrasound-induced bubble activity – cavitation. Cavitation is also known to result in microstreaming and could have the added benefit of actively enhancing diffusion into the tumors. Here, we report the ability to enhance chemotherapeutic drug doxorubicin (Dox) penetration using ultrasound-induced cavitation in a genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma. To induce localized inertial cavitation in pancreatic tumors, pulsed high intensity focused ultrasound (pHIFU) was used either during or before doxorubicin administration to elucidate the mechanisms of enhanced drug delivery (active versus passive drug diffusion). For both types, the pHIFU exposures which were associated with high cavitation activity resulted in disruption of the highly fibrotic stromal matrix and enhanced the normalized Dox concentration by up to 4.5 fold compared to controls. Furthermore, normalized Dox concentration was associated with the cavitation metrics (p < 0.01), indicating that high and sustained cavitation results in increased chemotherapy penetration. No significant difference between the outcomes of the two types, i.e., Dox infusion during or after pHIFU treatment, was observed, suggesting that passive diffusion into previously permeabilized tissue is the major mechanism for the increase in drug concentration. Together, the data indicate that pHIFU treatment of pancreatic tumors when resulting in high and sustained cavitation can efficiently enhance chemotherapy delivery to pancreatic tumors. PMID:26216548

Ultrasound-microbubble-mediated intercellular adhesion molecule-1 small interfering ribonucleic acid transfection attenuates neointimal formation after arterial injury in mice.

PubMed

Suzuki, Jun-ichi; Ogawa, Masahito; Takayama, Kiyoshi; Taniyama, Yoshiaki; Morishita, Ryuichi; Hirata, Yasunobu; Nagai, Ryozo; Isobe, Mitsuaki

2010-03-02

The purpose of this study was to investigate the efficiency of small interfering ribonucleic acid (siRNA) in murine arteries. We transfected it using a nonviral ultrasound-microbubble-mediated in vivo gene delivery system. siRNA is an effective methodology to suppress gene function. The siRNA can be synthesized easily; however, a major obstacle in the use of siRNA as therapeutics is the difficulty involved in effective in vivo delivery. To investigate the efficiency of nonviral ultrasound-microbubble-mediated in vivo siRNA delivery, we used a fluorescein-labeled siRNA, green fluorescent protein (GFP) siRNA, and intercellular adhesion molecule (ICAM)-1 siRNA in murine arteries. Murine femoral arteries were injured using flexible wires to establish arterial injury. The fluorescein-labeled siRNA and GFP siRNA showed that this nonviral approach could deliver siRNA into target arteries effectively without any tissue damage and systemic adverse effects. ICAM-1 siRNA transfection into murine injured arteries significantly suppressed the development of neointimal formation in comparison to those in the control group. Immunohistochemistry revealed that accumulation of T cells and adhesion molecule positive cells was observed in nontreated injured arteries, whereas siRNA suppressed accumulation. The nonviral ultrasound-microbubble delivery of siRNA ensures effective transfection into target arteries. ICAM-1 siRNA has the potential to suppress arterial neointimal formation. Transfection of siRNA can be beneficial for the clinical treatment of cardiovascular and other inflammatory diseases. Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Ultrasound triggered drug delivery with liposomal nested microbubbles.

PubMed

Wallace, N; Wrenn, S P

2015-12-01

When ultrasound contrast agent microbubbles are nested within a liposome, damage to the liposome membrane caused by both stable and inertial cavitation of the microbubble allows for release of the aqueous core of the liposome. Triggered release was not accomplished unless microbubbles were present within the liposome. Leakage was tested using fluorescence assays developed specifically for this drug delivery vehicle and qualitative measurements using an optical microscope. These studies were done using a 1 MHz focused ultrasound transducer while varying parameters including peak negative ultrasound pressure, average liposome diameter, and microbubble concentration. Two regimes exist for membrane disruption caused by cavitating microbubbles. A faster release rate, as well as permanent membrane damage are seen for samples exposed to high pressure (2.1-3.7 MPa). A slower release rate and dilation/temporary poration are characteristic of stable cavitation for low pressure studies (0.54-1.7 MPa). Copyright © 2015 Elsevier B.V. All rights reserved.

Lipid-shelled vehicles: engineering for ultrasound molecular imaging and drug delivery.

PubMed

Ferrara, Katherine W; Borden, Mark A; Zhang, Hua

2009-07-21

Ultrasound pressure waves can map the location of lipid-stabilized gas micro-bubbles after their intravenous administration in the body, facilitating an estimate of vascular density and microvascular flow rate. Microbubbles are currently approved by the Food and Drug Administration as ultrasound contrast agents for visualizing opacification of the left ventricle in echocardiography. However, the interaction of ultrasound waves with intravenously-injected lipid-shelled particles, including both liposomes and microbubbles, is a far richer field. Particles can be designed for molecular imaging and loaded with drugs or genes; the mechanical and thermal properties of ultrasound can then effect localized drug release. In this Account, we provide an overview of the engineering of lipid-shelled microbubbles (typical diameter 1000-10 000 nm) and liposomes (typical diameter 65-120 nm) for ultrasound-based applications in molecular imaging and drug delivery. The chemistries of the shell and core can be optimized to enhance stability, circulation persistence, drug loading and release, targeting to and fusion with the cell membrane, and therapeutic biological effects. To assess the biodistribution and pharmacokinetics of these particles, we incorporated positron emission tomography (PET) radioisotopes on the shell. The radionuclide (18)F (half-life approximately 2 h) was covalently coupled to a dipalmitoyl lipid, followed by integration of the labeled lipid into the shell, facilitating short-term analysis of particle pharmacokinetics and metabolism of the lipid molecule. Alternately, labeling a formed particle with (64)Cu (half-life 12.7 h), after prior covalent incorporation of a copper-chelating moiety onto the lipid shell, permits pharmacokinetic study of particles over several days. Stability and persistence in circulation of both liposomes and microbubbles are enhanced by long acyl chains and a poly(ethylene glycol) coating. Vascular targeting has been demonstrated with both nano- and microdiameter particles. Targeting affinity of the microbubble can be modulated by burying the ligand within a polymer brush layer; the application of ultrasound then reveals the ligand, enabling specific targeting of only the insonified region. Microbubbles and liposomes require different strategies for both drug loading and release. Microbubble loading is inhibited by the gas core and enhanced by layer-by-layer construction or conjugation of drug-entrapped particles to the surface. Liposome loading is typically internal and is enhanced by drug-specific loading techniques. Drug release from a microbubble results from the oscillation of the gas core diameter produced by the sound wave, whereas that from a liposome is enhanced by heat produced from the local absorption of acoustic energy within the tissue microenvironment. Biological effects induced by ultrasound, such as changes in cell membrane and vascular permeability, can enhance drug delivery. In particular, as microbubbles oscillate near a vessel wall, shock waves or liquid jets enhance drug transport. Mild heating induced by ultrasound, either before or after injection of the drug, facilitates the transport of liposomes from blood vessels to the tissue interstitium, thus increasing drug accumulation in the target region. Lipid-shelled vehicles offer many opportunities for chemists and engineers; ultrasound-based applications beyond the few currently in common use will undoubtedly soon multiply as molecular construction techniques are further refined.

Photoacoustic/ultrasound dual-modality contrast agent and its application to thermotherapy.

PubMed

Wang, Yu-Hsin; Liao, Ai-Ho; Chen, Jui-Hao; Wang, Churng-Ren Chris; Li, Pai-Chi

2012-04-01

This study investigates a photoacoustic/ultrasound dual-modality contrast agent, including extending its applications from image-contrast enhancement to combined diagnosis and therapy with site-specific targeting. The contrast agent comprises albumin-shelled microbubbles with encapsulated gold nanorods (AuMBs). The gas-filled microbubbles, whose diameters range from submicrometer to several micrometers, are not only echogenic but also can serve as drug-delivery vehicles. The gold nanorods are used to enhance the generation of both photoacoustic and photothermal signals. The optical absorption peak of the gold nanorods is tuned to 760 nm and is invariant after microbubble encapsulation. Dual-modality contrast enhancement is first described here, and the applications to cellular targeting and laser-induced thermotherapy in a phantom are demonstrated. Photoacoustic imaging can be used to monitor temperature increases during the treatment. The targeting capability of AuMBs was verified, and the temperature increased by 26°C for a laser power of 980 mW, demonstrating the potential of combined diagnosis and therapy with the dual-modality agent. Targeted photo- or acoustic-mediated delivery is also possible.

Gd(III)-DOTA-modified sonosensitive liposomes for ultrasound-triggered release and MR imaging

NASA Astrophysics Data System (ADS)

Jung, Suk Hyun; Na, Kyunga; Lee, Seul A.; Cho, Sun Hang; Seong, Hasoo; Shin, Byung Cheol

2012-08-01

Ultrasound-sensitive (sonosensitive) liposomes for tumor targeting have been studied in order to increase the antitumor efficacy of drugs and decrease the associated severe side effects. Liposomal contrast agents having Gd(III) are known as a nano-contrast agent system for the efficient and selective delivery of contrast agents into pathological sites. The objective of this study was to prepare Gd(III)-DOTA-modified sonosensitive liposomes (GdSL), which could deliver a model drug, doxorubicin (DOX), to a specific site and, at the same time, be capable of magnetic resonance (MR) imaging. The GdSL was prepared using synthesized Gd(III)-DOTA-1,2-distearoyl- sn-glycero-3-phosphoethanolamine lipid. Sonosensitivity of GdSL to 20-kHz ultrasound induced 33% to 40% of DOX release. The relaxivities ( r 1) of GdSL were 6.6 to 7.8 mM-1 s-1, which were higher than that of MR-bester®. Intracellular uptake properties of GdSL were evaluated according to the intensity of ultrasound. Intracellular uptake of DOX for ultrasound-triggered GdSL was higher than that for non-ultrasound-triggered GdSL. The results of our study suggest that the paramagnetic and sonosensitive liposomes, GdSL, may provide a versatile platform for molecular imaging and targeted drug delivery.

Ultrasound-mediated destruction of oxygen and paclitaxel loaded lipid microbubbles for combination therapy in hypoxic ovarian cancer cells.

PubMed

Sun, Jiangchuan; Yin, Mingyue; Zhu, Shenyin; Liu, Li; Zhu, Yi; Wang, Zhigang; Xu, Ronald X; Chang, Shufang

2016-01-01

We synthesized oxygen and paclitaxel (PTX) loaded lipid microbubbles (OPLMBs) for ultrasound mediated combination therapy in hypoxic ovarian cancer cells. Our experiments successfully demonstrated that ultrasound induced OPLMBs destruction significantly enhanced the local oxygen release. We also demonstrated that OPLMBs in combination with ultrasound (300 kHz, 0.5 W/cm(2), 15s) yielded anti-proliferative activities of 52.8 ± 2.75% and cell apoptosis ratio of 35.25 ± 0.17% in hypoxic cells at 24h after the treatment, superior to other treatment groups such as PTX only and PTX-loaded MBs (PLMBs) with or without ultrasound mediation. RT-PCR and Western blot tests further confirmed the reduced expression of HIF-1α and MDR-1/P-gp after ultrasound mediation of OPLMBs. Our experiment suggests that ultrasound mediation of oxygen and drug-loaded MBs may be a useful method to overcome chemoresistance in the hypoxic ovarian cancer cells. Copyright © 2015 Elsevier B.V. All rights reserved.

Modulation control over ultrasound-mediated gene delivery: evaluating the importance of standing waves.

PubMed

Hassan, Mariame A; Buldakov, Mikhail A; Ogawa, Ryohei; Zhao, Qing-Li; Furusawa, Yukihiro; Kudo, Nobuki; Kondo, Takashi; Riesz, Peter

2010-01-04

Low modulation frequencies from 0.5 to 100Hz were shown to alter the characteristics of the ultrasound field producing solution agitation (<5Hz; region of "ultrasound streaming" prevalence) or stagnancy (>5Hz; region of standing waves establishment) (Buldakov et al., Ultrason. Sonochem., 2009). In this study, the same conditions were used to depict the changes in exogenous DNA delivery in these regions. The luciferase expression data revealed that lower modulations were more capable of enhancing delivery at the expense of viability. On the contrary, the viability was conserved at higher modulations whereas delivery was found to be null. Cavitational activity and acoustic streaming were the effecters beyond the observed pattern and delivery enhancement was shown to be mediated mainly through sonopermeation. To promote transfection, the addition of calcium ions or an echo contrast agent (Levovist((R))) was proposed. Depending on the mechanism involved in each approach, differential enhancement was observed in both regions and at the interim zone (5Hz). In both cases, enhancement in standing waves field was significant reaching 16.0 and 3.3 folds increase, respectively. Therefore, it is concluded that although the establishment of standing waves is not the only prerequisite for high transfection rates, yet, it is a key element in optimization when other factors such as proximity and cavitation are considered.

Ultrasound image-guided therapy enhances antitumor effect of cisplatin.

PubMed

Sasaki, Noboru; Kudo, Nobuki; Nakamura, Kensuke; Lim, Sue Yee; Murakami, Masahiro; Kumara, W R Bandula; Tamura, Yu; Ohta, Hiroshi; Yamasaki, Masahiro; Takiguchi, Mitsuyoshi

2014-01-01

The aim of this study was to clarify whether ultrasound image-guided cisplatin delivery with an intratumor microbubble injection enhances the antitumor effect in a xenograft mouse model. Canine thyroid adenocarcinoma cells were used for all experiments. Before in vivo experiments, the cisplatin and microbubble concentration and ultrasound exposure time were optimized in vitro. For in vivo experiments, cells were implanted into the back of nude mice. Observed by a diagnostic ultrasound machine, a mixture of cisplatin and ultrasound contrast agent, Sonazoid, microbubbles was injected directly into tumors. The amount of injected cisplatin and microbubbles was 1 μg/tumor and 1.2 × 10(7) microbubbles/tumor, respectively, with a total injected volume of 20 μl. Using the same diagnostic machine, tumors were exposed to ultrasound for 15 s. The treatment was repeated four times. The combination of cisplatin, microbubbles, and ultrasound significantly delayed tumor growth as compared with no treatment (after 18 days, 157 ± 55 vs. 398 ± 49 mm(3), P = 0.049). Neither cisplatin alone nor the combination of cisplatin and ultrasound delayed tumor growth. The treatment did not decrease the body weight of mice. Ultrasound image-guided anticancer drug delivery may enhance the antitumor effects of drugs without obvious side effects.

CT and Ultrasound Guided Stereotactic High Intensity Focused Ultrasound (HIFU)

NASA Astrophysics Data System (ADS)

Wood, Bradford J.; Yanof, J.; Frenkel, V.; Viswanathan, A.; Dromi, S.; Oh, K.; Kruecker, J.; Bauer, C.; Seip, R.; Kam, A.; Li, K. C. P.

2006-05-01

To demonstrate the feasibility of CT and B-mode Ultrasound (US) targeted HIFU, a prototype coaxial focused ultrasound transducer was registered and integrated to a CT scanner. CT and diagnostic ultrasound were used for HIFU targeting and monitoring, with the goals of both thermal ablation and non-thermal enhanced drug delivery. A 1 megahertz coaxial ultrasound transducer was custom fabricated and attached to a passive position-sensing arm and an active six degree-of-freedom robotic arm via a CT stereotactic frame. The outer therapeutic transducer with a 10 cm fixed focal zone was coaxially mounted to an inner diagnostic US transducer (2-4 megahertz, Philips Medical Systems). This coaxial US transducer was connected to a modified commercial focused ultrasound generator (Focus Surgery, Indianapolis, IN) with a maximum total acoustic power of 100 watts. This pre-clinical paradigm was tested for ability to heat tissue in phantoms with monitoring and navigation from CT and live US. The feasibility of navigation via image fusion of CT with other modalities such as PET and MRI was demonstrated. Heated water phantoms were tested for correlation between CT numbers and temperature (for ablation monitoring). The prototype transducer and integrated CT/US imaging system enabled simultaneous multimodality imaging and therapy. Pre-clinical phantom models validated the treatment paradigm and demonstrated integrated multimodality guidance and treatment monitoring. Temperature changes during phantom cooling corresponded to CT number changes. Contrast enhanced or non-enhanced CT numbers may potentially be used to monitor thermal ablation with HIFU. Integrated CT, diagnostic US, and therapeutic focused ultrasound bridges a gap between diagnosis and therapy. Preliminary results show that the multimodality system may represent a relatively inexpensive, accessible, and simple method of both targeting and monitoring HIFU effects. Small animal pre-clinical models may be translated to large animals and humans for HIFU-induced ablation and drug delivery. Integrated CT-guided focused ultrasound holds promise for tissue ablation, enhancing local drug delivery, and CT thermometry for monitoring ablation in near real-time.

Transdermal delivery of lercanidipine hydrochloride: effect of chemical enhancers and ultrasound.

PubMed

Shetty, Pallavi K; Suthar, Neelam A; Menon, Jyothsna; Deshpande, Praful B; Avadhani, Kiran; Kulkarni, Raghavendra V; Mutalik, Srinivas

2013-08-01

The effects of permeation enhancers and sonophoresis on the transdermal permeation of lercanidipine hydrochloride (LRDP) across mouse skin were investigated. Parameters including drug solubility, partition coefficient, drug degradation and drug permeation in skin were determined. Tween-20, dimethyl formamide, propylene glycol, poly ethylene glycol (5% v/v) and different concentration of ethanol were used for permeation enhancement. Low frequency ultrasound was also applied in the presence and absence of permeation enhancers to assess its effect on augmenting the permeation of drug. All the permeation enhancers, except propylene glycol, increased the transdermal permeation of LRDP. Sonophoresis significantly increased the cumulative amount of LRDP permeating through the skin in comparison to passive diffusion. A synergistic effect was noted when sonophoresis was applied in presence of permeation enhancers. The results suggest that the formulation of LRDP with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver LRDP across the skin for a prolonged period (i.e., 24 h). The application of ultrasound in association with permeation enhancers could further serve as non-oral and non-invasive drug delivery modality for the immediate therapeutic effect.

Cell-Mediated Drugs Delivery

PubMed Central

Batrakova, Elena V.; Gendelman, Howard E.; Kabanov, Alexander V.

2011-01-01

INTRODUCTION Drug targeting to sites of tissue injury, tumor or infection with limited toxicity is the goal for successful pharmaceutics. Immunocytes (including mononuclear phagocytes (dendritic cells, monocytes and macrophages), neutrophils, and lymphocytes) are highly mobile; they can migrate across impermeable barriers and release their drug cargo at sites of infection or tissue injury. Thus immune cells can be exploited as trojan horses for drug delivery. AREAS COVERED IN THIS REVIEW This paper reviews how immunocytes laden with drugs can cross the blood brain or blood tumor barriers, to facilitate treatments for infectious diseases, injury, cancer, or inflammatory diseases. The promises and perils of cell-mediated drug delivery are reviewed, with examples of how immunocytes can be harnessed to improve therapeutic end points. EXPERT OPINION Using cells as delivery vehicles enables targeted drug transport, and prolonged circulation times, along with reductions in cell and tissue toxicities. Such systems for drug carriage and targeted release represent a novel disease combating strategy being applied to a spectrum of human disorders. The design of nanocarriers for cell-mediated drug delivery may differ from those used for conventional drug delivery systems; nevertheless, engaging different defense mechanisms into drug delivery may open new perspectives for the active delivery of drugs. PMID:21348773

Drug delivery across the blood-brain barrier using focused ultrasound

PubMed Central

Burgess, Alison; Hynynen, Kullervo H.

2015-01-01

Introduction The presence of the blood-brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been developed as a non-invasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain. Areas Covered The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed. Expert Opinion The introduction of MRI guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient, and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development. PMID:24650132

Drug delivery across the blood-brain barrier using focused ultrasound.

PubMed

Burgess, Alison; Hynynen, Kullervo

2014-05-01

The presence of the blood-brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been developed as a noninvasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain. The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed. The introduction of magnetic resonance imaging guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development.

In situ targeted activation of an anticancer agent using ultrasound-triggered release of composite droplets.

PubMed

Bezagu, Marine; Clarhaut, Jonathan; Renoux, Brigitte; Monti, Fabrice; Tanter, Mickael; Tabeling, Patrick; Cossy, Janine; Couture, Olivier; Papot, Sebastien; Arseniyadis, Stellios

2017-12-15

The efficiency of a drug is usually highly dependent on the way it is administered or delivered. As such, targeted-therapy, which requires conceiving drug-delivery vehicles that will change their state from a relatively stable structure with a very slow leak-rate to an unstable structure with a fast release, clearly improves the pharmacokinetics, the absorption, the distribution, the metabolism and the therapeutic index of a given drug. In this context, we have developed a particularly effective double stimuli-responsive drug-delivery method allowing an ultrasound-induced release of a monomethylauristatin E-glucuronide prodrug and its subsequent activation by a β-glucuronidase. This led to an increase of cytotoxicity of about 80% on cancer cells. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

[Smart drug delivery systems based on nanoscale ZnO].

PubMed

Huang, Xiao; Chen, Chun; Yi, Caixia; Zheng, Xi

2018-04-01

In view of the excellent biocompatibility as well as the low cost, nanoscale ZnO shows great potential for drug delivery application. Moreover, The charming character enable nanoscale ZnO some excellent features (e.g. dissolution in acid, ultrasonic permeability, microwave absorbing, hydrophobic/hydrophilic transition). All of that make nanoscale ZnO reasonable choices for smart drug delivery. In the recent decade, more and more studies have focused on controlling the drug release behavior via smart drug delivery systems based on nanoscale ZnO responsive to some certain stimuli. Herein, we review the recent exciting progress on the pH-responsive, ultrasound-responsive, microwave-responsive and UV-responsive nanoscale ZnO-based drug delivery systems. A brief introduction of the drug controlled release behavior and its effect of the drug delivery systems is presented. The biocompatibility of nanoscale ZnO is also discussed. Moreover, its development prospect is looked forward.

Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer.

PubMed

Wang, Tzu-Yin; Choe, Jung Woo; Pu, Kanyi; Devulapally, Rammohan; Bachawal, Sunitha; Machtaler, Steven; Chowdhury, Sayan Mullick; Luong, Richard; Tian, Lu; Khuri-Yakub, Butrus; Rao, Jianghong; Paulmurugan, Ramasamy; Willmann, Jürgen K

2015-04-10

Ultrasound induced microbubble cavitation can cause enhanced permeability across natural barriers of tumors such as vessel walls or cellular membranes, allowing for enhanced therapeutic delivery into the target tissues. While enhanced delivery of small (<1nm) molecules has been shown at acoustic pressures below 1MPa both in vitro and in vivo, the delivery efficiency of larger (>100nm) therapeutic carriers into cancer remains unclear and may require a higher pressure for sufficient delivery. Enhanced delivery of larger therapeutic carriers such as FDA approved pegylated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NP) has significant clinical value because these nanoparticles have been shown to protect encapsulated drugs from degradation in the blood circulation and allow for slow and prolonged release of encapsulated drugs at the target location. In this study, various acoustic parameters were investigated to facilitate the successful delivery of two nanocarriers, a fluorescent semiconducting polymer model drug nanoparticle as well as PLGA-PEG-NP into human colon cancer xenografts in mice. We first measured the cavitation dose produced by various acoustic parameters (pressure, pulse length, and pulse repetition frequency) and microbubble concentration in a tissue mimicking phantom. Next, in vivo studies were performed to evaluate the penetration depth of nanocarriers using various acoustic pressures, ranging between 1.7 and 6.9MPa. Finally, a therapeutic microRNA, miR-122, was loaded into PLGA-PEG-NP and the amount of delivered miR-122 was assessed using quantitative RT-PCR. Our results show that acoustic pressures had the strongest effect on cavitation. An increase of the pressure from 0.8 to 6.9MPa resulted in a nearly 50-fold increase in cavitation in phantom experiments. In vivo, as the pressures increased from 1.7 to 6.9MPa, the amount of nanoparticles deposited in cancer xenografts was increased from 4- to 14-fold, and the median penetration depth of extravasated nanoparticles was increased from 1.3-fold to 3-fold, compared to control conditions without ultrasound, as examined on 3D confocal microscopy. When delivering miR-122 loaded PLGA-PEG-NP using optimal acoustic settings with minimum tissue damage, miR-122 delivery into tumors with ultrasound and microbubbles was 7.9-fold higher compared to treatment without ultrasound. This study demonstrates that ultrasound induced microbubble cavitation can be a useful tool for delivery of therapeutic miR loaded nanocarriers into cancer in vivo. Copyright © 2015 Elsevier B.V. All rights reserved.

WE-H-209-01: Advances in Ultrasound Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hynynen, K.

Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for image-guided drug delivery. In this presentation, the advances in ultrasound phased array technology for energy delivery, exposure monitoring and control will be discussed. Experimental results from novel multi-frequency transmit/receive arrays will be presented. In addition, the feasibility of fully electronically focused and steered high power arrays with many thousands of transducer elements will be discussed. Finally, some of the recent clinical and preclinical results for the treatment of brain disease will be reviewed. Learning Objectives:more » Introduce FUS therapy principles and modern techniques Discuss use of FUS for drug delivery Cover the technology required to deliver FUS and monitor therapy Present clinical examples of the uses of these techniques This research was supported by funding from The Canada Research Chair Program, Grants from CIHR and NIH (no. EB003268).; K. Hynynen, Canada Foundation for Innovation; Canadian Institutes of Health Research; Focused Ultrasound Surgery Foundation; Canada Research Chair Program; Natural Sciences and Engineering Research Council of Canada; Ontario Research Fund; National Institutes of Health; Canadian Cancer Society Research Institute; The Weston Brain Institute; Harmonic Medical; Focused Ultrasound Instruments.« less

WE-H-209-00: Carson/Zagzebski Distinguished Lectureship: Image Guided Ultrasound Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for image-guided drug delivery. In this presentation, the advances in ultrasound phased array technology for energy delivery, exposure monitoring and control will be discussed. Experimental results from novel multi-frequency transmit/receive arrays will be presented. In addition, the feasibility of fully electronically focused and steered high power arrays with many thousands of transducer elements will be discussed. Finally, some of the recent clinical and preclinical results for the treatment of brain disease will be reviewed. Learning Objectives:more » Introduce FUS therapy principles and modern techniques Discuss use of FUS for drug delivery Cover the technology required to deliver FUS and monitor therapy Present clinical examples of the uses of these techniques This research was supported by funding from The Canada Research Chair Program, Grants from CIHR and NIH (no. EB003268).; K. Hynynen, Canada Foundation for Innovation; Canadian Institutes of Health Research; Focused Ultrasound Surgery Foundation; Canada Research Chair Program; Natural Sciences and Engineering Research Council of Canada; Ontario Research Fund; National Institutes of Health; Canadian Cancer Society Research Institute; The Weston Brain Institute; Harmonic Medical; Focused Ultrasound Instruments.« less

Ultrasound-mediated cavitation does not decrease the activity of small molecule, antibody or viral-based medicines.

PubMed

Myers, Rachel; Grundy, Megan; Rowe, Cliff; Coviello, Christian M; Bau, Luca; Erbs, Philippe; Foloppe, Johann; Balloul, Jean-Marc; Story, Colin; Coussios, Constantin C; Carlisle, Robert

2018-01-01

The treatment of cancer using nanomedicines is limited by the poor penetration of these potentially powerful agents into and throughout solid tumors. Externally controlled mechanical stimuli, such as the generation of cavitation-induced microstreaming using ultrasound (US), can provide a means of improving nanomedicine delivery. Notably, it has been demonstrated that by focusing, monitoring and controlling the US exposure, delivery can be achieved without damage to surrounding tissue or vasculature. However, there is a risk that such stimuli may disrupt the structure and thereby diminish the activity of the delivered drugs, especially complex antibody and viral-based nanomedicines. In this study, we characterize the impact of cavitation on four different agents, doxorubicin (Dox), cetuximab, adenovirus (Ad) and vaccinia virus (VV), representing a scale of sophistication from a simple small-molecule drug to complex biological agents. To achieve tight regulation of the level and duration of cavitation exposure, a "cavitation test rig" was designed and built. The activity of each agent was assessed with and without exposure to a defined cavitation regime which has previously been shown to provide effective and safe delivery of agents to tumors in preclinical studies. The fluorescence profile of Dox remained unchanged after exposure to cavitation, and the efficacy of this drug in killing a cancer cell line remained the same. Similarly, the ability of cetuximab to bind its epidermal growth factor receptor target was not diminished following exposure to cavitation. The encoding of the reporter gene luciferase within the Ad and VV constructs tested here allowed the infectivity of these viruses to be easily quantified. Exposure to cavitation did not impact on the activity of either virus. These data provide compelling evidence that the US parameters used to safely and successfully delivery nanomedicines to tumors in preclinical models do not detrimentally impact on the structure or activity of these nanomedicines.

Ultrasound-mediated cavitation does not decrease the activity of small molecule, antibody or viral-based medicines

PubMed Central

Myers, Rachel; Grundy, Megan; Rowe, Cliff; Coviello, Christian M; Bau, Luca; Erbs, Philippe; Foloppe, Johann; Balloul, Jean-Marc; Story, Colin; Coussios, Constantin C; Carlisle, Robert

2018-01-01

The treatment of cancer using nanomedicines is limited by the poor penetration of these potentially powerful agents into and throughout solid tumors. Externally controlled mechanical stimuli, such as the generation of cavitation-induced microstreaming using ultrasound (US), can provide a means of improving nanomedicine delivery. Notably, it has been demonstrated that by focusing, monitoring and controlling the US exposure, delivery can be achieved without damage to surrounding tissue or vasculature. However, there is a risk that such stimuli may disrupt the structure and thereby diminish the activity of the delivered drugs, especially complex antibody and viral-based nanomedicines. In this study, we characterize the impact of cavitation on four different agents, doxorubicin (Dox), cetuximab, adenovirus (Ad) and vaccinia virus (VV), representing a scale of sophistication from a simple small-molecule drug to complex biological agents. To achieve tight regulation of the level and duration of cavitation exposure, a “cavitation test rig” was designed and built. The activity of each agent was assessed with and without exposure to a defined cavitation regime which has previously been shown to provide effective and safe delivery of agents to tumors in preclinical studies. The fluorescence profile of Dox remained unchanged after exposure to cavitation, and the efficacy of this drug in killing a cancer cell line remained the same. Similarly, the ability of cetuximab to bind its epidermal growth factor receptor target was not diminished following exposure to cavitation. The encoding of the reporter gene luciferase within the Ad and VV constructs tested here allowed the infectivity of these viruses to be easily quantified. Exposure to cavitation did not impact on the activity of either virus. These data provide compelling evidence that the US parameters used to safely and successfully delivery nanomedicines to tumors in preclinical models do not detrimentally impact on the structure or activity of these nanomedicines. PMID:29391793

Recent advances in light-responsive on-demand drug-delivery systems

PubMed Central

Linsley, Chase S; Wu, Benjamin M

2017-01-01

The convergence of wearable sensors and personalized medicine enhance the ability to sense and control the drug composition and dosage, as well as location and timing of administration. To date, numerous stimuli-triggered smart drug-delivery systems have been developed to detect changes in light, pH, temperature, biomolecules, electric field, magnetic field, ultrasound and mechanical forces. This review examines the major advances within the last 5 years for the three most common light-responsive drug delivery-on-demand strategies: photochemical, photoisomerization and photothermal. Examples are highlighted to illustrate progress of each strategy in drug delivery applications, and key limitations are identified to motivate future research to advance this important field. PMID:28088880

Recent advances in light-responsive on-demand drug-delivery systems.

PubMed

Linsley, Chase S; Wu, Benjamin M

2017-02-01

The convergence of wearable sensors and personalized medicine enhance the ability to sense and control the drug composition and dosage, as well as location and timing of administration. To date, numerous stimuli-triggered smart drug-delivery systems have been developed to detect changes in light, pH, temperature, biomolecules, electric field, magnetic field, ultrasound and mechanical forces. This review examines the major advances within the last 5 years for the three most common light-responsive drug delivery-on-demand strategies: photochemical, photoisomerization and photothermal. Examples are highlighted to illustrate progress of each strategy in drug delivery applications, and key limitations are identified to motivate future research to advance this important field.

Ultrasound-mediated nanoparticle delivery across ex vivo bovine retina after intravitreal injection.

PubMed

Huang, Di; Chen, Ying-Shan; Thakur, Sachin S; Rupenthal, Ilva D

2017-10-01

Intravitreal injection is the most common administration route for the treatment of retinal diseases. However, the vitreous and some of the retinal layers themselves act as significant barriers to efficient delivery of drugs administered intravitreally. This study aimed to improve the diffusive mobility of nanoparticles (NPs) in the vitreous and enhance their permeation across the retina after intravitreal injection by application of ultrasound (US). Ex vivo posterior bovine eye cups were used and the vitreous was either left intact or removed gently from the neural retina. Hyaluronic acid coated human serum albumin NPs were administered into the eye cups and continuous US with a frequency of 1MHz, an intensity of 0.5W/cm 2 , and a duration of 30s was applied once or repeatedly via the transscleral route. After pre-determined time points, fluorescence intensities in the vitreous and the retina were analyzed. Short pulses of US significantly improved the diffusive mobility of NPs through the vitreous as well as their penetration across the neural retina into the retinal pigment epithelium and choroid without causing any detectable damage to the ocular tissues. Therefore, transscleral US could be a powerful and safe tool to enhance retinal delivery of intravitreally injected NPs. Copyright © 2017 Elsevier B.V. All rights reserved.

Nanodrug delivery in reversing multidrug resistance in cancer cells

PubMed Central

Kapse-Mistry, Sonali; Govender, Thirumala; Srivastava, Rohit; Yergeri, Mayur

2014-01-01

Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance (MDR) which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp), multidrug resistance-associated proteins (MRP1, MRP2), and breast cancer resistance protein (BCRP). Currently nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective, and promising platforms for treatment of drug resistant cancer cells. Nanocarriers have potential to improve drug therapeutic index, ability for multifunctionality, divert ABC-transporter mediated drug efflux mechanism and selective targeting to tumor cells, cancer stem cells, tumor initiating cells, or cancer microenvironment. Selective nanocarrier targeting to tumor overcomes dose-limiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses, and emergence of multiple drug resistance with conventional or combination chemotherapy. Current review highlights various nanodrug delivery systems to overcome mechanism of MDR by neutralizing, evading, or exploiting the drug efflux pumps and those independent of drug efflux pump mechanism by silencing Bcl-2 and HIF1α gene expressions by siRNA and miRNA, modulating ceramide levels and targeting NF-κB. “Theragnostics” combining a cytotoxic agent, targeting moiety, chemosensitizing agent, and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR. Physical approaches such as combination of drug with thermal/ultrasound/photodynamic therapies to overcome MDR are focused. The review focuses on newer drug delivery systems developed to overcome MDR in cancer cell. PMID:25071577

Applicator for in-vitro ultrasound-activated targeted drug delivery

NASA Astrophysics Data System (ADS)

Gerold, B.; Gourevich, D.; Volovick, A.; Xu, D.; Arditti, F.; Prentice, P.; Cochran, S.; Gnaim, J.; Medan, Y.; Wang, L.; Melzer, A.

2012-10-01

Reducing toxicity and improving uptake of cancer drugs in tumors are important goals of targeted drug delivery (TDD). Ultrasonic drug release from various encapsulants has been a focus of many research groups. However, a single standard ultrasonic device, viable for use by biologists, is not currently present in the market. The device reported here is designed to allow investigation of the impact of ultrasound on cellular uptake and cell viability in-vitro. In it, single-element transducers with different operating frequencies are mounted below a standard 96-well plate. The plate is moved above the transducers, such that each line of wells can be sonicated at a different frequency. To assess the device, 96-well plates were seeded with cells and sonicated using different ultrasonic parameters, with and without doxorubicin. Cell viability was measured by colorimetric MTT assay and the uptake of doxorubicin by cells was also determined. The device proved to be highly viable in preliminary tests; it demonstrated that change in ultrasonic parameters produces different effect on cells. For example, increase in uptake of doxorubicin was demonstrated following ultrasound application. The growing interest in ultrasound-activated TDD emphasizes the need for standardization of the ultrasound device and the one reported here may offer some indications of how that may be achieved. It is planned to further improve the prototype by increasing the number of ultrasonic frequencies and degrees of freedom for each transducer.

Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances

PubMed Central

Xu, Shi; Olenyuk, Bogdan Z.; Okamoto, Curtis T.; Hamm-Alvarez, Sarah F.

2012-01-01

Targeting of drugs and their carrier systems by using receptor-mediated endocytotic pathways was in its nascent stages 25 years ago. In the intervening years, an explosion of knowledge focused on design and synthesis of nanoparticulate delivery systems as well as elucidation of the cellular complexity of what was previously-termed receptor-mediated endocytosis has now created a situation when it has become possible to design and test the feasibility of delivery of highly specific nanoparticle drug carriers to specific cells and tissue. This review outlines the mechanisms governing the major modes of receptor-mediated endocytosis used in drug delivery and highlights recent approaches using these as targets for in vivo drug delivery of nanoparticles. The review also discusses some of the inherent complexity associated with the simple shift from a ligand-drug conjugate versus a ligand-nanoparticle conjugate, in terms of ligand valency and its relationship to the mode of receptor-mediated internalization. PMID:23026636

Nanomedicine and its application in treatment of microglia-mediated neuroinflammation.

PubMed

Baby, N; Patnala, R; Ling, Eng-Ang; Dheen, S T

2014-01-01

Nanomedicine, an emerging therapeutic tool in current medical frontiers, offers targeted drug delivery for many neurodegenerative disorders. Neuroinflammation, a hallmark of many neurodegenerative disorders, is mediated by microglia, the resident immunocompetent cells of the central nervous system (CNS). Microglial cells respond to various stimuli in the CNS resulting in their activation which may have a beneficial or a detrimental effect. In general, the activated microglia remove damaged neurons and infectious agents by phagocytosis, therefore being neuroprotective. However, their chronic activation exacerbates neuronal damage through excessive release of proinflammatory cytokines, chemokines and other inflammatory mediators which contribute to neuroinflammation and subsequent neurodegeneration in the CNS. Hence, controlling microglial inflammatory response and their proliferation has been considered as an important aspect in treating neurodegenerative disorders. Regulatory factors that control microglial activation and proliferation also play an important role in microglia-mediated neuroinflammation and neurotoxicity. Various anti-inflammatory drugs and herbal compounds have been identified in treating microglia-mediated neuroinflammation in the CNS. However, hurdles in crossing blood brain barrier (BBB), expression of metabolic enzymes, presence of efflux pumps and several other factors prevent the entry of these drugs into the CNS. Use of non-degradable delivery systems and microglial activation in response to the drug delivery system further complicate drug delivery to the CNS. Nanomedicine, a nanoparticle-mediated drug delivery system, exhibits immense potential to overcome these hurdles in drug delivery to the CNS enabling new alternatives with significant promises in revolutionising the field of neurodegenerative disease therapy. This review attempts to summarise various regulatory factors in microglia, existing therapeutic strategies in controlling microglial activation, and how nanotechnology can serve to improve the delivery of therapeutic drugs across the BBB for treating microglia- mediated neuroinflammation and neurodegeneration.

Thermal safety of ultrasound-enhanced ocular drug delivery: A modeling study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nabili, Marjan, E-mail: mnabili@gwmail.gwu.edu; Geist, Craig, E-mail: cgeist@mfa.gwu.edu, E-mail: zderic@gwu.edu; Zderic, Vesna, E-mail: cgeist@mfa.gwu.edu, E-mail: zderic@gwu.edu

Purpose: Delivery of sufficient amounts of therapeutic drugs into the eye for treatment of various ocular diseases is often a challenging task. Ultrasound was shown to be effective in enhancing ocular drug delivery in the authors’ previous in vitro and in vivo studies. Methods: The study reported here was designed to investigate the safety of ultrasound application and its potential thermal effects in the eye using PZFlex modeling software. The safety limit in this study was set as a temperature increase of no more than 1.5 °C based on regulatory recommendations and previous experimental safety studies. Acoustic and thermal specifications ofmore » different human eye tissues were obtained from the published literature. The tissues of particular interest in this modeling safety study were cornea, lens, and the location of optic nerve in the posterior eye. Ultrasound application was modeled at frequencies of 400 kHz–1 MHz, intensities of 0.3–1 W/cm{sup 2}, and exposure duration of 5 min, which were the parameters used in the authors’ previous drug delivery experiments. The baseline eye temperature was 37 °C. Results: The authors’ results showed that the maximal tissue temperatures after 5 min of ultrasound application were 38, 39, 39.5, and 40 °C in the cornea, 39.5, 40, 42, and 43 °C in the center of the lens, and 37.5, 38.5, and 39 °C in the back of the eye (at the optic nerve location) at frequencies of 400, 600, 800 kHz, and 1 MHz, respectively. Conclusions: The ocular temperatures reached at higher frequencies were considered unsafe based on current recommendations. At a frequency of 400 kHz and intensity of 0.8 W/cm{sup 2} (parameters shown in the authors’ previous in vivo studies to be optimal for ocular drug delivery), the temperature increase was small enough to be considered safe inside different ocular tissues. However, the impact of orbital bone and tissue perfusion should be included in future modeling efforts to determine the safety of this method in the whole orbit especially regarding potential adverse optic nerve heating at the location of the bone.« less

Ultrasound-Mediated Microbubble Destruction (UMMD) Facilitates the Delivery of CA19-9 Targeted and Paclitaxel Loaded mPEG-PLGA-PLL Nanoparticles in Pancreatic Cancer.

PubMed

Xing, Lingxi; Shi, Qiusheng; Zheng, Kailiang; Shen, Ming; Ma, Jing; Li, Fan; Liu, Yang; Lin, Lizhou; Tu, Wenzhi; Duan, Yourong; Du, Lianfang

2016-01-01

Pancreatic cancer, one of the most lethal human malignancies with dismal prognosis, is refractory to existing radio-chemotherapeutic treatment modalities. There is a critical unmet need to develop effective approaches, especially for targeted pancreatic cancer drug delivery. Targeted and drug-loaded nanoparticles (NPs) combined with ultrasound-mediated microbubble destruction (UMMD) have been shown to significantly increase the cellular uptake in vitro and drug retention in vivo, suggesting a promising strategy for cancer therapy. In this study, we synthesized pancreatic cancer-targeting organic NPs that were modified with anti CA19-9 antibody and encapsulated paclitaxol (PTX). The three-block copolymer methoxy polyethylene glycol-polylacticco-glycolic acid-polylysine (mPEG-PLGA-PLL) constituted the skeleton of the NPs. We speculated that the PTX-NPs-anti CA19-9 would circulate long-term in vivo, "actively target" pancreatic cancer cells, and sustainably release the loaded PTX while UMMD would "passively target" the irradiated tumor and effectively increase the permeability of cell membrane and capillary gaps. Our results demonstrated that the combination of PTX-NPs-anti CA19-9 with UMMD achieved a low IC50, significant cell cycle arrest, and cell apoptosis in vitro. In mouse pancreatic tumor xenografts, the combined application of PTX-NP-anti CA19-9 NPs with UMMD attained the highest tumor inhibition rate, promoted the pharmacokinetic profile by increasing AUC, t1/2, and mean residence time (MRT), and decreased clearance. Consequently, the survival of the tumor-bearing nude mice was prolonged without obvious toxicity. The dynamic change in cellular uptake, targeted real-time imaging, and the concentration of PTX in the plasma and tumor were all closely associated with the treatment efficacy both in vitro and in vivo. Our study suggests that PTX-NP-anti CA19-9 NPs combined with UMMD is a promising strategy for the treatment of pancreatic cancer.

Interactions of inertial cavitation bubbles with stratum corneum lipid bilayers during low-frequency sonophoresis.

PubMed

Tezel, Ahmet; Mitragotri, Samir

2003-12-01

Interactions of acoustic cavitation bubbles with biological tissues play an important role in biomedical applications of ultrasound. Acoustic cavitation plays a particularly important role in enhancing transdermal transport of macromolecules, thereby offering a noninvasive mode of drug delivery (sonophoresis). Ultrasound-enhanced transdermal transport is mediated by inertial cavitation, where collapses of cavitation bubbles microscopically disrupt the lipid bilayers of the stratum corneum. In this study, we describe a theoretical analysis of the interactions of cavitation bubbles with the stratum corneum lipid bilayers. Three modes of bubble-stratum corneum interactions including shock wave emission, microjet penetration into the stratum corneum, and impact of microjet on the stratum corneum are considered. By relating the mechanical effects of these events on the stratum corneum structure, the relationship between the number of cavitation events and collapse pressures with experimentally measured increase in skin permeability was established. Theoretical predictions were compared to experimentally measured parameters of cavitation events.

Ultrasound-mediated vascular gene transfection by cavitation of endothelial-targeted cationic microbubbles.

PubMed

Xie, Aris; Belcik, Todd; Qi, Yue; Morgan, Terry K; Champaneri, Shivam A; Taylor, Sarah; Davidson, Brian P; Zhao, Yan; Klibanov, Alexander L; Kuliszewski, Michael A; Leong-Poi, Howard; Ammi, Azzdine; Lindner, Jonathan R

2012-12-01

Ultrasound-mediated gene delivery can be amplified by acoustic disruption of microbubble carriers that undergo cavitation. We hypothesized that endothelial targeting of microbubbles bearing cDNA is feasible and, through optimizing proximity to the vessel wall, increases the efficacy of gene transfection. Contrast ultrasound-mediated gene delivery is a promising approach for site-specific gene therapy, although there are concerns with the reproducibility of this technique and the safety when using high-power ultrasound. Cationic lipid-shelled decafluorobutane microbubbles bearing a targeting moiety were prepared and compared with nontargeted microbubbles. Microbubble targeting efficiency to endothelial adhesion molecules (P-selectin or intercellular adhesion molecule [ICAM]-1) was tested using in vitro flow chamber studies, intravital microscopy of tumor necrosis factor-alpha (TNF-α)-stimulated murine cremaster muscle, and targeted contrast ultrasound imaging of P-selectin in a model of murine limb ischemia. Ultrasound-mediated transfection of luciferase reporter plasmid charge coupled to microbubbles in the post-ischemic hindlimb muscle was assessed by in vivo optical imaging. Charge coupling of cDNA to the microbubble surface was not influenced by the presence of targeting ligand, and did not alter the cavitation properties of cationic microbubbles. In flow chamber studies, surface conjugation of cDNA did not affect attachment of targeted microbubbles at microvascular shear stresses (0.6 and 1.5 dyne/cm(2)). Attachment in vivo was also not affected by cDNA according to intravital microscopy observations of venular adhesion of ICAM-1-targeted microbubbles and by ultrasound molecular imaging of P-selectin-targeted microbubbles in the post-ischemic hindlimb in mice. Transfection at the site of high acoustic pressures (1.0 and 1.8 MPa) was similar for control and P-selectin-targeted microbubbles but was associated with vascular rupture and hemorrhage. At 0.6 MPa, there were no adverse bioeffects, and transfection was 5-fold greater with P-selectin-targeted microbubbles. We conclude that ultrasound-mediated transfection at safe acoustic pressures can be markedly augmented by endothelial juxtaposition. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Ultrasound-Mediated Vascular Gene Transfection by Cavitation of Endothelial-Targeted Cationic Microbubbles

PubMed Central

Xie, Aris; Belcik, Todd; Qi, Yue; Morgan, Terry K.; Champaneri, Shivam A.; Taylor, Sarah; Davidson, Brian P.; Zhao, Yan; Klibanov, Alexander L.; Kuliszewski, Michael A.; Leong-Poi, Howard; Ammi, Azzdine; Lindner, Jonathan R.

2013-01-01

OBJECTIVES Ultrasound-mediated gene delivery can be amplified by acoustic disruption of microbubble carriers that undergo cavitation. We hypothesized that endothelial targeting of microbubbles bearing cDNA is feasible and, through optimizing proximity to the vessel wall, increases the efficacy of gene transfection. BACKGROUND Contrast ultrasound-mediated gene delivery is a promising approach for site-specific gene therapy, although there are concerns with the reproducibility of this technique and the safety when using high-power ultrasound. METHODS Cationic lipid-shelled decafluorobutane microbubbles bearing a targeting moiety were prepared and compared with nontargeted microbubbles. Microbubble targeting efficiency to endothelial adhesion molecules (P-selectin or intercellular adhesion molecule [ICAM]-1) was tested using in vitro flow chamber studies, intravital microscopy of tumor necrosis factor-alpha (TNF-α)–stimulated murine cremaster muscle, and targeted contrast ultrasound imaging of P-selectin in a model of murine limb ischemia. Ultrasound-mediated transfection of luciferase reporter plasmid charge coupled to microbubbles in the post-ischemic hindlimb muscle was assessed by in vivo optical imaging. RESULTS Charge coupling of cDNA to the microbubble surface was not influenced by the presence of targeting ligand, and did not alter the cavitation properties of cationic microbubbles. In flow chamber studies, surface conjugation of cDNA did not affect attachment of targeted microbubbles at microvascular shear stresses (0.6 and 1.5 dyne/cm2). Attachment in vivo was also not affected by cDNA according to intravital microscopy observations of venular adhesion of ICAM-1–targeted microbubbles and by ultrasound molecular imaging of P-selectin–targeted microbubbles in the post-ischemic hindlimb in mice. Transfection at the site of high acoustic pressures (1.0 and 1.8 MPa) was similar for control and P-selectin–targeted microbubbles but was associated with vascular rupture and hemorrhage. At 0.6 MPa, there were no adverse bioeffects, and transfection was 5-fold greater with P-selectin–targeted microbubbles. CONCLUSIONS We conclude that ultrasound-mediated transfection at safe acoustic pressures can be markedly augmented by endothelial juxtaposition. PMID:23236976

CAVITATION THRESHOLD OF MICROBUBBLES IN GEL TUNNELS BY FOCUSED ULTRASOUND

PubMed Central

Sassaroli, E.; Hynynen, K.

2007-01-01

The investigation of inertial cavitation in micro-tunnels has significant implications for the development of therapeutic applications of ultrasound such as ultrasound-mediated drug and gene delivery. The threshold for inertial cavitation was investigated using a passive cavitation detector with a center frequency of 1 MHz. Micro-tunnels of various diameters (90 to 800 μm) embedded in gel were fabricated and injected with a solution of Optison™ contrast agent of concentrations 1.2% and 0.2% diluted in water. An ultrasound pulse of duration 500 ms and center frequency 1.736 MHz was used to insonate the microbubbles. The acoustic pressure was increased at one second intervals until broadband noise emission was detected. The pressure threshold at which broadband noise emission was observed was found to be dependent on the diameter of the micro-tunnels, with an average increase of 1.2 to 1.5 between the smallest and the largest tunnels, depending on the microbubble concentration. The evaluation of inertial cavitation in gel tunnels rather than tubes provides a novel opportunity to investigate microbubble collapse in a situation that simulates in vivo blood vessels better than tubes with solid walls do. PMID:17590501

Nanoparticle mediated non-covalent drug delivery☆

PubMed Central

Doane, Tennyson; Burda, Clemens

2013-01-01

The use of nanoparticles (NPs) for enhanced drug delivery has been heavily explored during the last decade. Within the field, it is has become increasingly apparent that the physical properties of the particles themselves dictate their efficacy, and the relevant non-covalent chemistry at the NP interface also influences how drugs are immobilized and delivered. In this review, we reflect on the physical chemistry of NP mediated drug delivery (and more specifically, non-covalent drug delivery) at the three main experimental stages of drug loading, NP–drug conjugate transport, and the resulting cellular drug delivery. Through a critical evaluation of advances in drug delivery within the last decade, an outlook for biomedical applications of nanoscale transport vectors will be presented. PMID:22664231

A REVIEW OF LOW-INTENSITY ULTRASOUND FOR CANCER THERAPY

PubMed Central

WOOD, ANDREW K. W.; SEHGAL, CHANDRA M.

2015-01-01

The literature describing the use of low-intensity ultrasound in four major areas of cancer therapy was reviewed - sonodynamic therapy, ultrasound mediated chemotherapy, ultrasound mediated gene delivery and antivascular ultrasound therapy. Each technique consistently resulted in the death of cancer cells and the bioeffects of ultrasound were primarily attributed to thermal actions and inertial cavitation. In each therapeutic modality, theranostic contrast agents composed of microbubbles played a role in both therapy and vascular imaging. The development of these agents is important as it establishes a therapeutic-diagnostic platform which can monitor the success of anti-cancer therapy. Little attention, however, has been given to either the direct assessment of the underlying mechanisms of the observed bioeffects or to the viability of these therapies in naturally occurring cancers in larger mammals; if such investigations provided encouraging data there could be a prompt application of a therapy technique in treating cancer patients. PMID:25728459

Peptides for Specific Intracellular Delivery and Targeting of Nanoparticles: Implications for Developing Nanoparticle-Mediated Drug Delivery

DTIC Science & Technology

2010-01-01

for selective delivery of therapeutics and imaging agents to the tumour vasculature. Drug Resist. Update 8(6), 381–402 (2005). 89 Smith BR, Cheng Z...component can be realized. Select examples from the literature have already demonstrated the feasibility of generating hybrid NP–peptide constructs in...peptide-mediated delivery of NP-based imaging agents (fluorescence and magnetic resonance), drug-delivery vehicles, therapeutic proteins and nucleic

Deep tissue penetration of nanoparticles using pulsed-high intensity focused ultrasound

NASA Astrophysics Data System (ADS)

You, Dong Gil; Yoon, Hong Yeol; Jeon, Sangmin; Um, Wooram; Son, Sejin; Park, Jae Hyung; Kwon, Ick Chan; Kim, Kwangmeyung

2017-11-01

Recently, ultrasound (US)-based drug delivery strategies have received attention to improve enhanced permeation and retention (EPR) effect-based passive targeting efficiency of nanoparticles in vitro and in vivo conditions. Among the US treatment techniques, pulsed-high intensity focused ultrasound (pHIFU) have specialized for improving tissue penetration of various macromolecules and nanoparticles without irreversible tissue damages. In this study, we have demonstrated that pHIFU could be utilized to improve tissue penetration of fluorescent dye-labeled glycol chitosan nanoparticles (FCNPs) in femoral tissue of mice. pHIFU could improve blood flow of the targeted-blood vessel in femoral tissue. In addition, tissue penetration of FCNPs was specifically increased 5.7-, 8- and 9.3-folds than that of non-treated (0 W pHIFU) femoral tissue, when the femoral tissue was treated with 10, 20 and 50 W of pHIFU, respectively. However, tissue penetration of FCNPs was significantly reduced after 3 h post-pHIFU treatment (50 W). Because overdose (50 W) of pHIFU led to irreversible tissue damages, including the edema and chapped red blood cells. These overall results support that pHIFU treatment can enhance the extravasation and tissue penetration of FCNPs as well as induce irreversible tissue damages. We expect that our results can provide advantages to optimize pHIFU-mediated delivery strategy of nanoparticles for further clinical applications.

The Endoplasmic Reticulum Stress Protein Calreticulin in Diabetic Chronic Kidney Disease

DTIC Science & Technology

2015-07-01

lines and for use in long-term assays. For aim 2, we established that 0.7 mPa of ultrasound to deliver cre- recombinase plasmid to the kidney is...using kidney targeted microbubble/ ultrasound -mediated plasmid delivery. We will also examine non-targeted CRT knockdown in these mice. Aim 2.b: We will...diabetes, chronic kidney disease, diabetic nephropathy, calreticulin, TGF-beta, ER stress, ultrasound , tubulointerstitial fibrosis 4 3. ACCOMPLISHMENTS a

Comparison of gene delivery techniques for therapeutic angiogenesis ultrasound-mediated destruction of carrier microbubbles versus direct intramuscular injection.

PubMed

Kobulnik, Jeremy; Kuliszewski, Michael A; Stewart, Duncan J; Lindner, Jonathan R; Leong-Poi, Howard

2009-10-27

This study was designed to compare the efficacy of angiogenic gene delivery by ultrasound-mediated (UM) destruction of intravenous carrier microbubbles to direct intramuscular (IM) injections. Current trials of gene therapy for angiogenesis remain limited by suboptimal, invasive delivery techniques. Hind-limb ischemia was produced by iliac artery ligation in 99 rats. In 32 rats, UM delivery of green fluorescent protein (GFP)/vascular endothelial growth factor-165 (VEGF(165)) plasmid deoxyribonucleic acid was performed. Thirty-five animals received IM injections of VEGF(165)/GFP plasmid. Remaining rats received no treatment. Before delivery (day 14 after ligation) and at days 17, 21, and 28 and week 8 after ligation, microvascular blood volume and microvascular blood flow to the proximal hind limbs were assessed by contrast-enhanced ultrasound (n = 8 per group). Total transfection was assessed by reverse transcriptase-polymerase chain reaction, and localization of transfection was determined by immunohistochemistry. By day 28, both IM and UM delivery of VEGF(165) produced significant increases in microvascular blood volume and microvascular blood flow. Whereas increases in microvascular blood volume were similar between treatment groups, microvascular blood flow was greater (p < 0.005) in UM-treated animals as compared with IM-treated animals, persisting to week 8. The VEGF(165)/GFP messenger ribonucleic acid expression was greater (p < 0.05) for IM-treated animals. A strong GFP signal was detected for both groups and was localized to focal perivascular regions and myocytes around injection sites for IM and to the vascular endothelium of arterioles/capillaries in a wider distribution for UM delivery. Despite lower transfection levels, UM delivery of VEGF(165) is as effective as IM injections. The UM delivery results in directed vascular transfection over a wider distribution, which may account for the more efficient angiogenesis.

Stably engineered nanobubbles and ultrasound - An effective platform for enhanced macromolecular delivery to representative cells of the retina.

PubMed

Thakur, Sachin S; Ward, Micheal S; Popat, Amirali; Flemming, Nicole B; Parat, Marie-Odile; Barnett, Nigel L; Parekh, Harendra S

2017-01-01

Herein we showcase the potential of ultrasound-responsive nanobubbles in enhancing macromolecular permeation through layers of the retina, ultimately leading to significant and direct intracellular delivery; this being effectively demonstrated across three relevant and distinct retinal cell lines. Stably engineered nanobubbles of a highly homogenous and echogenic nature were fully characterised using dynamic light scattering, B-scan ultrasound and transmission electron microscopy (TEM). The nanobubbles appeared as spherical liposome-like structures under TEM, accompanied by an opaque luminal core and darkened corona around their periphery, with both features indicative of efficient gas entrapment and adsorption, respectively. A nanobubble +/- ultrasound sweeping study was conducted next, which determined the maximum tolerated dose for each cell line. Detection of underlying cellular stress was verified using the biomarker heat shock protein 70, measured before and after treatment with optimised ultrasound. Next, with safety to nanobubbles and optimised ultrasound demonstrated, each human or mouse-derived cell population was incubated with biotinylated rabbit-IgG in the presence and absence of ultrasound +/- nanobubbles. Intracellular delivery of antibody in each cell type was then quantified using Cy3-streptavidin. Nanobubbles and optimised ultrasound were found to be negligibly toxic across all cell lines tested. Macromolecular internalisation was achieved to significant, yet varying degrees in all three cell lines. The results of this study pave the way towards better understanding mechanisms underlying cellular responsiveness to ultrasound-triggered drug delivery in future ex vivo and in vivo models of the posterior eye.

Stably engineered nanobubbles and ultrasound - An effective platform for enhanced macromolecular delivery to representative cells of the retina

PubMed Central

Thakur, Sachin S.; Ward, Micheal S.; Popat, Amirali; Flemming, Nicole B.; Parat, Marie-Odile; Barnett, Nigel L.

2017-01-01

Herein we showcase the potential of ultrasound-responsive nanobubbles in enhancing macromolecular permeation through layers of the retina, ultimately leading to significant and direct intracellular delivery; this being effectively demonstrated across three relevant and distinct retinal cell lines. Stably engineered nanobubbles of a highly homogenous and echogenic nature were fully characterised using dynamic light scattering, B-scan ultrasound and transmission electron microscopy (TEM). The nanobubbles appeared as spherical liposome-like structures under TEM, accompanied by an opaque luminal core and darkened corona around their periphery, with both features indicative of efficient gas entrapment and adsorption, respectively. A nanobubble +/- ultrasound sweeping study was conducted next, which determined the maximum tolerated dose for each cell line. Detection of underlying cellular stress was verified using the biomarker heat shock protein 70, measured before and after treatment with optimised ultrasound. Next, with safety to nanobubbles and optimised ultrasound demonstrated, each human or mouse-derived cell population was incubated with biotinylated rabbit-IgG in the presence and absence of ultrasound +/- nanobubbles. Intracellular delivery of antibody in each cell type was then quantified using Cy3-streptavidin. Nanobubbles and optimised ultrasound were found to be negligibly toxic across all cell lines tested. Macromolecular internalisation was achieved to significant, yet varying degrees in all three cell lines. The results of this study pave the way towards better understanding mechanisms underlying cellular responsiveness to ultrasound-triggered drug delivery in future ex vivo and in vivo models of the posterior eye. PMID:28542473

Acoustic Cluster Therapy: In Vitro and Ex Vivo Measurement of Activated Bubble Size Distribution and Temporal Dynamics.

PubMed

Healey, Andrew John; Sontum, Per Christian; Kvåle, Svein; Eriksen, Morten; Bendiksen, Ragnar; Tornes, Audun; Østensen, Jonny

2016-05-01

Acoustic cluster technology (ACT) is a two-component, microparticle formulation platform being developed for ultrasound-mediated drug delivery. Sonazoid microbubbles, which have a negative surface charge, are mixed with micron-sized perfluoromethylcyclopentane droplets stabilized with a positively charged surface membrane to form microbubble/microdroplet clusters. On exposure to ultrasound, the oil undergoes a phase change to the gaseous state, generating 20- to 40-μm ACT bubbles. An acoustic transmission technique is used to measure absorption and velocity dispersion of the ACT bubbles. An inversion technique computes bubble size population with temporal resolution of seconds. Bubble populations are measured both in vitro and in vivo after activation within the cardiac chambers of a dog model, with catheter-based flow through an extracorporeal measurement flow chamber. Volume-weighted mean diameter in arterial blood after activation in the left ventricle was 22 μm, with no bubbles >44 μm in diameter. After intravenous administration, 24.4% of the oil is activated in the cardiac chambers. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Micro- and nanobubbles: a versatile non-viral platform for gene delivery.

PubMed

Cavalli, Roberta; Bisazza, Agnese; Lembo, David

2013-11-18

Micro- and nanobubbles provide a promising non-viral strategy for ultrasound mediated gene delivery. Microbubbles are spherical gas-filled structures with a mean diameter of 1-8 μm, characterised by their core-shell composition and their ability to circulate in the bloodstream following intravenous injection. They undergo volumetric oscillations or acoustic cavitation when insonified by ultrasound and, most importantly, they are able to resonate at diagnostic frequencies. It is due to this behaviour that microbubbles are currently being used as ultrasound contrast agents, but their use in therapeutics is still under investigation. For example, microbubbles could play a role in enhancing gene delivery to cells: when combined with clinical ultrasound exposure, microbubbles are able to favour gene entry into cells by cavitation. Two different delivery strategies have been used to date: DNA can be co-administered with the microbubbles (i.e. the contrast agent) or 'loaded' in purposed-built bubble systems - indeed a number of different technological approaches have been proposed to associate genes within microbubble structures. Nanobubbles, bubbles with sizes in the nanometre order of magnitude, have also been developed with the aim of obtaining more efficient gene delivery systems. Their small sizes allow the possibility of extravasation from blood vessels into the surrounding tissues and ultrasound-targeted site-specific release with minimal invasiveness. In contrast, microbubbles, due to their larger sizes, are unable to extravasate, thus and their targeting capacity is limited to specific antigens present within the vascular lumen. This review provides an overview of the use of microbubbles as gene delivery systems, with a specific focus on recent research into the development of nanosystems. In particular, ultrasound delivery mechanisms, formulation parameters, gene-loading approaches and the advantages of nanometric systems will be described. Copyright © 2013 Elsevier B.V. All rights reserved.

Targeted Soft Biodegradable Glycine/PEG/RGD-Modified Poly(methacrylic acid) Nanobubbles as Intelligent Theranostic Vehicles for Drug Delivery.

PubMed

Li, Yongjing; Wan, Jiaxun; Zhang, Zihao; Guo, Jia; Wang, Changchun

2017-10-18

The development of multifunctional ultrasound contrast agents has inspired considerable interest in the application of biomedical imaging and anticancer therapeutics. However, combining multiple components that can preferentially accumulate in tumors in a nanometer scale poses one of the major challenges in targeting drug delivery for theranostic application. Herein, reflux-precipitation polymerization, and N-(3-(dimethylamino)propyl)-N'-ethylcarbodiimide-meditated amidation reaction were introduced to effectively generate a new type of soft glycine/poly(ethylene glycol) (PEG)/RGD-modified poly(methacrylic acid) nanobubbles with a uniform morphology and desired particle size (less than 100 nm). Because of the enhanced biocompatibility resulting from the glycine modification, over 80% of the cells survived, even though the dosage of glycine-modified polymeric nanobubbles was up to 5 mg/mL. By loading doxorubicin as an anticancer drug and perfluorohexane as an ultrasound probe, the resulting glycine/PEG/RGD-modified nanobubbles showed remarkable cancer therapeutic efficacy and a high quality of ultrasonic imaging; thus, the ultrasonic signal exhibited a 1.47-fold enhancement at the tumor site after intravenous injection. By integrating diagnostic and therapeutic functions into a single nanobubble, the new type of theranostic nanobubbles offers a promising strategy to monitor the therapeutic effects, giving important insights into the ultrasound-traced and enhanced targeting drug delivery in biomedical applications.

Polymer Coated Echogenic Lipid Nanoparticles with Dual Release Triggers

PubMed Central

Nahire, Rahul; Haldar, Manas K.; Paul, Shirshendu; Mergoum, Anaas; Ambre, Avinash H.; Katti, Kalpana S.; Gange, Kara N.; Srivastava, D. K.; Sarkar, Kausik; Mallik, Sanku

2013-01-01

Although lipid nanoparticles are promising drug delivery vehicles, passive release of encapsulated contents at the target site is often slow. Herein, we report contents release from targeted, polymer coated, echogenic lipid nanoparticles in the cell cytoplasm by redox trigger and simultaneously enhanced by diagnostic frequency ultrasound. The lipid nanoparticles were polymerized on the external leaflet using a disulfide cross-linker. In the presence of cytosolic concentrations of glutathione, the lipid nanoparticles released 76% of encapsulated contents. Plasma concentrations of glutathione failed to release the encapsulated contents. Application of 3 MHz ultrasound for 2 minutes simultaneously with the reducing agent enhanced the release to 96%. Folic acid conjugated, doxorubicin loaded nanoparticles showed enhanced uptake and higher cytotoxicity in cancer cells overexpressing the folate receptor (compared to the control). With further developments, these lipid nanoparticles have the potential to be used as multimodal nanocarriers for simultaneous targeted drug delivery and ultrasound imaging. PMID:23394107

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

PubMed Central

2013-01-01

Brain diseases are notoriously difficult to treat due to the presence of the blood-brain barrier (BBB). Here, we review the development of focused ultrasound (FUS) as a noninvasive method for BBB disruption, aiding in drug delivery to the brain. FUS can be applied through the skull to a targeted region in the brain. When combined with microbubbles, FUS causes localized and reversible disruption of the BBB. The cellular mechanisms of BBB disruption are presented. Several therapeutic agents have been delivered to the brain resulting in significant improvements in pathology in models of glioblastoma and Alzheimer’s disease. The requirements for clinical translation of FUS will be discussed. PMID:23379618

Microbubble Compositions, Properties and Biomedical Applications

PubMed Central

Sirsi, Shashank

2010-01-01

Over the last decade, there has been significant progress towards the development of microbubbles as theranostics for a wide variety of biomedical applications. The unique ability of microbubbles to respond to ultrasound makes them useful agents for contrast ultrasound imaging, molecular imaging, and targeted drug and gene delivery. The general composition of a microbubble is a gas core stabilized by a shell comprised of proteins, lipids or polymers. Each type of microbubble has its own unique advantages and can be tailored for specialized functions. In this review, different microbubbles compositions and physiochemical properties are discussed in the context of current progress towards developing novel constructs for biomedical applications, with specific emphasis on molecular imaging and targeted drug/gene delivery. PMID:20574549

Cardiac Gene Expression Knockdown Using Small Inhibitory RNA-Loaded Microbubbles and Ultrasound.

PubMed

Kopechek, Jonathan A; Carson, Andrew R; McTiernan, Charles F; Chen, Xucai; Klein, Edwin C; Villanueva, Flordeliza S

2016-01-01

RNA interference has potential therapeutic value for cardiac disease, but targeted delivery of interfering RNA is a challenge. Custom designed microbubbles, in conjunction with ultrasound, can deliver small inhibitory RNA to target tissues in vivo. The efficacy of cardiac RNA interference using a microbubble-ultrasound theranostic platform has not been demonstrated in vivo. Therefore, our objective was to test the hypothesis that custom designed microbubbles and ultrasound can mediate effective delivery of small inhibitory RNA to the heart. Microbubble and ultrasound mediated cardiac RNA interference was tested in transgenic mice displaying cardiac-restricted luciferase expression. Luciferase expression was assayed in select tissues of untreated mice (n = 14). Mice received intravenous infusion of cationic microbubbles bearing small inhibitory RNA directed against luciferase (n = 9) or control RNA (n = 8) during intermittent cardiac-directed ultrasound at mechanical index of 1.6. Simultaneous echocardiography in a separate group of mice (n = 3) confirmed microbubble destruction and replenishment during treatment. Three days post treatment, cardiac luciferase messenger RNA and protein levels were significantly lower in ultrasound-treated mice receiving microbubbles loaded with small inhibitory RNA directed against luciferase compared to mice receiving microbubbles bearing control RNA (23±7% and 33±7% of control mice, p<0.01 and p = 0.03, respectively). Passive cavitation detection focused on the heart confirmed that insonification resulted in inertial cavitation. In conclusion, small inhibitory RNA-loaded microbubbles and ultrasound directed at the heart significantly reduced the expression of a reporter gene. Ultrasound-targeted destruction of RNA-loaded microbubbles may be an effective image-guided strategy for therapeutic RNA interference in cardiac disease.

Ultrasound imaging beyond the vasculature with new generation contrast agents.

PubMed

Perera, Reshani H; Hernandez, Christopher; Zhou, Haoyan; Kota, Pavan; Burke, Alan; Exner, Agata A

2015-01-01

Current commercially available ultrasound contrast agents are gas-filled, lipid- or protein-stabilized microbubbles larger than 1 µm in diameter. Because the signal generated by these agents is highly dependent on their size, small yet highly echogenic particles have been historically difficult to produce. This has limited the molecular imaging applications of ultrasound to the blood pool. In the area of cancer imaging, microbubble applications have been constrained to imaging molecular signatures of tumor vasculature and drug delivery enabled by ultrasound-modulated bubble destruction. Recently, with the rise of sophisticated advancements in nanomedicine, ultrasound contrast agents, which are an order of magnitude smaller (100-500 nm) than their currently utilized counterparts, have been undergoing rapid development. These agents are poised to greatly expand the capabilities of ultrasound in the field of targeted cancer detection and therapy by taking advantage of the enhanced permeability and retention phenomenon of many tumors and can extravasate beyond the leaky tumor vasculature. Agent extravasation facilitates highly sensitive detection of cell surface or microenvironment biomarkers, which could advance early cancer detection. Likewise, when combined with appropriate therapeutic agents and ultrasound-mediated deployment on demand, directly at the tumor site, these nanoparticles have been shown to contribute to improved therapeutic outcomes. Ultrasound's safety profile, broad accessibility and relatively low cost make it an ideal modality for the changing face of healthcare today. Aided by the multifaceted nano-sized contrast agents and targeted theranostic moieties described herein, ultrasound can considerably broaden its reach in future applications focused on the diagnosis and staging of cancer. © 2015 Wiley Periodicals, Inc.

Ultrasound Imaging Beyond the Vasculature with New Generation Contrast Agents

PubMed Central

Perera, Reshani H.; Hernandez, Christopher; Zhou, Haoyan; Kota, Pavan; Burke, Alan

2015-01-01

Current commercially available ultrasound contrast agents are gas-filled, lipid- or protein-stabilized microbubbles larger than 1 μm in diameter. Because the signal generated by these agents is highly dependent on their size, small yet highly echogenic particles have been historically difficult to produce. This has limited the molecular imaging applications of ultrasound to the blood pool. In the area of cancer imaging, microbubble applications have been constrained to imaging molecular signatures of tumor vasculature and drug delivery enabled by ultrasound-modulated bubble destruction. Recently, with the rise of sophisticated advancements in nanomedicine, ultrasound contrast agents, which are an order of magnitude smaller (100-500 nm) than their currently utilized counterparts, have been undergoing rapid development. These agents are poised to greatly expand the capabilities of ultrasound in the field of targeted cancer detection and therapy by taking advantage of the enhanced permeability and retention phenomenon of many tumors and can extravasate beyond the leaky tumor vasculature. Agent extravasation facilitates highly sensitive detection of cell surface or microenvironment biomarkers, which could advance early cancer detection. Likewise, when combined with appropriate therapeutic agents and ultrasound-mediated deployment on demand, directly at the tumor site, these nanoparticles have been shown to contribute to improved therapeutic outcomes. Ultrasound's safety profile, broad accessibility and relatively low cost make it an ideal modality for the changing face of healthcare today. Aided by the multifaceted nano-sized contrast agents and targeted theranostic moieties described herein, ultrasound can considerably broaden its reach in future applications focused on the diagnosis and staging of cancer. PMID:25580914

Routes for Drug Translocation Across the Blood-Brain Barrier: Exploiting Peptides as Delivery Vectors.

PubMed

Kristensen, Mie; Brodin, Birger

2017-09-01

A number of potent drugs for the treatment of brain diseases are available. However, in order for them to reach their target site of action, they must pass the blood-brain barrier (BBB). The capillary endothelium comprises the major barrier of the BBB and allows only passive permeation of some small lipophilic molecules. Brain delivery of the larger biopharmaceuticals, which today includes an increasing number of novel drug entities, is therefore restricted, both due to their molecular size and their hydrophilic nature. Thus, the development of novel drug entities intended for the treatment of brain diseases such as neurodegenerative diseases or brain cancers require a delivery strategy for overcoming the BBB before reaching its final target within the brain. Peptide-based delivery vector is an emerging tool as shuttles for drug delivery across the BBB and one may explore receptor-mediated transcytosis, adsorptive-mediated transcytosis, and the paracellular route. The latter, however, being controversial due to the risk of co-delivery of blood-borne potential harmful substances. On the other hand, a number of studies report on drug delivery across the BBB exploiting receptor-mediated transcytosis and adsorptive-mediated transcytosis, indicating that peptides and peptide vectors may be of use in a central nervous system delivery context. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Phase-shift, stimuli-responsive drug carriers for targeted delivery

PubMed Central

O’Neill, Brian E; Rapoport, Natalya

2011-01-01

The intersection of particles and directed energy is a rich source of novel and useful technology that is only recently being realized for medicine. One of the most promising applications is directed drug delivery. This review focuses on phase-shift nanoparticles (that is, particles of submicron size) as well as micron-scale particles whose action depends on an external-energy triggered, first-order phase shift from a liquid to gas state of either the particle itself or of the surrounding medium. These particles have tremendous potential for actively disrupting their environment for altering transport properties and unloading drugs. This review covers in detail ultrasound and laser-activated phase-shift nano- and micro-particles and their use in drug delivery. Phase-shift based drug-delivery mechanisms and competing technologies are discussed. PMID:22059114

Development and characterization of multifunctional nanoparticles for drug delivery to cancer cells

NASA Astrophysics Data System (ADS)

Nahire, Rahul Rajaram

Lipid and polymeric nanoparticles, although proven to be effective drug delivery systems compared to free drugs, have shown considerable limitations pertaining to their uptake and release at tumor sites. Spatial and temporal control over the delivery of anticancer drugs has always been challenge to drug delivery scientists. Here, we have developed and characterized multifunctional nanoparticles (liposomes and polymersomes) which are targeted specifically to cancer cells, and release their contents with tumor specific internal triggers. To enable these nanoparticles to be tracked in blood circulation, we have imparted them with echogenic characteristic. Echogenicity of nanoparticles is evaluated using ultrasound scattering and imaging experiments. Nanoparticles demonstrated effective release with internal triggers such as elevated levels of MMP-9 enzyme found in the extracellular matrix of tumor cells, decreased pH of lysosome, and differential concentration of reducing agents in cytosol of cancer cells. We have also successfully demonstrated the sensitivity of these particles towards ultrasound to further enhance the release with internal triggers. To ensure the selective uptake by folate receptor- overexpressing cancer cells, we decorated these nanoparticles with folic acid on their surface. Fluorescence microscopic images showed significantly higher uptake of folate-targeted nanoparticles by MCF-7 (breast cancer) and PANC-1 (pancreatic cancer) cells compared to particles without any targeting ligand on their surface. To demonstrate the effectiveness of these nanoparticles to carry the drugs inside and kill cancer cells, we encapsulated doxorubicin and/or gemcitabine employing the pH gradient method. Drug loaded nanoparticles showed significantly higher killing of the cancer cells compared to their non-targeted counterparts and free drugs. With further development, these nanoparticles certainly have potential to be used as a multifunctional nanocarriers for image guided, targeted delivery of anticancer drugs.

MR-Guided Pulsed High-Intensity Focused Ultrasound Enhancement of Gene Therapy Combined With Androgen Deprivation and Radiotherapy for Prostate Cancer Treatment

DTIC Science & Technology

2009-09-01

first statement of work is to determine if high intensity focused ultrasound ( HIFU ) increases the cellular uptake of AS-MDM2, AS-bcl-2 and AS-PKA...Drug Delivery in Prostate Tumor in vivo Using MR Guided Focused Ultrasound (MRg HIFU ). WC, IFMBE Proceedings 25: pp341-344, 2009 6...pharmaceutical agents in the treatment target. In the model system proposed, pulsed high intensity focused ultrasound ( HIFU ) is hypothesized to improve

Theranostic system for drug delivery and pharmacokinetic imaging based on nanosecond pulsed light-induced photomechanical and photoacoustic effects

NASA Astrophysics Data System (ADS)

Tsunoi, Yasuyuki; Sato, Shunichi; Kawauchi, Satoko; Akutsu, Yusuke; Miyagawa, Yoshihiro; Araki, Koji; Shiotani, Akihiro; Terakawa, Mitsuhiro

2015-11-01

For efficient and side effects-free pharmacological treatment, we here propose a theranostic system that enables transvascular drug delivery by photomechanical waves (PMWs) and photoacoustic (PA) imaging of the drug distribution; both functions are based on nanosecond laser pulses and can therefore be integrated in one system. Through optical fibers arranged around an ultrasound sensor, low-energy and high-energy nanosecond light pulses were transmitted respectively for PA imaging and PMW-based drug delivery by temporal switching. With the system, we delivered a test drug (Evans blue) to tumors in mice and visualized distributions of both the blood vessels and drug in the tissue in vivo, showing the validity of the system.

Mechanisms of the ultrasound-mediated intracellular delivery of liposomes and dextrans.

PubMed

Afadzi, Mercy; Strand, Sabina P; Nilssen, Esben A; Måsøy, Svein-Erik; Johansen, Tonni F; Hansen, Rune; Angelsen, Bjørn A; de L Davies, Catharina

2013-01-01

The mechanism involved in the ultrasoundenhanced intracellular delivery of fluorescein-isothiocyanate (FITC)-dextran (molecular weight 4 to 2000 kDa) and liposomes containing doxorubicin (Dox) was studied using HeLa cells and an ultrasound transducer at 300 kHz, varying the acoustic power. The cellular uptake and cell viability were measured using flow cytometry and confocal microscopy. The role of endocytosis was investigated by inhibiting clathrin- and caveolae-mediated endocytosis, as well as macropinocytosis. Microbubbles were found to be required during ultrasound treatment to obtain enhanced cellular uptake. The percentage of cells internalizing Dox and dextran increased with increasing mechanical index. Confocal images and flow cytometric analysis indicated that the liposomes were disrupted extracellularly and that released Dox was taken up by the cells. The percentage of cells internalizing dextran was independent of the molecular weight of dextrans, but the amount of the small 4-kDa dextran molecules internalized per cell was higher than for the other dextrans. The inhibition of endocytosis during ultrasound exposure resulted in a significant decrease in cellular uptake of dextrans. Therefore, the improved uptake of Dox and dextrans may be a result of both sonoporation and endocytosis.

Intraparenchymal ultrasound application and improved distribution of infusate with convection-enhanced delivery in rodent and nonhuman primate brain.

PubMed

Mano, Yui; Saito, Ryuta; Haga, Yoichi; Matsunaga, Tadao; Zhang, Rong; Chonan, Masashi; Haryu, Shinya; Shoji, Takuhiro; Sato, Aya; Sonoda, Yukihiko; Tsuruoka, Noriko; Nishiyachi, Keisuke; Sumiyoshi, Akira; Nonaka, Hiroi; Kawashima, Ryuta; Tominaga, Teiji

2016-05-01

OBJECT Convection-enhanced delivery (CED) is an effective drug delivery method that delivers high concentrations of drugs directly into the targeted lesion beyond the blood-brain barrier. However, the drug distribution attained using CED has not satisfactorily covered the entire targeted lesion in tumors such as glioma. Recently, the efficacy of ultrasound assistance was reported for various drug delivery applications. The authors developed a new ultrasound-facilitated drug delivery (UFD) system that enables the application of ultrasound at the infusion site. The purpose of this study was to demonstrate the efficacy of the UFD system and to examine effective ultrasound profiles. METHODS The authors fabricated a steel bar-based device that generates ultrasound and enables infusion of the aqueous drug from one end of the bar. The volume of distribution (Vd) after infusion of 10 ml of 2% Evans blue dye (EBD) into rodent brain was tested with different frequencies and applied voltages: 252 kHz/30 V; 252 kHz/60 V; 524 kHz/13 V; 524 kHz/30 V; and 524 kHz/60 V. In addition, infusion of 5 mM gadopentetate dimeglumine (Gd-DTPA) was tested with 260 kHz/60 V, the distribution of which was evaluated using a 7-T MRI unit. In a nonhuman primate (Macaca fascicularis) study, 300 μl of 1 mM Gd-DTPA/EBD was infused. The final distribution was evaluated using MRI. Two-sample comparisons were made by Student t-test, and 1-way ANOVA was used for multiple comparisons. Significance was set at p < 0.05. RESULTS After infusion of 10 μl of EBD into the rat brain using the UFD system, the Vds of EBD in the UFD groups were significantly larger than those of the control group. When a frequency of 252 kHz was applied, the Vd of the group in which 60 V was applied was significantly larger than that of the group in which 30 V was used. When a frequency of 524 kHz was applied, the Vd tended to increase with application of a higher voltage; however, the differences were not significant (1-way ANOVA). The Vd of Gd-DTPA was also significantly larger in the UFD group than in the control group (p < 0.05, Student t-test). The volume of Gd-DTPA in the nonhuman primate used in this study was 1209.8 ± 193.6 mm(3). This volume was much larger than that achieved by conventional CED (568.6 ± 141.0 mm(3)). CONCLUSIONS The UFD system facilitated the distribution of EBD and Gd-DTPA more effectively than conventional CED. Lower frequency and higher applied voltage using resonance frequencies might be more effective to enlarge the Vd. The UFD system may provide a new treatment approach for CNS disorders.

Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma of a metastatic brain tumour model

PubMed Central

Baghirov, Habib; Snipstad, Sofie; Sulheim, Einar; Berg, Sigrid; Hansen, Rune; Thorsen, Frits; Mørch, Yrr; Åslund, Andreas K. O.

2018-01-01

The treatment of brain diseases is hindered by the blood-brain barrier (BBB) preventing most drugs from entering the brain. Focused ultrasound (FUS) with microbubbles can open the BBB safely and reversibly. Systemic drug injection might induce toxicity, but encapsulation into nanoparticles reduces accumulation in normal tissue. Here we used a novel platform based on poly(2-ethyl-butyl cyanoacrylate) nanoparticle-stabilized microbubbles to permeabilize the BBB in a melanoma brain metastasis model. With a dual-frequency ultrasound transducer generating FUS at 1.1 MHz and 7.8 MHz, we opened the BBB using nanoparticle-microbubbles and low-frequency FUS, and applied high-frequency FUS to generate acoustic radiation force and push nanoparticles through the extracellular matrix. Using confocal microscopy and image analysis, we quantified nanoparticle extravasation and distribution in the brain parenchyma. We also evaluated haemorrhage, as well as the expression of P-glycoprotein, a key BBB component. FUS and microbubbles distributed nanoparticles in the brain parenchyma, and the distribution depended on the extent of BBB opening. The results from acoustic radiation force were not conclusive, but in a few animals some effect could be detected. P-glycoprotein was not significantly altered immediately after sonication. In summary, FUS with our nanoparticle-stabilized microbubbles can achieve accumulation and displacement of nanoparticles in the brain parenchyma. PMID:29338016

Drug delivery monitoring by photoacoustic tomography with an ICG encapsulated double emulsion

NASA Astrophysics Data System (ADS)

Rajian, Justin Rajesh; Fabiilli, Mario L.; Fowlkes, J. Brian; Carson, Paul L.; Wang, Xueding

2011-07-01

The absorption spectrum of indocyanine green (ICG), a nontoxic dye used for medical diagnostics, depends upon its concentration as well as the nature of its environment, i.e., the solvent medium into which it is dissolved. In blood, ICG binds with plasma proteins, thus causing changes in its photoacoustic spectrum. We successfully encapsulated ICG in an ultrasound-triggerable perfluorocarbon double emulsion that prevents ICG from binding with plasma proteins. Photoacoustic spectral measurements on point target as well as 2-D photoacoustic images of blood vessels revealed that the photoacoustic spectrum changes significantly in blood when the ICG-loaded emulsion undergoes acoustic droplet vaporization (ADV), which is the conversion of liquid droplets into gas bubbles using ultrasound. We propose that these changes in the photoacoustic spectrum of the ICG emulsion in blood, coupled with photoacoustic tomography, could be used to spatially and quantitatively monitor ultrasound initiated drug delivery. In addition, we suggest that the photoacoustic spectral change induced by ultrasound exposure could also be used as contrast in photoacoustic imaging to obtain a background free image.

Treatment of Parkinson's disease in rats by Nrf2 transfection using MRI-guided focused ultrasound delivery of nanomicrobubbles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Long, Ling; Cai, Xiaodong; Guo, Ruomi

Parkinson's disease (PD) is a very common neurological disorder. However, effective therapy is lacking. Although the blood-brain-barrier (BBB) protects the brain, it prevents the delivery of about 90% of drugs and nucleotides into the brain, thereby hindering the development of gene therapy for PD. Magnetic resonance imaging (MRI)-guided focused ultrasound delivery of microbubbles enhances the delivery of gene therapy vectors across the BBB and improves transfection efficiency. In the present study, we delivered nuclear factor E2-related factor 2 (Nrf2, NFE2L2) contained in nanomicrobubbles into the substantia nigra of PD rats by MRI-guided focused ultrasound, and we examined the effect ofmore » Nrf2 over-expression in this animal model of PD. The rat model of PD was established by injecting 6-OHDA in the right substantia nigra stereotactically. Plasmids (pDC315 or pDC315/Nrf2) were loaded onto nanomicrobubbles, and then injected through the tail vein with the assistance of MRI-guided focused ultrasound. MRI-guided focused ultrasound delivery of nanomicrobubbles increased gene transfection efficiency. Furthermore, Nrf2 gene transfection reduced reactive oxygen species levels, thereby protecting neurons in the target region. - Highlights: • MRI-guided focused ultrasound enhances gene transfection into the brain of rats. • Increased Nrf2 expression protects neurons in the rat model of PD. • Nrf2 protects neurons in PD by inhibiting ROS production.« less

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction.

PubMed

Zhang, Li; Sun, Zhenxing; Ren, Pingping; You, Manjie; Zhang, Jing; Fang, Lingyun; Wang, Jing; Chen, Yihan; Yan, Fei; Zheng, Hairong; Xie, Mingxing

2017-01-01

Hypoxia-inducible factor 1α (HIF-1α) plays a critical protective role in ischemic heart disease. Under normoxic conditions, HIF-1α was degraded by oxygen-dependent prolyl hydroxylase-2 (PHD2). Gene therapy has become a promising strategy to inhibit the degradation of HIF-1α and to improve cardiac function after ischemic injury. However, conventional gene delivery systems are difficult to achieve a targeted and localized gene delivery into the ischemic myocardia. Here, we report the localized myocardial delivery of shRNA against PHD2 through ultrasound-targeted microbubble destruction (UTMD) for protection the heart from acute myocardial infarction. In this study, a novel cationic microbubble was fabricated by using of the thin-film hydration and sonication method. The resulting microbubbles had a 28.2 ± 2.21 mV surface zeta potential and could greatly improve DNA binding performance, achieving 17.81 ± 1.46 μg of DNA loading capacity per 5 × 10 8 microbubbles. Combined with these cationic microbubbles, UTMD-mediated gene delivery was evaluated and the gene transfection efficiency was optimized in the H9C2 cardiac cells. Knockdown of PHD2 gene was successfully realized by UTMD-mediated shPHD2 transfection, resulting in HIF-1α-dependent protective effects on H9C2 cells through increasing the expression of HIF-1α, VEGF and bFGF. We further employed UTMD-mediated shPHD2 transfection into the localized ischemic myocardia in a rat ischemia model, demonstrating significantly reduced infarct size and greatly improved the heart function. The silencing of PHD2 and the up-regulation of its downstream genes in the treated myocardia were confirmed. Histological analysis further revealed numbers of HIF-1α- and VEGF-, and CD31-positive cells/mm 2 in the shPHD2-treated group were significantly greater than those in the sham or control vector groups (P < 0.05). In conclusion, our study provides a promising strategy to realize ultrasound-mediated localized myocardial shRNA delivery to protect the heart from acute myocardial infarction via cationic microbubbles.

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction

PubMed Central

Zhang, Li; Sun, Zhenxing; Ren, Pingping; You, Manjie; Zhang, Jing; Fang, Lingyun; Wang, Jing; Chen, Yihan; Yan, Fei; Zheng, Hairong; Xie, Mingxing

2017-01-01

Hypoxia-inducible factor 1α (HIF-1α) plays a critical protective role in ischemic heart disease. Under normoxic conditions, HIF-1α was degraded by oxygen-dependent prolyl hydroxylase-2 (PHD2). Gene therapy has become a promising strategy to inhibit the degradation of HIF-1α and to improve cardiac function after ischemic injury. However, conventional gene delivery systems are difficult to achieve a targeted and localized gene delivery into the ischemic myocardia. Here, we report the localized myocardial delivery of shRNA against PHD2 through ultrasound-targeted microbubble destruction (UTMD) for protection the heart from acute myocardial infarction. In this study, a novel cationic microbubble was fabricated by using of the thin-film hydration and sonication method. The resulting microbubbles had a 28.2 ± 2.21 mV surface zeta potential and could greatly improve DNA binding performance, achieving 17.81 ± 1.46 μg of DNA loading capacity per 5 × 108 microbubbles. Combined with these cationic microbubbles, UTMD-mediated gene delivery was evaluated and the gene transfection efficiency was optimized in the H9C2 cardiac cells. Knockdown of PHD2 gene was successfully realized by UTMD-mediated shPHD2 transfection, resulting in HIF-1α-dependent protective effects on H9C2 cells through increasing the expression of HIF-1α, VEGF and bFGF. We further employed UTMD-mediated shPHD2 transfection into the localized ischemic myocardia in a rat ischemia model, demonstrating significantly reduced infarct size and greatly improved the heart function. The silencing of PHD2 and the up-regulation of its downstream genes in the treated myocardia were confirmed. Histological analysis further revealed numbers of HIF-1α- and VEGF-, and CD31-positive cells/mm2 in the shPHD2-treated group were significantly greater than those in the sham or control vector groups (P < 0.05). In conclusion, our study provides a promising strategy to realize ultrasound-mediated localized myocardial shRNA delivery to protect the heart from acute myocardial infarction via cationic microbubbles. PMID:28042316

Ultrasound for Drug and Gene Delivery to the Brain

PubMed Central

Hynynen, Kullervo

2008-01-01

Noninvasive, transient, and local image-guided blood-brain barrier disruption (BBBD) has been demonstrated with focused ultrasound exposure in animal models. Most studies have combined low pressure amplitude and low time average acoustic power burst sonications with intra-vascular injection of pre-formed micro-bubbles to produce BBBD without damage to the neurons. The BBB has been shown to be healed within a few hours after the exposure. The combination of focused ultrasound beams with MR image guidance allows precise anatomical targeting as demonstrated by the delivery of several marker molecules in different animal models. This method may in the future have a significant impact on the diagnosis and treatment of central nervous system (CNS) disorders. Most notably, the delivery of the chemotherapy agents liposomal Doxorubicin and Herceptin has been shown in a rat model. PMID:18486271

Experimental analysis of behavior in nanobubbles using echograms under ultrasound exposure

NASA Astrophysics Data System (ADS)

Wada, Hikaru; Koido, Jun; Miyazawa, Shinya; Mochizuki, Takashi; Masuda, Kohji; Unga, Johan; Oda, Yusuke; Suzuki, Ryo; Maruyama, Kazuo

2016-07-01

Although we have reported our attempts to actively control microbubbles in flow using acoustic radiation force for future drug delivery systems, the microbubbles we used are not applicable for in vivo experiments. Thus, we examined two types of nanobubble with a drug-retaining function. Because the nanobubbles are invisible in a conventional optical observation, we observed the behavior of nanobubbles using ultrasound images (echograms). First, we found the optimal settings of echography to guarantee the relationship between the brightness variation and lipid concentration of nanobubbles. Then, we derived the destructive coefficient using two types of path under continuous ultrasound exposure of 5 MHz. Results indicate that the controllability is related to the construction of nanobubbles and the spatial distribution of the ultrasound field. We realized that the design of the ultrasound field is important with Bubble A, whereas the frequency of ultrasound emission needs to be discussed with Bubble B.

Cardiac Gene Expression Knockdown Using Small Inhibitory RNA-Loaded Microbubbles and Ultrasound

PubMed Central

McTiernan, Charles F.; Chen, Xucai; Klein, Edwin C.; Villanueva, Flordeliza S.

2016-01-01

RNA interference has potential therapeutic value for cardiac disease, but targeted delivery of interfering RNA is a challenge. Custom designed microbubbles, in conjunction with ultrasound, can deliver small inhibitory RNA to target tissues in vivo. The efficacy of cardiac RNA interference using a microbubble-ultrasound theranostic platform has not been demonstrated in vivo. Therefore, our objective was to test the hypothesis that custom designed microbubbles and ultrasound can mediate effective delivery of small inhibitory RNA to the heart. Microbubble and ultrasound mediated cardiac RNA interference was tested in transgenic mice displaying cardiac-restricted luciferase expression. Luciferase expression was assayed in select tissues of untreated mice (n = 14). Mice received intravenous infusion of cationic microbubbles bearing small inhibitory RNA directed against luciferase (n = 9) or control RNA (n = 8) during intermittent cardiac-directed ultrasound at mechanical index of 1.6. Simultaneous echocardiography in a separate group of mice (n = 3) confirmed microbubble destruction and replenishment during treatment. Three days post treatment, cardiac luciferase messenger RNA and protein levels were significantly lower in ultrasound-treated mice receiving microbubbles loaded with small inhibitory RNA directed against luciferase compared to mice receiving microbubbles bearing control RNA (23±7% and 33±7% of control mice, p<0.01 and p = 0.03, respectively). Passive cavitation detection focused on the heart confirmed that insonification resulted in inertial cavitation. In conclusion, small inhibitory RNA-loaded microbubbles and ultrasound directed at the heart significantly reduced the expression of a reporter gene. Ultrasound-targeted destruction of RNA-loaded microbubbles may be an effective image-guided strategy for therapeutic RNA interference in cardiac disease. PMID:27471848

pH/Ultrasound Dual-Responsive Gas Generator for Ultrasound Imaging-Guided Therapeutic Inertial Cavitation and Sonodynamic Therapy.

PubMed

Feng, Qianhua; Zhang, Wanxia; Yang, Xuemei; Li, Yuzhen; Hao, Yongwei; Zhang, Hongling; Hou, Lin; Zhang, Zhenzhong

2018-03-01

Herein, a pH/ultrasound dual-responsive gas generator is reported, which is based on mesoporous calcium carbonate (MCC) nanoparticles by loading sonosensitizer (hematoporphyrin monomethyl ether (HMME)) and modifying surface hyaluronic acid (HA). After pinpointing tumor regions with prominent targeting efficiency, HMME/MCC-HA decomposes instantaneously under the cotriggering of tumoral inherent acidic condition and ultrasound (US) irradiation, concurrently accompanying with CO 2 generation and HMME release with spatial/temporal resolution. Afterward, the CO 2 bubbling and bursting effect under US stimulus results in cavitation-mediated irreversible cell necrosis, as well as the blood vessel destruction to further occlude the blood supply, providing a "bystander effect." Meanwhile, reactive oxygen species generated from HMME can target the apoptotic pathways for effective sonodynamic therapy. Thus, the combination of apoptosis/necrosis with multimechanisms consequently results in a remarkable antitumor therapeutic efficacy, simultaneously minimizing the side effects on major organs. Moreover, the echogenic property of CO 2 make the nanoplatform as a powerful ultrasound contrast agent to identify cancerous lesions. Based on the above findings, such all-in-one drug delivery platform of HMME/MCC-HA is utilized to provide the US imaging guidance for therapeutic inertial cavitation and sonodynamic therapy simultaneously, which highlights possibilities of advancing cancer theranostics in biomedical fields. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ultrasound enhances retrovirus-mediated gene transfer.

PubMed

Naka, Toshio; Sakoda, Tsuyoshi; Doi, Takashi; Tsujino, Takeshi; Masuyama, Tohru; Kawashima, Seinosuke; Iwasaki, Tadaaki; Ohyanagi, Mitsumasa

2007-01-01

Viral vector systems are efficient for transfection of foreign genes into many tissues. Especially, retrovirus based vectors integrate the transgene into the genome of the target cells, which can sustain long term expression. However, it has been demonstrated that the transduction efficiency using retrovirus is relatively lower than those of other viruses. Ultrasound was recently reported to increase gene expression using plasmid DNA, with or without, a delivery vehicle. However, there are no reports, which show an ultrasound effect to retrovirus-mediated gene transfer efficiency. Retrovirus-mediated gene transfer systems were used for transfection of 293T cells, bovine aortic endothelial cells (BAECs), rat aortic smooth muscle cells (RASMCs), and rat skeletal muscle myoblasts (L6 cells) with beta-galactosidase (beta-Gal) genes. Transduction efficiency and cell viability assay were performed on 293T cells that were exposed to varying durations (5 to 30 seconds) and power levels (1.0 watts/cm(2) to 4.0 watts/cm(2)) of ultrasound after being transduced by a retrovirus. Effects of ultrasound to the retrovirus itself was evaluated by transduction efficiency of 293T cells. After exposure to varying power levels of ultrasound to a retrovirus for 5 seconds, 293T cells were transduced by a retrovirus, and transduction efficiency was evaluated. Below 1.0 watts/cm(2) and 5 seconds exposure, ultrasound showed increased transduction efficiency and no cytotoxicity to 293T cells transduced by a retrovirus. Also, ultrasound showed no toxicity to the virus itself at the same condition. Exposure of 5 seconds at the power of 1.0 watts/cm(2) of an ultrasound resulted in significant increases in retrovirus-mediated gene expression in all four cell types tested in this experiment. Transduction efficiencies by ultrasound were enhanced 6.6-fold, 4.8-fold, 2.3-fold, and 3.2-fold in 293T cells, BAECs, RASMCs, and L6 cells, respectively. Furthermore, beta-Gal activities were also increased by the retrovirus with ultrasound exposure in these cells. Adjunctive ultrasound exposure was associated with enhanced retrovirus-mediated transgene expression in vitro. Ultrasound associated local gene therapy has potential for not only plasmid-DNA-, but also retrovirus-mediated gene transfer.

External triggering and triggered targeting strategies for drug delivery

NASA Astrophysics Data System (ADS)

Wang, Yanfei; Kohane, Daniel S.

2017-06-01

Drug delivery systems that are externally triggered to release drugs and/or target tissues hold considerable promise for improving the treatment of many diseases by minimizing nonspecific toxicity and enhancing the efficacy of therapy. These drug delivery systems are constructed from materials that are sensitive to a wide range of external stimuli, including light, ultrasound, electrical and magnetic fields, and specific molecules. The responsiveness conferred by these materials allows the release of therapeutics to be triggered on demand and remotely by a physician or patient. In this Review, we describe the rationales for such systems and the types of stimuli that can be deployed, and provide an outlook for the field.

Duration of ultrasound-mediated enhanced plasma membrane permeability.

PubMed

Lammertink, Bart; Deckers, Roel; Storm, Gert; Moonen, Chrit; Bos, Clemens

2015-03-30

Ultrasound (US) induced cavitation can be used to enhance the intracellular delivery of drugs by transiently increasing the cell membrane permeability. The duration of this increased permeability, termed temporal window, has not been fully elucidated. In this study, the temporal window was investigated systematically using an endothelial- and two breast cancer cell lines. Model drug uptake was measured as a function of time after sonication, in the presence of SonoVue™ microbubbles, in HUVEC, MDA-MB-468 and 4T1 cells. In addition, US pressure amplitude was varied in MDA-MB-468 cells to investigate its effect on the temporal window. Cell membrane permeability of HUVEC and MDA-MB-468 cells returned to control level within 1-2 h post-sonication, while 4T1 cells needed over 3h. US pressure affected the number of cells with increased membrane permeability, as well as the temporal window in MDA-MB-468 cells. This study shows that the duration of increased membrane permeability differed between the cell lines and US pressures used here. However, all were consistently in the order of 1-3 h after sonication. Copyright © 2014 Elsevier B.V. All rights reserved.

Receptor-Mediated Drug Delivery Systems Targeting to Glioma

PubMed Central

Wang, Shanshan; Meng, Ying; Li, Chengyi; Qian, Min; Huang, Rongqin

2015-01-01

Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS). The complexity of glioma, especially the existence of the blood-brain barrier (BBB), makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications. PMID:28344260

Mesoporous silica nanoparticles for stimuli-responsive controlled drug delivery: advances, challenges, and outlook

PubMed Central

Song, Yuanhui; Li, Yihong; Xu, Qien; Liu, Zhe

2017-01-01

With the development of nanotechnology, the application of nanomaterials in the field of drug delivery has attracted much attention in the past decades. Mesoporous silica nanoparticles as promising drug nanocarriers have become a new area of interest in recent years due to their unique properties and capabilities to efficiently entrap cargo molecules. This review describes the latest advances on the application of mesoporous silica nanoparticles in drug delivery. In particular, we focus on the stimuli-responsive controlled release systems that are able to respond to intracellular environmental changes, such as pH, ATP, GSH, enzyme, glucose, and H2O2. Moreover, drug delivery induced by exogenous stimuli including temperature, light, magnetic field, ultrasound, and electricity is also summarized. These advanced technologies demonstrate current challenges, and provide a bright future for precision diagnosis and treatment. PMID:28053526

Mesoporous silica nanoparticles for stimuli-responsive controlled drug delivery: advances, challenges, and outlook.

PubMed

Song, Yuanhui; Li, Yihong; Xu, Qien; Liu, Zhe

With the development of nanotechnology, the application of nanomaterials in the field of drug delivery has attracted much attention in the past decades. Mesoporous silica nanoparticles as promising drug nanocarriers have become a new area of interest in recent years due to their unique properties and capabilities to efficiently entrap cargo molecules. This review describes the latest advances on the application of mesoporous silica nanoparticles in drug delivery. In particular, we focus on the stimuli-responsive controlled release systems that are able to respond to intracellular environmental changes, such as pH, ATP, GSH, enzyme, glucose, and H 2 O 2 . Moreover, drug delivery induced by exogenous stimuli including temperature, light, magnetic field, ultrasound, and electricity is also summarized. These advanced technologies demonstrate current challenges, and provide a bright future for precision diagnosis and treatment.

Comparing microbubble cavitation at 500 kHz and 70 kHz related to micellar drug delivery using ultrasound.

PubMed

Diaz de la Rosa, Mario A; Husseini, Ghaleb A; Pitt, William G

2013-02-01

We have previously reported that ultrasonic drug release at 70kHz was found to correlate with the presence of subharmonic emissions. No evidence of drug release or of the subharmonic emissions were detected in experiments at 500kHz. In an attempt to understand the difference in drug release behavior between low- and mid-frequency ultrasound, a mathematical model of a bubble oscillator was developed to explore the difference in the behavior of a single 10-μm bubble under 500- and 70-kHz ultrasound. The dynamics were found to be fundamentally different; the 500-kHz bubble follows a period-doubling route to chaos while a 70-kHz bubble follows an intermittent route to chaos. We propose that this type of "intermittent subharmonic" oscillation behavior is associated with the drug release observed experimentally. Copyright © 2012 Elsevier B.V. All rights reserved.

Preparation and in vitro characterization of chitosan nanobubbles as theranostic agents.

PubMed

Cavalli, R; Argenziano, M; Vigna, E; Giustetto, P; Torres, E; Aime, S; Terreno, E

2015-05-01

Theranostic delivery systems are nanostructures that combine the modality of therapy and diagnostic imaging. Polymeric micro- and nanobubbles, spherical vesicles containing a gas core, have been proposed as new theranostic carriers for MRI-guided therapy. In this study, chitosan nanobubbles were purposely tuned for the co-delivery of prednisolone phosphate and a Gd(III) complex, as therapeutic and MRI diagnostic agent, respectively. Perfluoropentane was used for filling up the internal core of the formulation. These theranostic nanobubbles showed diameters of about 500nm and a positive surface charge that allows the interaction with the negatively charged Gd-DOTP complex. Pluronic F68 was added to the nanobubble aqueous suspension as stabilizer agent. The encapsulation efficiency was good for both the active compounds, and a prolonged drug release profile was observed in vitro. The effect of ultrasound stimulation on prednisolone phosphate release was evaluated at 37°C. A marked increase on drug release kinetics with no burst effect was obtained after the exposure of the system to ultrasound. Furthermore, the relaxivity of the MRI probe changed upon incorporation in the nanobubble shell, thereby offering interesting opportunity in dual MRI-US experiments. The ultrasound characterization showed a good in vitro echogenicity of the theranostic nanobubbles. In summary, chitosan drug-loaded nanobubbles with Gd(III) complex bound to their shell might be considered a new platform for imaging and drug delivery with the potential of improving anti-cancer treatments. Copyright © 2015 Elsevier B.V. All rights reserved.

PROGRESS AND PROBLEMS IN THE APPLICATION OF FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION

PubMed Central

Vykhodtseva, Natalia; McDannold, Nathan; Hynynen, Kullervo

2008-01-01

Advances in neuroscience have resulted in the development of new diagnostic and therapeutic agents for potential use in the central nervous system (CNS). However, the ability to deliver the majority of these agents to the brain is limited by the blood–brain barrier (BBB), a specialized structure of the blood vessel wall that hampers transport and diffusion from the blood to the brain. Many CNS disorders could be treated with drugs, enzymes, genes, or large-molecule biotechnological products such as recombinant proteins, if they could cross the BBB. This article reviews the problems of the BBB presence in treating the vast majority of CNS diseases and the efforts to circumvent the BBB through the design of new drugs and the development of more sophisticated delivery methods. Recent advances in the development of noninvasive, targeted drug delivery by MRI-guided ultrasound-induced BBB disruption are also summarized. PMID:18511095

Pharmacokinetic analysis and drug delivery efficiency of the focused ultrasound-induced blood-brain barrier opening in non-human primates

PubMed Central

Samiotaki, Gesthimani; Karakatsani, Maria Eleni; Buch, Amanda; Papadopoulos, Stephanos; Wu, Shih Ying; Jambawalikar, Sachin; Konofagou, Elisa E.

2016-01-01

Purpose Focused Ultrasound (FUS) in conjunction with systemically administered microbubbles has been shown to open the Blood-Brain Barrier (BBB) locally, non-invasively and reversibly in rodents and non-human primates (NHP), suggesting the immense potential of this technique. The objective of this study entailed the investigation of the physiologic changes in the brain following the FUS-induced BBB opening and their relationship with the underlying anatomy. Materials and Methods Pharmacokinetic analysis was implemented in NHP’s that received FUS at various acoustic pressures. Relaxivity mapping enabled the robust quantitative detection of the BBB opening as well as gray and white matter segmentation. Drug delivery efficiency was measured for pre-clinical validation of the technique. Results Based on our results, the opening volume and the amount of the gadolinium delivered were found mostly contained in the grey matter, while FUS-induced permeability and drug concentration varied depending upon the underlying brain inhomogeneity, and increased with the acoustic pressure. Conclusions Overall, apart from the in vivo protocols for BBB analysis developed here, this study also suggests the important role that FUS can have in efficient drug delivery via localized and transient BBB opening. PMID:27916657

Irinotecan delivery by microbubble-assisted ultrasound - A pilot preclinical study

NASA Astrophysics Data System (ADS)

Escoffre, Jean-Michel; Novell, Anthony; Serrière, Sophie; Bouakaz, Ayache

2012-11-01

Irinotecan is conventionally used for the treatment of colorectal cancer. However, its administration is associated with severe side effects. Targeted drug delivery using ultrasound (US) combined with microbubbles offers new opportunities to increase the therapeutic effectiveness of antitumor treatment and to reduce toxic exposure to healthy tissues. The objective of this study is to investigate the safety and efficacy of in-vivo delivery of irinotecan by microbubble-assisted US in human glioblastoma model (U-87 MG). In order to validate the potential of this new method in-vivo, subcutaneous tumors were implanted in the flank of nude mouse and treated when they reached a volume of 100 mm3. In the first study, the measured volumes with caliper and anatomic ultrasound imaging were compared for the monitoring and the quantification of tumor growth during 27 days. Ultrasound imaging measurements were positively correlated to caliper measurements. The tumor treatment consisted of an i.v. injection of irinotecan (20 mg/kg) followed one hour later by i.v. administration of MM1 microbubble and an US insonation using a single-element transducer operating at 1MHz (400 kPa, 10 kHz PRF 40% DC, 3 min). The therapeutic efficacy was evaluated for 39 days by measuring the tumor volume before and after treatment using a caliper and based on ultrasound images using an 18 MHz probe (Vevo 2100). Our results showed that anatomical ultrasound imaging was as efficient as caliper for the monitoring and the quantification of tumor growth. Moreover, irinotecan delivery by sonoporation induced a significant decrease of glioblastoma tumor volume and an increase of tumor-doubling time compared to the tumor treated by irinotecan alone. In conclusion, this novel therapeutic approach has promising features since it can be used to reduce the injected drug dose and to achieve a better therapeutic efficacy.

Focused ultrasound-mediated sonochemical internalization: an alternative to light-based therapies

NASA Astrophysics Data System (ADS)

Gonzales, Jonathan; Nair, Rohit Kumar; Madsen, Steen J.; Krasieva, Tatiana; Hirschberg, Henry

2016-07-01

Activation of sonosensitizers via focused ultrasound (FUS), i.e., sonodynamic therapy has been proposed as an extension to light-activated photodynamic therapy for the treatment of brain as well as other tumors. The use of FUS, as opposed to light, allows treatment to tumor sites buried deep within tissues as well as through the intact skull. We have examined ultrasonic activation of sonosensitizers together with the anticancer agent bleomycin (BLM), i.e., sonochemical internalization (SCI). SCI is a technique that utilizes FUS for the enhanced delivery of endo-lysosomal trapped macromolecules into the cell cytoplasm in a similar manner to light-based photochemical internalization. The released agent can, therefore, exert its full biological activity, in contrast to being degraded by lysosomal hydrolases. Our results indicate that, compared to drug or FUS treatment alone, FUS activation of the sonosensitizer AlPcS2a together with BLM significantly inhibits the ability of treated glioma cells to grow as three-dimensional tumor spheroids in vitro.

Multifunctional polymersomes for cytosolic delivery of gemcitabine and doxorubicin to cancer cells.

PubMed

Nahire, Rahul; Haldar, Manas K; Paul, Shirshendu; Ambre, Avinash H; Meghnani, Varsha; Layek, Buddhadev; Katti, Kalpana S; Gange, Kara N; Singh, Jagdish; Sarkar, Kausik; Mallik, Sanku

2014-08-01

Although liposomes are widely used as carriers of drugs and imaging agents, they suffer from a lack of stability and the slow release of the encapsulated contents at the targeted site. Polymersomes (vesicles of amphiphilic polymers) are considerably more stable compared to liposomes; however, they also demonstrate a slow release for the encapsulated contents, limiting their efficacy as a drug-delivery tool. As a solution, we prepared and characterized echogenic polymersomes, which are programmed to release the encapsulated drugs rapidly when incubated with cytosolic concentrations of glutathione. These vesicles encapsulated air bubbles inside and efficiently reflected diagnostic-frequency ultrasound. Folate-targeted polymersomes showed an enhanced uptake by breast and pancreatic-cancer cells in a monolayer as well as in three-dimensional spheroid cultures. Polymersomes encapsulated with the anticancer drugs gemcitabine and doxorubicin showed significant cytotoxicity to these cells. With further improvements, these vesicles hold the promise to serve as multifunctional nanocarriers, offering a triggered release as well as diagnostic ultrasound imaging. Copyright © 2014 Elsevier Ltd. All rights reserved.

Gene therapy for ocular diseases meditated by ultrasound and microbubbles (Review)

PubMed Central

WAN, CAIFENG; LI, FENGHUA; LI, HONGLI

2015-01-01

The eye is an ideal target organ for gene therapy as it is easily accessible and immune-privileged. With the increasing insight into the underlying molecular mechanisms of ocular diseases, gene therapy has been proposed as an effective approach. Successful gene therapy depends on efficient gene transfer to targeted cells to prove stable and prolonged gene expression with minimal toxicity. At present, the main hindrance regarding the clinical application of gene therapy is not the lack of an ideal gene, but rather the lack of a safe and efficient method to selectively deliver genes to target cells and tissues. Ultrasound-targeted microbubble destruction (UTMD), with the advantages of high safety, repetitive applicability and tissue targeting, has become a potential strategy for gene- and drug delivery. When gene-loaded microbubbles are injected, UTMD is able to enhance the transport of the gene to the targeted cells. High-amplitude oscillations of microbubbles act as cavitation nuclei which can effectively focus ultrasound energy, produce oscillations and disruptions that increase the permeability of the cell membrane and create transient pores in the cell membrane. Thereby, the efficiency of gene therapy can be significantly improved. The UTMD-mediated gene delivery system has been widely used in pre-clinical studies to enhance gene expression in a site-specific manner in a variety of organs. With reasonable application, the effects of sonoporation can be spatially and temporally controlled to improve localized tissue deposition of gene complexes for ocular gene therapy applications. In addition, appropriately powered, focused ultrasound combined with microbubbles can induce a reversible disruption of the blood-retinal barrier with no significant side effects. The present review discusses the current status of gene therapy of ocular diseases as well as studies on gene therapy of ocular diseases meditated by UTMD. PMID:26151686

2ND International Symposium on HIFU Therapy HIFU Seattle 2002

DTIC Science & Technology

2002-12-01

Drug Delivery, and Sonodynamic Therapy. One can see from this topic coverage that the symposium was largely on HIFU (essentially the first five topics), yet also broad enough to cover most aspects of therapeutic ultrasound ....This book is a compilation of papers presented at the 2nd International Symposium on Therapeutic Ultrasound , held in Seattle, Washington, July 29...number of topic categories, viz., Clinical Studies, Laboratory Studies, Simulation and Monitoring, Dosimetry, Engineering, Lithotripsy, Ultrasound -Enhanced

Inertial cavitation to non-invasively trigger and monitor intratumoral release of drug from intravenously delivered liposomes.

PubMed

Graham, Susan M; Carlisle, Robert; Choi, James J; Stevenson, Mark; Shah, Apurva R; Myers, Rachel S; Fisher, Kerry; Peregrino, Miriam-Bazan; Seymour, Len; Coussios, Constantin C

2014-03-28

The encapsulation of cytotoxic drugs within liposomes enhances pharmacokinetics and allows passive accumulation within tumors. However, liposomes designed to achieve good stability during the delivery phase often have compromised activity at the target site. This problem of inefficient and unpredictable drug release is compounded by the present lack of low-cost, non-invasive methods to measure such release. Here we show that focused ultrasound, used at pressures similar to those applied during diagnostic ultrasound scanning, can be utilised to both trigger and monitor release of payload from liposomes. Notably, drug release was influenced by liposome composition and the presence of SonoVue® microbubbles, which provided the nuclei for the initiation of an event known as inertial cavitation. In vitro studies demonstrated that liposomes formulated with a high proportion of 1,2 distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) released up to 30% of payload following ultrasound exposure in the presence of SonoVue®, provided that the exposure created sufficient inertial cavitation events, as characterised by violent bubble collapse and the generation of broadband acoustic emissions. In contrast a 'Doxil'-like liposome formulation gave no such triggered release. In pre-clinical studies, ultrasound was used as a non-invasive, targeted stimulus to trigger a 16-fold increase in the level of payload release within tumors following intravenous delivery. The inertial cavitation events driving this release could be measured remotely in real-time and were a reliable predictor of drug release. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Contrast-enhanced and targeted ultrasound.

PubMed

Postema, Michiel; Gilja, Odd Helge

2011-01-07

Ultrasonic imaging is becoming the most popular medical imaging modality, owing to the low price per examination and its safety. However, blood is a poor scatterer of ultrasound waves at clinical diagnostic transmit frequencies. For perfusion imaging, markers have been designed to enhance the contrast in B-mode imaging. These so-called ultrasound contrast agents consist of microscopically small gas bubbles encapsulated in biodegradable shells. In this review, the physical principles of ultrasound contrast agent microbubble behavior and their adjustment for drug delivery including sonoporation are described. Furthermore, an outline of clinical imaging applications of contrast-enhanced ultrasound is given. It is a challenging task to quantify and predict which bubble phenomenon occurs under which acoustic condition, and how these phenomena may be utilized in ultrasonic imaging. Aided by high-speed photography, our improved understanding of encapsulated microbubble behavior will lead to more sophisticated detection and delivery techniques. More sophisticated methods use quantitative approaches to measure the amount and the time course of bolus or reperfusion curves, and have shown great promise in revealing effective tumor responses to anti-angiogenic drugs in humans before tumor shrinkage occurs. These are beginning to be accepted into clinical practice. In the long term, targeted microbubbles for molecular imaging and eventually for directed anti-tumor therapy are expected to be tested.

Contrast-enhanced and targeted ultrasound

PubMed Central

Postema, Michiel; Gilja, Odd Helge

2011-01-01

Ultrasonic imaging is becoming the most popular medical imaging modality, owing to the low price per examination and its safety. However, blood is a poor scatterer of ultrasound waves at clinical diagnostic transmit frequencies. For perfusion imaging, markers have been designed to enhance the contrast in B-mode imaging. These so-called ultrasound contrast agents consist of microscopically small gas bubbles encapsulated in biodegradable shells. In this review, the physical principles of ultrasound contrast agent microbubble behavior and their adjustment for drug delivery including sonoporation are described. Furthermore, an outline of clinical imaging applications of contrast-enhanced ultrasound is given. It is a challenging task to quantify and predict which bubble phenomenon occurs under which acoustic condition, and how these phenomena may be utilized in ultrasonic imaging. Aided by high-speed photography, our improved understanding of encapsulated microbubble behavior will lead to more sophisticated detection and delivery techniques. More sophisticated methods use quantitative approaches to measure the amount and the time course of bolus or reperfusion curves, and have shown great promise in revealing effective tumor responses to anti-angiogenic drugs in humans before tumor shrinkage occurs. These are beginning to be accepted into clinical practice. In the long term, targeted microbubbles for molecular imaging and eventually for directed anti-tumor therapy are expected to be tested. PMID:21218081

Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery

NASA Astrophysics Data System (ADS)

Wu, Shih-Ying; Fix, Samantha M.; Arena, Christopher B.; Chen, Cherry C.; Zheng, Wenlan; Olumolade, Oluyemi O.; Papadopoulou, Virginie; Novell, Anthony; Dayton, Paul A.; Konofagou, Elisa E.

2018-02-01

Focused ultrasound with nanodroplets could facilitate localized drug delivery after vaporization with potentially improved in vivo stability, drug payload, and minimal interference outside of the focal zone compared with microbubbles. While the feasibility of blood-brain barrier (BBB) opening using nanodroplets has been previously reported, characterization of the associated delivery has not been achieved. It was hypothesized that the outcome of drug delivery was associated with the droplet’s sensitivity to acoustic energy, and can be modulated with the boiling point of the liquid core. Therefore, in this study, octafluoropropane (OFP) and decafluorobutane (DFB) nanodroplets were used both in vitro for assessing their relative vaporization efficiency with high-speed microscopy, and in vivo for delivering molecules with a size relevant to proteins (40 kDa dextran) to the murine brain. It was found that at low pressures (300-450 kPa), OFP droplets vaporized into a greater number of microbubbles compared to DFB droplets at higher pressures (750-900 kPa) in the in vitro study. In the in vivo study, successful delivery was achieved with OFP droplets at 300 kPa and 450 kPa without evidence of cavitation damage using ¼ dosage, compared to DFB droplets at 900 kPa where histology indicated tissue damage due to inertial cavitation. In conclusion, the vaporization efficiency of nanodroplets positively impacted the amount of molecules delivered to the brain. The OFP droplets due to the higher vaporization efficiency served as better acoustic agents to deliver large molecules efficiently to the brain compared with the DFB droplets.

Focused Ultrasound Surgery in Oncology: Overview and Principles

PubMed Central

McDannold, Nathan J.; Hynynen, Kullervo; Jolesz, Ferenc A.

2011-01-01

Focused ultrasound surgery (FUS) is a noninvasive image-guided therapy and an alternative to surgical interventions. It presents an opportunity to revolutionize cancer therapy and to affect or change drug delivery of therapeutic agents in new focally targeted ways. In this article the background, principles, technical devices, and clinical cancer applications of image-guided FUS are reviewed. © RSNA, 2011 PMID:21436096

Dual-targeted and pH-sensitive Doxorubicin Prodrug-Microbubble Complex with Ultrasound for Tumor Treatment

PubMed Central

Luo, Wanxian; Wen, Ge; Yang, Li; Tang, Jiao; Wang, Jianguo; Wang, Jihui; Zhang, Shiyu; Zhang, Li; Ma, Fei; Xiao, Liling; Wang, Ying; Li, Yingjia

2017-01-01

In this study, we investigated the potential of a dual-targeted pH-sensitive doxorubicin prodrug-microbubble complex (DPMC) in ultrasound (US)-assisted antitumor therapy. The doxorubicin prodrug (DP) consists of a succinylated-heparin carrier conjugated with doxorubicin (DOX) via hydrazone linkage and decorated with dual targeting ligands, folate and cRGD peptide. Combination of microbubble (MB) and DP, generated via avidin-biotin binding, promoted intracellular accumulation and improved therapeutic efficiency assisted by US cavitation and sonoporation. Aggregates of prepared DP were observed with an inhomogeneous size distribution (average diameters: 149.6±29.8 nm and 1036.2±38.8 nm, PDI: 1.0) while DPMC exhibited a uniform distribution (average diameter: 5.804±2.1 μm), facilitating its usage for drug delivery. Notably, upon US exposure, DPMC was disrupted and aggregated DP dispersed into homogeneous small-sized nanoparticles (average diameter: 128.6±42.3 nm, PDI: 0.21). DPMC could target to angiogenic endothelial cells in tumor region via αvβ3-mediated recognition and subsequently facilitate its specific binding to tumor cells mediated via recognition of folate receptor (FR) after US exposure. In vitro experiments showed higher tumor specificity and killing ability of DPMC with US than free DOX and DP for breast cancer MCF-7 cells. Furthermore, significant accumulation and specificity for tumor tissues of DPMC with US were detected using in vivo fluorescence and ultrasound molecular imaging, indicating its potential to integrate tumor imaging and therapy. In particular, through inducing apoptosis, inhibiting cell proliferation and antagonizing angiogenesis, DPMC with US produced higher tumor inhibition rates than DOX or DPMC without US in MCF-7 xenograft tumor-bearing mice while inducing no obvious body weight loss. Our strategy provides an effective platform for the delivery of large-sized or aggregated particles to tumor sites, thereby extending their therapeutic applications in vivo. PMID:28255342

Transcranial MR-Guided Focused Ultrasound: A Review of the Technology and Neuro Applications

PubMed Central

Ghanouni, Pejman; Pauly, Kim Butts; Elias, W. Jeff; Henderson, Jaimie; Sheehan, Jason; Monteith, Stephen; Wintermark, Max

2015-01-01

MR guided focused ultrasound is a new, minimally invasive method of targeted tissue thermal ablation that may be of use to treat central neuropathic pain, essential tremor, Parkinson tremor, and brain tumors. The system has also been used to temporarily disrupt the blood-brain barrier to allow targeted drug delivery to brain tumors. This article reviews the physical principles of MR guided focused ultrasound and discusses current and potential applications of this exciting technology. PMID:26102394

Application of light and ultrasound for medical diagnostics and treatment

NASA Astrophysics Data System (ADS)

Esenaliev, Rinat O.

2002-07-01

We develop novel optical and ultrasound techniques for medical noninvasive diagnostics and treatment. In this review, we present our results on the development of: (1) optoacoustic technique for detection of small tumors; (2) optoacoustic monitoring of blood oxygenation; (3) optoacoustic monitoring during thermotherapy; (4) optical coherence tomography for monitoring of blood glucose concentration; and (5) laser- and ultrasound-based anti- cancer drug delivery technique. Motivation, experimental methods, results obtained in vitro and in vivo with the use of these techniques are presented.

Overcoming T. gondii infection and intracellular protein nanocapsules as biomaterials for ultrasonically controlled drug release.

PubMed

Aw, M S; Paniwnyk, L

2017-09-26

One of the pivotal matters of concern in intracellular drug delivery is the preparation of biomaterials containing drugs that are compatible with the host target. Nanocapsules for oral delivery are found to be suitable candidates for targeting Toxoplasma gondii (T. gondii), a maneuvering and smart protozoic parasite found across Europe and America that causes a subtle but deadly infection. To overcome this disease, there is much potential of integrating protein-based cells into bioinspired nanocompartments such as via biodegradable cross-linked disulfide polyelectrolyte nanoparticles. The inner membrane vesicle system of these protein-drugs is not as simple as one might think. It is a complex transport network that includes sequential pathways, namely, endocytosis, exocytosis and autophagy. Unfortunately, the intracellular trafficking routes for nanoparticles in cells have not been extensively and intensively investigated. Hence, there lies the need to create robust protein nanocapsules for precise tracing and triggering of drug release to combat this protozoic disease. Protein nanocapsules have the advantage over other biomaterials due to their biocompatibility, use of natural ingredients, non-invasiveness, patient compliance, cost and time effectiveness. They also offer low maintenance, non-toxicity to healthy cells and a strictly defined route toward intracellular elimination through controlled drug delivery within the therapeutic window. This review covers the unprecedented opportunities that exist for constructing advanced nanocapsules to meet the growing needs arising from many therapeutic fields. Their versatile use includes therapeutic ultrasound for tumor imaging, recombinant DNA, ligand and functional group binding, the delivery of drugs and peptides via protein nanocapsules and polyelectrolytes, ultrasound-(US)-aided drug release through the gastrointestinal (GI) tract, and the recent progress in targeting tumor cells and a vast range of cancer therapies. This review also outlines the limitations of current technologies and the directions of future outlook.

Circulating Magnetic Microbubbles for Localized Real-Time Control of Drug Delivery by Ultrasonography-Guided Magnetic Targeting and Ultrasound

PubMed Central

Chertok, Beata; Langer, Robert

2018-01-01

Image-guided and target-selective modulation of drug delivery by external physical triggers at the site of pathology has the potential to enable tailored control of drug targeting. Magnetic microbubbles that are responsive to magnetic and acoustic modulation and visible to ultrasonography have been proposed as a means to realize this drug targeting strategy. To comply with this strategy in vivo, magnetic microbubbles must circulate systemically and evade deposition in pulmonary capillaries, while also preserving magnetic and acoustic activities in circulation over time. Unfortunately, challenges in fabricating magnetic microbubbles with such characteristics have limited progress in this field. In this report, we develop magnetic microbubbles (MagMB) that display strong magnetic and acoustic activities, while also preserving the ability to circulate systemically and evade pulmonary entrapment. Methods: We systematically evaluated the characteristics of MagMB including their pharmacokinetics, biodistribution, visibility to ultrasonography and amenability to magneto-acoustic modulation in tumor-bearing mice. We further assessed the applicability of MagMB for ultrasonography-guided control of drug targeting. Results: Following intravenous injection, MagMB exhibited a 17- to 90-fold lower pulmonary entrapment compared to previously reported magnetic microbubbles and mimicked circulation persistence of the clinically utilized Definity microbubbles (>10 min). In addition, MagMB could be accumulated in tumor vasculature by magnetic targeting, monitored by ultrasonography and collapsed by focused ultrasound on demand to activate drug deposition at the target. Furthermore, drug delivery to target tumors could be enhanced by adjusting the magneto-acoustic modulation based on ultrasonographic monitoring of MagMB in real-time. Conclusions: Circulating MagMB in conjunction with ultrasonography-guided magneto-acoustic modulation may provide a strategy for tailored minimally-invasive control over drug delivery to target tissues. PMID:29290812

UTMD-Promoted Co-Delivery of Gemcitabine and miR-21 Inhibitor by Dendrimer-Entrapped Gold Nanoparticles for Pancreatic Cancer Therapy

PubMed Central

Lin, Lizhou; Fan, Yu; Gao, Feng; Jin, Lifang; Li, Dan; Sun, Wenjie; Li, Fan; Qin, Peng; Shi, Qiusheng; Shi, Xiangyang; Du, Lianfang

2018-01-01

Conventional chemotherapy of pancreatic cancer (PaCa) suffers the problems of low drug permeability and inherent or acquired drug resistance. Development of new strategies for enhanced therapy still remains a great challenge. Herein, we report a new ultrasound-targeted microbubble destruction (UTMD)-promoted delivery system based on dendrimer-entrapped gold nanoparticles (Au DENPs) for co-delivery of gemcitabine (Gem) and miR-21 inhibitor (miR-21i). Methods: In this study, Gem-Au DENPs/miR-21i was designed and synthesized. The designed polyplexes were characterized via transmission electron microscopy (TEM), Gel retardation assay and dynamic light scattering (DLS). Then, the optimum exposure parameters were examined by an ultrasound exposure platform. The cellular uptake, cytotoxicity and anticancer effects in vitro were analyzed by confocal laser microscopy, spectra microplate reader, flow cytometry and a chemiluminescence imaging system. Lastly, the anticancer effects in vivo were evaluated by contrast-enhanced ultrasound (CEUS), hematoxylin and eosin (H&E) staining, TUNEL staining and comparison of tumor volume. Results: The results showed that the Gem-Au DENPs/miR-21i can be uptake by cancer cells and the cellular uptake was further facilitated by UTMD with an ultrasound power of 0.4 W/cm2 to enhance the cell permeability. Further, the co-delivery of Gem and miR-21i with or without UTMD treatment displayed 82-fold and 13-fold lower IC50 values than the free Gem, respectively. The UTMD-promoted co-delivery of Gem and miR-21i was further validated by in vivo treatment and showed a significant tumor volume reduction and an increase in blood perfusion of xenografted pancreatic tumors. Conclusion: The co-delivery of Gem and miR-21i using Au DENPs can be significantly promoted by UTMD technology, hence providing a promising strategy for effective pancreatic cancer treatments. PMID:29556365

A New Low-frequency Sonophoresis System Combined with Ultrasonic Motor and Transducer

NASA Astrophysics Data System (ADS)

Zhu, Pancheng; Peng, Hanmin; Yang, Jianzhi; Mao, Ting; Sheng, Juan

2018-03-01

Low frequency sonophoresis (LFS) is currently being attempted as a transdermal drug delivery method in clinical areas. However, it lacks both an effective control method and the equipment to satisfy the varying drug dosage requirements of individual patients. Herein, a novel method aimed at controlling permeability is proposed and developed, using a pressure control strategy which is based on an accurate, adjustable and non-invasive ultrasound transdermal drug delivery system in in vitro LFS. The system mainly consists of a lead screw linear ultrasonic motor and an ultrasonic transducer, in which the former offers pressure and the latter provides ultrasound wave in the liquid. The ultrasound can enhance non-invasive permeation and the pressure from the motor can control the permeability. The calculated and experimental results demonstrate that the maximum pressure on artificial skin is under the area with the maximum vibration amplitude of the ultrasonic transducer, and the total pressure consists of acoustic pressure from the transducer and approximate static pressure from the motor. Changing the static pressure from the ultrasonic motor can effectively control the non-invasive permeability, by adjusting the duty ratio or the amplitude of the motor’s driving voltage. In addition, the permeability control of calcein by thrust control is realized in 15 min, indicating the suitability of this method for application in accurate medical technology. The obtained results reveal that the issue of difficult permeability control can be addressed, using this control method in in vitro LFS to open up a route to the design of accurate drug delivery technology for individual patients.

Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters.

PubMed

Shin, Jaewoo; Kong, Chanho; Cho, Jae Sung; Lee, Jihyeon; Koh, Chin Su; Yoon, Min-Sik; Na, Young Cheol; Chang, Won Seok; Chang, Jin Woo

2018-02-01

OBJECTIVE The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals. METHODS Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H & E staining was used to identify blood vessel damage. RESULTS Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication. CONCLUSIONS The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future.

Ultrasound, liposomes, and drug delivery: principles for using ultrasound to control the release of drugs from liposomes.

PubMed

Schroeder, Avi; Kost, Joseph; Barenholz, Yechezkel

2009-11-01

Ultrasound is used in many medical applications, such as imaging, blood flow analysis, dentistry, liposuction, tumor and fibroid ablation, and kidney stone disruption. In the past, low frequency ultrasound (LFUS) was the main method to downsize multilamellar (micron range) vesicles into small (nano scale) unilamellar vesicles. Recently, the ability of ultrasound to induce localized and controlled drug release from liposomes, utilizing thermal and/or mechanical effects, has been shown. This review, deals with the interaction of ultrasound with liposomes, focusing mainly on the mechanical mechanism of drug release from liposomes using LFUS. The effects of liposome lipid composition and physicochemical properties, on one hand, and of LFUS parameters, on the other, on liposomal drug release, are addressed. Acoustic cavitation, in which gas bubbles oscillate and collapse in the medium, thereby introducing intense mechanical strains, increases release substantially. We suggest that the mechanism of release may involve formation and collapse of small gas nuclei in the hydrophobic region of the lipid bilayer during exposure to LFUS, thereby inducing the formation of transient pores through which drugs are released. Introducing PEG-lipopolymers to the liposome bilayer enhances responsivity to LFUS, most likely due to absorption of ultrasonic energy by the highly hydrated PEG headgroups. The presence of amphiphiles, such as phospholipids with unsaturated acyl chains, which destabilize the lipid bilayer, also increases liposome susceptibility to LFUS. Application of these principles to design highly LFUS-responsive liposomes is discussed.

Membrane-targeting liquid crystal nanoparticles (LCNPs) for drug delivery

NASA Astrophysics Data System (ADS)

Nag, Okhil K.; Naciri, Jawad; Spillmann, Christopher M.; Delehanty, James B.

2016-03-01

In addition to maintaining the structural integrity of the cell, the plasma membrane regulates multiple important cellular processes, such as endocytosis and trafficking, apoptotic pathways and drug transport. The modulation or tracking of such cellular processes by means of controlled delivery of drugs or imaging agents via nanoscale delivery systems is very attractive. Nanoparticle-mediated delivery systems that mediate long-term residence (e.g., days) and controlled release of the cargoes in the plasma membrane while simultaneously not interfering with regular cellular physiology would be ideal for this purpose. Our laboratory has developed a plasma membrane-targeted liquid crystal nanoparticle (LCNP) formulation that can be loaded with dyes or drugs which can be slowly released from the particle over time. Here we highlight the utility of these nanopreparations for membrane delivery and imaging.

Enhancement of non-invasive trans-membrane drug delivery using ultrasound and microbubbles during physiologically relevant flow.

PubMed

Shamout, Farah E; Pouliopoulos, Antonios N; Lee, Patrizia; Bonaccorsi, Simone; Towhidi, Leila; Krams, Rob; Choi, James J

2015-09-01

Sonoporation has been associated with drug delivery across cell membranes and into target cells, yet several limitations have prohibited further advancement of this technology. Higher delivery rates were associated with increased cellular death, thus implying a safety-efficacy trade-off. Meanwhile, there has been no reported study of safe in vitro sonoporation in a physiologically relevant flow environment. The objective of our study was not only to evaluate sonoporation under physiologically relevant flow conditions, such as fluid velocity, shear stress and temperature, but also to design ultrasound parameters that exploit the presence of flow to maximize sonoporation efficacy while minimizing or avoiding cellular damage. Human umbilical vein endothelial cells (EA.hy926) were seeded in flow chambers as a monolayer to mimic the endothelium. A peristaltic pump maintained a constant fluid velocity of 12.5 cm/s. A focused 0.5 MHz transducer was used to sonicate the cells, while an inserted focused 7.5 MHz passive cavitation detector monitored microbubble-seeded cavitation emissions. Under these conditions, propidium iodide, which is normally impermeable to the cell membrane, was traced to determine whether it could enter cells after sonication. Meanwhile, calcein-AM was used as a cell viability marker. A range of focused ultrasound parameters was explored, with several unique bioeffects observed: cell detachment, preservation of cell viability with no membrane penetration, cell death and preservation of cell viability with sonoporation. The parameters were then modified further to produce safe sonoporation with minimal cell death. To increase the number of favourable cavitation events, we lowered the ultrasound exposure pressure to 40 kPapk-neg and increased the number of cavitation nuclei by 50 times to produce a trans-membrane delivery rate of 62.6% ± 4.3% with a cell viability of 95% ± 4.2%. Furthermore, acoustic cavitation analysis showed that the low pressure sonication produced stable and non-inertial cavitation throughout the pulse sequence. To our knowledge, this is the first study to demonstrate a high drug delivery rate coupled with high cell viability in a physiologically relevant in vitro flow system. Copyright © 2015. Published by Elsevier Inc.

Fluid and solid mechanics in a poroelastic network induced by ultrasound.

PubMed

Wang, Peng; Olbricht, William L

2011-01-04

We made a theoretical analysis on the fluid and solid mechanics in a poroelastic medium induced by low-power ultrasound. Using a perturbative approach, we were able to linearize the governing equations and obtain analytical solutions. We found that ultrasound could propagate in the medium as a mechanical wave, but would dissipate due to frictional forces between the fluid and the solid phase. The amplitude of the wave depends on the ultrasonic power input. We applied this model to the problem of drug delivery to soft biological tissues by low-power ultrasound and proposed a mechanism for enhanced drug penetration. We have also found the coexistence of two acoustic waves under certain circumstances and pointed out the importance of very accurate experimental determination of the high-frequency properties of brain tissue. Copyright © 2010 Elsevier Ltd. All rights reserved.

Design and development of hyaluronan-functionalized polybenzofulvene nanoparticles as CD44 receptor mediated drug delivery system

NASA Astrophysics Data System (ADS)

Licciardi, Mariano; Scialabba, Cinzia; Giammona, Gaetano; Paolino, Marco; Razzano, Vincenzo; Grisci, Giorgio; Giuliani, Germano; Makovec, Francesco; Cappelli, Andrea

2017-06-01

A tri-component polymer brush (TCPB ), composed of a polybenzofulvene copolymer bearing low molecular weight hyaluronic acid (HA) on the surface of its cylindrical brush-like backbone and oligo-PEG fractions, was employed in the preparation of 350 nm nanostructured drug delivery systems capable of delivering the anticancer drug doxorubicin. The obtained drug delivery systems were characterized on the basis of drug loading and release, dimensions and zeta potential, morphology and in vitro cell activity, and uptake on three different human cell lines, namely the bronchial epithelial 16HBE, the breast adenocarcinoma MCF-7, and the colon cancer HCT116 cells. Finally, the ability of doxorubicin-loaded TCPB nanoparticles (DOXO-TCPB) to be internalized into cancer cells by CD44 receptor mediated uptake was assessed by means of uptake studies in HCT cells. These data were supported by anti-CD44-FITC staining assay. The proposed TCPB nanostructured drug delivery systems have many potential applications in nanomedicine, including cancer targeted drug delivery.

Streaming flow from ultrasound contrast agents by acoustic waves in a blood vessel model.

PubMed

Cho, Eunjin; Chung, Sang Kug; Rhee, Kyehan

2015-09-01

To elucidate the effects of streaming flow on ultrasound contrast agent (UCA)-assisted drug delivery, streaming velocity fields from sonicated UCA microbubbles were measured using particle image velocimetry (PIV) in a blood vessel model. At the beginning of ultrasound sonication, the UCA bubbles formed clusters and translated in the direction of the ultrasound field. Bubble cluster formation and translation were faster with 2.25MHz sonication, a frequency close to the resonance frequency of the UCA. Translation of bubble clusters induced streaming jet flow that impinged on the vessel wall, forming symmetric vortices. The maximum streaming velocity was about 60mm/s at 2.25MHz and decreased to 15mm/s at 1.0MHz for the same acoustic pressure amplitude. The effect of the ultrasound frequency on wall shear stress was more noticeable. Maximum wall shear stress decreased from 0.84 to 0.1Pa as the ultrasound frequency decreased from 2.25 to 1.0MHz. The maximum spatial gradient of the wall shear stress also decreased from 1.0 to 0.1Pa/mm. This study showed that streaming flow was induced by bubble cluster formation and translation and was stronger upon sonication by an acoustic wave with a frequency near the UCA resonance frequency. Therefore, the secondary radiant force, which is much stronger at the resonance frequency, should play an important role in UCA-assisted drug delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

Ultrasound-enhanced delivery of doxorubicin/all-trans retinoic acid-loaded nanodiamonds into tumors.

PubMed

Li, Huanan; Zeng, Deping; Wang, Zhenyu; Fang, Liaoqiong; Li, Faqi; Wang, Zhibiao

2018-03-14

To build up a combined therapy strategy to address limitations of the enhanced permeability and retention (EPR) effect and improve the efficiency of tumor therapy. A pH-sensitive nanocomplex for co-delivery of doxorubicin (DOX) and all-trans retinoic acid (ATRA) was developed based on nanodiamonds (DOX/ATRA-NDs) to enhance intracellular retention of drugs. Meanwhile, ultrasound was employed to enhance tumor vascular penetration of DOX-ATRA-NDs. The distribution of DOX/ATRA-NDs in the tumor tissues increased threefold when ultrasound was applied at 1 MHz and 0.6 W/cm 2 . Comparing with unmodified chemotherapeutics, the combined therapy induced more tumor cells apoptosis and greater tumor growth inhibition in both liver and breast tumor models. DOX-ATRA-NDs demonstrate great potential in clinical applications.

Microbubbles and ultrasound: a bird's eye view.

PubMed

Kaul, Sanjiv

2004-01-01

Gas-filled microbubbles were initially used as ultrasound contrast agent because of their intravascular rheology, which is similar to that of red blood cells. Their transit through tissue can thus be quantified with ultrasound. More recently, these bubbles have been successfully used for molecular imaging by incorporating ligands on their surfaces that will adhere to cellular and other components within the microvasculature and can be detected by ultrasound. These bubbles have also been used for delivery of genes and drugs which can be released locally by disruption of the bubbles with high-energy ultrasound. Finally, bioeffects produced by localized ultrasound disruption of microbubbles have been shown to induce angiogenesis. This brief review will provide a bird's eye view of these applications.

Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence

NASA Astrophysics Data System (ADS)

Xue, Jingwei; Zhao, Zekai; Zhang, Lei; Xue, Lingjing; Shen, Shiyang; Wen, Yajing; Wei, Zhuoyuan; Wang, Lu; Kong, Lingyi; Sun, Hongbin; Ping, Qineng; Mo, Ran; Zhang, Can

2017-07-01

Cell-mediated drug-delivery systems have received considerable attention for their enhanced therapeutic specificity and efficacy in cancer treatment. Neutrophils (NEs), the most abundant type of immune cells, are known to penetrate inflamed brain tumours. Here we show that NEs carrying liposomes that contain paclitaxel (PTX) can penetrate the brain and suppress the recurrence of glioma in mice whose tumour has been resected surgically. Inflammatory factors released after tumour resection guide the movement of the NEs into the inflamed brain. The highly concentrated inflammatory signals in the brain trigger the release of liposomal PTX from the NEs, which allows delivery of PTX into the remaining invading tumour cells. We show that this NE-mediated delivery of drugs efficiently slows the recurrent growth of tumours, with significantly improved survival rates, but does not completely inhibit the regrowth of tumours.

Acoustic microstreaming due to an ultrasound contrast microbubble near a wall

NASA Astrophysics Data System (ADS)

Mobadersany, Nima; Sarkar, Kausik

2017-11-01

In an ultrasound field, in addition to the sinusoidal motion of fluid particles, particles experience a steady streaming velocity due to nonlinear second order effects. Here, we have simulated the microstreaming flow near a plane rigid wall caused by the pulsations of contrast microbubbles. Although these microbubbles were initially developed as a contrast enhancing agents for ultrasound imaging, they generate additional therapeutic effects that can be harnessed for targeted drug delivery or blood brain barrier (BBB) opening. The microbubbles have a gas core coated with a stabilizing layer of lipids or proteins. We use analytical models as well as boundary element (BEM) simulation to simulate the flow around these bubbles implementing interfacial rheology models for the coating. The microstreaming flow is characterized by two wall bounded vortices. The size of the vortices decreases with the decrease of the separation from the wall. The vortex-induced shear stress is simulated and analyzed as a function of excitation parameters and geometry. These microstreaming shear stress plays a critical role in increasing the membrane permeability facilitating drug delivery or rupturing biological tissues.

Characterization and destruction of Definity® microbubbles used for ultrasound imaging and drug delivery

NASA Astrophysics Data System (ADS)

Sarkar, Kausik; Chatterjee, Dhiman; Jain, Pankaj

2004-11-01

Intravenously injected encapsulated microbubbles improve the contrast of an ultrasound image. Their destruction is used in measuring blood flow, stimulating arteriogenesis, and drug delivery. We measure attenuation and scattering of ultrasound through solution of contrast agent Definity (Bristol Meyer-Squibb Imaging, North Ballerina, MA). We have developed an interfacial rheology model for the stabilizing encapsulation of such microbubbles. By matching with attenuation data, we obtain the characteristic rheological parameters for Definity. We compare model predictions with measured scattering. We investigate microbubble destruction under acoustic excitation by measuring time-varying attenuation data. Three regions of acoustic pressure amplitudes are found: at low pressure, there is no destruction; at slightly higher pressure bubbles are destroyed, and the rate of destruction depends on a combination of PRF and amplitude. At a still higher pressure amplitude, the attenuation decreases catastrophically. The last two regimes correspond respectively to 1) slow destruction of bubbles due to increased gas diffusion and 2) complete bubble destruction leading to release of free bubbles. (Supported by DOD, NSF and University of Delaware Research Foundation)

Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques.

PubMed

McDannold, Nathan; Arvanitis, Costas D; Vykhodtseva, Natalia; Livingstone, Margaret S

2012-07-15

The blood-brain barrier (BBB) prevents entry of most drugs into the brain and is a major hurdle to the use of drugs for brain tumors and other central nervous system disorders. Work in small animals has shown that ultrasound combined with an intravenously circulating microbubble agent can temporarily permeabilize the BBB. Here, we evaluated whether this targeted drug delivery method can be applied safely, reliably, and in a controlled manner on rhesus macaques using a focused ultrasound system. We identified a clear safety window during which BBB disruption could be produced without evident tissue damage, and the acoustic pressure amplitude where the probability for BBB disruption was 50% and was found to be half of the value that would produce tissue damage. Acoustic emission measurements seem promising for predicting BBB disruption and damage. In addition, we conducted repeated BBB disruption to central visual field targets over several weeks in animals trained to conduct complex visual acuity tasks. All animals recovered from each session without behavioral deficits, visual deficits, or loss in visual acuity. Together, our findings show that BBB disruption can be reliably and repeatedly produced without evident histologic or functional damage in a clinically relevant animal model using a clinical device. These results therefore support clinical testing of this noninvasive-targeted drug delivery method.

Localized delivery of curcumin into brain with polysorbate 80-modified cerasomes by ultrasound-targeted microbubble destruction for improved Parkinson's disease therapy

PubMed Central

Zhang, Nisi; Yan, Fei; Liang, Xiaolong; Wu, Manxiang; Shen, Yuanyuan; Chen, Min; Xu, Yunxue; Zou, Guangyang; Jiang, Peng; Tang, Caiyun; Zheng, Hairong; Dai, Zhifei

2018-01-01

Rationale: Treatment for Parkinson's disease (PD) is challenged by the presence of the blood-brain barrier (BBB) that significantly limits the effective drug concentration in a patient's brain for therapeutic response throughout various stages of PD. Curcumin holds the potential for α-synuclein clearance to treat PD; however, its applications are still limited due to its low bioavailability and poor permeability through the BBB in a free form. Methods: Herein, this paper fabricated curcumin-loaded polysorbate 80-modified cerasome (CPC) nanoparticles (NPs) with a mean diameter of ~110 nm for enhancing the localized curcumin delivery into the targeted brain nuclei via effective BBB opening in combination with ultrasound-targeted microbubble destruction (UTMD). Results: The liposomal nanohybrid cerasome exhibited superior stability towards PS 80 surfactant solubilization and longer circulation lifetime (t1/2 = 6.22 h), much longer than free curcumin (t1/2 = 0.76 h). The permeation was found to be 1.7-fold higher than that of CPC treatment only at 6 h after the systemic administration of CPC NPs. Notably, motor behaviors, dopamine (DA) level and tyrosine hydroxylase (TH) expression all returned to normal, thanks to α-synuclein (AS) removal mediated by efficient curcumin delivery to the striatum. Most importantly, the animal experiment demonstrated that the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice had notably improved behavior disorder and dopamine depletion during two-week post-observation after treatment with CPC NPs (15 mg curcumin/kg) coupled with UTMD. Conclusion: This novel CPC-UTMD formulation approach could be an effective, safe and amenable choice with higher therapeutic relevance and fewer unwanted complications than conventional chemotherapeutics delivery systems for PD treatment in the near future. PMID:29721078

Ultra-fast bright field and fluorescence imaging of the dynamics of micrometer-sized objects

NASA Astrophysics Data System (ADS)

Chen, Xucai; Wang, Jianjun; Versluis, Michel; de Jong, Nico; Villanueva, Flordeliza S.

2013-06-01

High speed imaging has application in a wide area of industry and scientific research. In medical research, high speed imaging has the potential to reveal insight into mechanisms of action of various therapeutic interventions. Examples include ultrasound assisted thrombolysis, drug delivery, and gene therapy. Visual observation of the ultrasound, microbubble, and biological cell interaction may help the understanding of the dynamic behavior of microbubbles and may eventually lead to better design of such delivery systems. We present the development of a high speed bright field and fluorescence imaging system that incorporates external mechanical waves such as ultrasound. Through collaborative design and contract manufacturing, a high speed imaging system has been successfully developed at the University of Pittsburgh Medical Center. We named the system "UPMC Cam," to refer to the integrated imaging system that includes the multi-frame camera and its unique software control, the customized modular microscope, the customized laser delivery system, its auxiliary ultrasound generator, and the combined ultrasound and optical imaging chamber for in vitro and in vivo observations. This system is capable of imaging microscopic bright field and fluorescence movies at 25 × 106 frames per second for 128 frames, with a frame size of 920 × 616 pixels. Example images of microbubble under ultrasound are shown to demonstrate the potential application of the system.

Ultra-fast bright field and fluorescence imaging of the dynamics of micrometer-sized objects

PubMed Central

Chen, Xucai; Wang, Jianjun; Versluis, Michel; de Jong, Nico; Villanueva, Flordeliza S.

2013-01-01

High speed imaging has application in a wide area of industry and scientific research. In medical research, high speed imaging has the potential to reveal insight into mechanisms of action of various therapeutic interventions. Examples include ultrasound assisted thrombolysis, drug delivery, and gene therapy. Visual observation of the ultrasound, microbubble, and biological cell interaction may help the understanding of the dynamic behavior of microbubbles and may eventually lead to better design of such delivery systems. We present the development of a high speed bright field and fluorescence imaging system that incorporates external mechanical waves such as ultrasound. Through collaborative design and contract manufacturing, a high speed imaging system has been successfully developed at the University of Pittsburgh Medical Center. We named the system “UPMC Cam,” to refer to the integrated imaging system that includes the multi-frame camera and its unique software control, the customized modular microscope, the customized laser delivery system, its auxiliary ultrasound generator, and the combined ultrasound and optical imaging chamber for in vitro and in vivo observations. This system is capable of imaging microscopic bright field and fluorescence movies at 25 × 106 frames per second for 128 frames, with a frame size of 920 × 616 pixels. Example images of microbubble under ultrasound are shown to demonstrate the potential application of the system. PMID:23822346

Recent Advances in Endogenous and Exogenous Stimuli-Responsive Nanocarriers for Drug Delivery and Therapeutics.

PubMed

Hatakeyama, Hiroto

2017-01-01

Significant progress has been achieved in the development of stimuli-responsive nanocarriers for drug delivery, diagnosis, and therapy. Various types of triggers are utilized in the development of nanocarrier delivery. Endogenous factors such as changes in pH, redox, gradient, and enzyme concentration which are linked to disease progression have been utilized for controlling biodistribution and releasing drugs from nanocarriers, as well as increasing subsequent pharmacological activity at the disease site. Nanocarriers which respond to artificially-induced exogenous factors (such as temperature, light, magnetic field, and ultrasound) have also been developed. This review aims to discuss recent advances in the design of stimuli-responsive nanocarriers which appear to have a promising future in medicine.

Nerve growth factor delivery by ultrasound-mediated nanobubble destruction as a treatment for acute spinal cord injury in rats

PubMed Central

Song, Zhaojun; Wang, Zhigang; Shen, Jieliang; Xu, Shengxi; Hu, Zhenming

2017-01-01

Background Spinal cord injuries (SCIs) can cause severe disability or death. Treatment options include surgical intervention, drug therapy, and stem cell transplantation. However, the efficacy of these methods for functional recovery remains unsatisfactory. Purpose This study was conducted to explore the effect of ultrasound (US)-mediated destruction of poly(lactic-co-glycolic acid) (PLGA) nanobubbles (NBs) expressing nerve growth factor (NGF) (NGF/PLGA NBs) on nerve regeneration in rats following SCI. Materials and methods Adult male Sprague Dawley rats were randomly divided into four treatment groups after Allen hit models of SCI were established. The groups were normal saline (NS) group, NGF and NBs group, NGF and US group, and NGF/PLGA NBs and US group. Histological changes after SCI were observed by hematoxylin and eosin staining. Neuron viability was determined by Nissl staining. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining was used to examine cell apoptosis. NGF gene and protein expressions were detected by quantitative reverse transcription polymerase chain reaction and Western blotting. Green fluorescent protein expression in the spinal cord was examined using an inverted fluorescence microscope. The recovery of neural function was determined using the Basso, Beattie, and Bresnahan test. Results NGF therapy using US-mediated NGF/PLGA NBs destruction significantly increased NGF expression, attenuated histological injury, decreased neuron loss, inhibited neuronal apoptosis in injured spinal cords, and increased BBB scores in rats with SCI. Conclusion US-mediated NGF/PLGA NBs destruction effectively transfects the NGF gene into target tissues and has a significant effect on the injured spinal cord. The combination of US irradiation and gene therapy through NGF/PLGA NBs holds great promise for the future of nanomedicine and the development of noninvasive treatment options for SCI and other diseases. PMID:28280337

Fabrication of Plasmonic Nanorod-Embedded Dipeptide Microspheres via the Freeze-Quenching Method for Near-Infrared Laser-Triggered Drug-Delivery Applications.

PubMed

Erdogan, Hakan; Yilmaz, Mehmet; Babur, Esra; Duman, Memed; Aydin, Halil M; Demirel, Gokhan

2016-05-09

Control of drug release by an external stimulus may provide remote controllability, low toxicity, and reduced side effects. In this context, varying physical external stimuli, including magnetic and electric fields, ultrasound, light, and pharmacological stimuli, have been employed to control the release rate of drug molecules in a diseased region. However, the design and development of alternative on-demand drug-delivery systems that permit control of the dosage of drug released via an external stimulus are still required. Here, we developed near-infrared laser-activatable microspheres based on Fmoc-diphenylalanine (Phe-Phe) dipeptides and plasmonic gold nanorods (AuNRs) via a simple freeze-quenching approach. These plasmonic nanoparticle-embedded microspheres were then employed as a smart drug-delivery platform for native, continuous, and pulsatile doxorubicin (DOX) release. Remarkable sustained, burst, and on-demand DOX release from the fabricated microspheres were achieved by manipulating the laser exposure time. Our results demonstrate that AuNR-embedded dipeptide microspheres have great potential for controlled drug-delivery systems.

Low-Pressure Burst-Mode Focused Ultrasound Wave Reconstruction and Mapping for Blood-Brain Barrier Opening: A Preclinical Examination

PubMed Central

Xia, Jingjing; Tsui, Po-Hsiang; Liu, Hao-Li

2016-01-01

Burst-mode focused ultrasound (FUS) exposure has been shown to induce transient blood-brain barrier (BBB) opening for potential CNS drug delivery. FUS-BBB opening requires imaging guidance during the intervention, yet current imaging technology only enables postoperative outcome confirmation. In this study, we propose an approach to visualize short-burst low-pressure focal beam distribution that allows to be applied in FUS-BBB opening intervention on small animals. A backscattered acoustic-wave reconstruction method based on synchronization among focused ultrasound emission, diagnostic ultrasound receiving and passively beamformed processing were developed. We observed that focal beam could be successfully visualized for in vitro FUS exposure with 0.5–2 MHz without involvement of microbubbles. The detectable level of FUS exposure was 0.467 MPa in pressure and 0.05 ms in burst length. The signal intensity (SI) of the reconstructions was linearly correlated with the FUS exposure level both in-vitro (r2 = 0.9878) and in-vivo (r2 = 0.9943), and SI level of the reconstructed focal beam also correlated with the success and level of BBB-opening. The proposed approach provides a feasible way to perform real-time and closed-loop control of FUS-based brain drug delivery. PMID:27295608

Low-Pressure Burst-Mode Focused Ultrasound Wave Reconstruction and Mapping for Blood-Brain Barrier Opening: A Preclinical Examination

NASA Astrophysics Data System (ADS)

Xia, Jingjing; Tsui, Po-Hsiang; Liu, Hao-Li

2016-06-01

Burst-mode focused ultrasound (FUS) exposure has been shown to induce transient blood-brain barrier (BBB) opening for potential CNS drug delivery. FUS-BBB opening requires imaging guidance during the intervention, yet current imaging technology only enables postoperative outcome confirmation. In this study, we propose an approach to visualize short-burst low-pressure focal beam distribution that allows to be applied in FUS-BBB opening intervention on small animals. A backscattered acoustic-wave reconstruction method based on synchronization among focused ultrasound emission, diagnostic ultrasound receiving and passively beamformed processing were developed. We observed that focal beam could be successfully visualized for in vitro FUS exposure with 0.5-2 MHz without involvement of microbubbles. The detectable level of FUS exposure was 0.467 MPa in pressure and 0.05 ms in burst length. The signal intensity (SI) of the reconstructions was linearly correlated with the FUS exposure level both in-vitro (r2 = 0.9878) and in-vivo (r2 = 0.9943), and SI level of the reconstructed focal beam also correlated with the success and level of BBB-opening. The proposed approach provides a feasible way to perform real-time and closed-loop control of FUS-based brain drug delivery.

Enhanced therapeutic anti-inflammatory effect of betamethasone upon topical administration with low frequency, low intensity (20 kHz, 100 mW/cm2) ultrasound exposure on carrageenan-induced arthritis in mice model

PubMed Central

Cohen, Gadi; Natsheh, Hiba; Sunny, Youhan; Bawiec, Christopher R.; Touitou, Elka; Lerman, Melissa A.; Lazarovici, Philip; Lewin, Peter A.

2015-01-01

The purpose of this work was to investigate whether low frequency, low intensity (LFLI, 20 kHz, <100 mW/cm2, spatial-peak, temporal-peak) ultrasound (US), delivered by a light-weight (<100g), tether-free, fully wearable, battery powered applicator is capable of reducing inflammation in a mouse model of Rheumatoid Arthritis (RA). The therapeutic, acute, anti-inflammatory effect was estimated by the relative swelling induced in mice hind limb paws. In an independent, indirect approach, the inflammation was bio-imaged by measuring glycolytic activity with near infrared labeled 2-deoxy-glucose (2DG). The outcome of the experiments indicated that the combination of US exposure with topical application of 0.1% w/w betamethasone gel, exhibited statistically significant (p<0.05) enhanced anti-inflammatory properties in comparison with the drug or US treatment alone. The present study underscores the potential benefits of LFLI US assisted drug delivery. However, the proof of concept presented indicates the need for additional experiments to systematically evaluate and optimize the potential of, and the conditions for, safe, LFLI ultrasound promoted non-invasive drug delivery. PMID:26003010

Development of an Optimised Application Protocol For Sonophoretic Transdermal Delivery of a Model Hydrophilic Drug

PubMed Central

Sarheed, Omar; Abdul Rasool, Bazigha K

2011-01-01

It has now been known for over a decade that low frequency ultrasound can be used to effectively enhance transdermal drug penetration - an approach termed sonophoresis. Mechanistically, acoustic cavitation results in the creation of defects in the stratum corneum that allow accelerated absorption of topically applied molecules. The aim of this study was to develop an optimised sonophoresis protocol for studying transdermal drug delivery in vitro. To this end, caffeine was selected as a model hydrophilic drug while porcine skin was used as a model barrier. Following acoustic validation, 20kHz ultrasound was applied for different durations (range: 5 s to 10 min) using three different modes (10%, 33% or 100% duty cycles) and two distinct sonication procedures (either before or concurrent with drug deposition). Each ultrasonic protocol was assessed in terms of its heating and caffeine flux-enhancing effects. It was found that the best regimen was a concurrent 5 min, pulsed (10% duty cycle) beam of SATA intensity 0.37 W/cm2. A key insight was that in the case of pulsed beams of 10% duty cycle, sonication concurrent with drug deposition was superior to sonication prior to drug deposition and potential mechanisms for this are discussed. PMID:21629673

Recent Advances in Skin Penetration Enhancers for Transdermal Gene and Drug Delivery.

PubMed

Amjadi, Morteza; Mostaghaci, Babak; Sitti, Metin

2017-01-01

There is a growing interest in transdermal delivery systems because of their noninvasive, targeted, and on-demand delivery of gene and drugs. However, efficient penetration of therapeutic compounds into the skin is still challenging largely due to the impermeability of the outermost layer of the skin, known as stratum corneum. Recently, there have been major research activities to enhance the skin penetration depth of pharmacological agents. This article reviews recent advances in the development of various strategies for skin penetration enhancement. We show that approaches such as ultrasound waves, laser, and microneedle patches have successfully been employed to physically disrupt the stratum corneum structure for enhanced transdermal delivery. Rather than physical approaches, several non-physical route have also been utilized for efficient transdermal delivery across the skin barrier. Finally, we discuss some clinical applications of transdermal delivery systems for gene and drug delivery. This paper shows that transdermal delivery devices can potentially function for diverse healthcare and medical applications while further investigations are still necessary for more efficient skin penetration of gene and drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Hot topics in biomedical ultrasound: ultrasound therapy and its integration with ultrasonic imaging

NASA Astrophysics Data System (ADS)

Everbach, E. Carr

2005-09-01

Since the development of biomedical ultrasound imaging from sonar after WWII, there has been a clear divide between ultrasonic imaging and ultrasound therapy. While imaging techniques are designed to cause as little change as possible in the tissues through which ultrasound propagates, ultrasound therapy typically relies upon heating or acoustic cavitation to produce a desirable therapeutic effect. Concerns over the increasingly high acoustic outputs of diagnostic ultrasound scanners prompted the adoption of the Mechanical Index (MI) and Thermal Index (TI) in the early 1990s. Therapeutic applications of ultrasound, meanwhile, have evolved from deep tissue heating in sports medicine to include targeted drug delivery, tumor and plaque ablation, cauterization via high intensity focused ultrasound (HIFU), and accelerated dissolution of blood clots. The integration of ultrasonic imaging and therapy in one device is just beginning, but the promise of improved patient outcomes is balanced by regulatory and practical impediments.

Delivery of molecules into cells using carbon nanoparticles activated by femtosecond laser pulses

PubMed Central

Chakravarty, Prerona; Qian, Wei; El-Sayed, Mostafa A.; Prausnitz, Mark R.

2010-01-01

A major barrier to drug and gene delivery is crossing the cell's plasma membrane. Physical forces applied to cells via electroporation1, ultrasound2 and laser-irradiation3–6 generate nanoscale holes in the plasma membrane for direct delivery of drugs into the cytoplasm. Inspired by previous work showing that laser excitation of carbon nanoparticles can drive the carbon-steam reaction to generate highly controlled shock waves7–10, here we show carbon black (CB) nanoparticles activated by femtosecond laser pulses can facilitate the delivery of small molecules, proteins and DNA into two types of cells. Our initial results suggest that interaction between the laser energy and CB nanoparticles may generate photoacoustic forces by chemical reaction to create transient holes in the membrane for delivery. PMID:20639882

Development of fluorous lipid-based nanobubbles for efficiently containing perfluoropropane.

PubMed

Oda, Yusuke; Suzuki, Ryo; Mori, Tatsuya; Takahashi, Hideyo; Natsugari, Hideaki; Omata, Daiki; Unga, Johan; Uruga, Hitoshi; Sugii, Mutsumi; Kawakami, Shigeru; Higuchi, Yuriko; Yamashita, Fumiyoshi; Hashida, Mitsuru; Maruyama, Kazuo

2015-06-20

Nano-/microbubbles are expected not only to function as ultrasound contrast agents but also as ultrasound-triggered enhancers in gene and drug delivery. Notably, nanobubbles have the ability to pass through tumor vasculature and achieve passive tumor targeting. Thus, nanobubbles would be an attractive tool for use as ultrasound-mediated cancer theranostics. However, the amounts of gas carried by nanobubbles are generally lower than those carried by microbubbles because nanobubbles have inherently smaller volumes. In order to reduce the injection volume and to increase echogenicity, it is important to develop nanobubbles with higher gas content. In this study, we prepared 5 kinds of fluoro-lipids and used these reagents as surfactants to generate "Bubble liposomes", that is, liposomes that encapsulate nanobubbles such that the lipids serve as stabilizers between the fluorous gas and water phases. Bubble liposome containing 1-stearoyl-2-(18,18-difluoro)stearoyl-sn-glycero-3-phosphocholine carried 2-fold higher amounts of C3F8 compared to unmodified Bubble liposome. The modified Bubble liposome also exhibited increased echogenicity by ultrasonography. These results demonstrated that the inclusion of fluoro-lipid is a promising tool for generating nanobubbles with increased efficiency of fluorous gas carrier. Copyright © 2015 Elsevier B.V. All rights reserved.

Ultrasound-Stimulated Drug Delivery Using Therapeutic Reconstituted High-Density Lipoprotein Nanoparticles.

PubMed

Xiong, Fangyuan; Nirupama, Sabnis; Sirsi, Shashank R; Lacko, Andras; Hoyt, Kenneth

2017-01-01

The abnormal tumor vasculature and the resulting abnormal microenvironment are major barriers to optimal chemotherapeutic drug delivery. It is well known that ultrasound (US) can increase the permeability of the tumor vessel walls and enhance the accumulation of anticancer agents. Reconstituted high-density lipoproteins (rHDL) nanoparticles (NPs) allow selective delivery of anticancer agents to tumor cells via their overexpressed scavenger receptor type B1 (SR-B1) receptor. The goal of this study is to investigate the potential of noninvasive US therapy to further improve delivery and tumor uptake of the payload from rHDL NPs, preloaded with an infrared dye (IR-780), aimed to establish a surrogate chemotherapeutic model with optical localization. Athymic nude mice were implanted orthotopically with one million breast cancer cells (MDA-MB-231/Luc). Three weeks later, animals were divided into seven groups with comparable mean tumor size: control, low, moderate, and high concentration of rHDL NPs alone groups, as well as these three levels of rHDL NPs plus US therapy groups ( N = 7 to 12 animals per group), where low, moderate and high denote 5, 10, and 50 µg of the IR-780 dye payload per rHDL NP injection, respectively. The US therapy system included a single element focused transducer connected in series with a function generator and power amplifier. A custom 3D printed cone with an acoustically transparent aperture and filled with degassed water allowed delivery of focused US energy to the tumor tissue. US exposure involved a pulsed sequence applied for a duration of 5 min. Each animal in the US therapy groups received a slow bolus co-injection of MB contrast agent and rHDL NPs. Animals were imaged using a whole-body optical system to quantify intratumoral rHDL NP accumulation at baseline and again at 1 min, 30 min, 24 h, and 48 h. At 48 h, all animals were euthanized and tumors were excised for ex vivo analysis. We investigated a noninvasive optical imaging method for monitoring the effects of US-stimulated drug delivery of IR-780 dye-loaded rHDL NPs in living animals. No change in optical imaging data was found in the control animals. However, there was considerable dye accumulation (surrogate drug) within 48 h in the low (5 µg), moderate (10 µg), and high (50 µg) rHDL NP concentration-dosed group animals ( p < 0.09). With US therapy added to the experimental protocol, there was an additional and significant increase in local tumor drug uptake at 48 h ( p < 0.02). Optical image data collected from ex vivo tumor samples confirmed tumor retention of the IR-780 dye-loaded rHDL NPs and correlated positively with in vivo optical imaging results ( R 2 > 0.69, p < 0.003). IR-780 dye extraction from the tumor tissue samples confirmed the in vivo and ex vivo US therapy findings. Overall, the addition of US therapy considerably improved local rHDL NP accumulation in tumor tissue. This study concludes that US-mediated drug delivery can facilitate tumor uptake of rHDL NPs and more research is warranted to optimize the drug dosing schedule and the respective therapeutic protocols.

Focused Ultrasound Immunotherapy for Central Nervous System Pathologies: Challenges and Opportunities

PubMed Central

Curley, Colleen T.; Sheybani, Natasha D.; Bullock, Timothy N.; Price, Richard J.

2017-01-01

Immunotherapy is rapidly emerging as the cornerstone for the treatment of several forms of metastatic cancer, as well as for a host of other pathologies. Meanwhile, several new high-profile studies have uncovered remarkable linkages between the central nervous and immune systems. With these recent developments, harnessing the immune system for the treatment of brain pathologies is a promising strategy. Here, we contend that MR image-guided focused ultrasound (FUS) represents a noninvasive approach that will allow for favorable therapeutic immunomodulation in the setting of the central nervous system. One obstacle to effective immunotherapeutic drug delivery to the brain is the blood brain barrier (BBB), which refers to the specialized structure of brain capillaries that prevents transport of most therapeutics from the blood into brain tissue. When applied in the presence of circulating microbubbles, FUS can safely and transiently open the BBB to facilitate the delivery of immunotherapeutic agents into the brain parenchyma. Furthermore, it has been demonstrated that physical perturbations of the tissue microenvironment via FUS can modulate immune response in both normal and diseased tissue. In this review article, we provide an overview of FUS energy regimens and corresponding tissue bioeffects, followed by a review of the literature pertaining to FUS for therapeutic antibody delivery in normal brain and preclinical models of brain disease. We provide an overview of studies that demonstrate FUS-mediated immune modulation in both the brain and peripheral settings. Finally, we provide remarks on challenges facing FUS immunotherapy and opportunities for future expansion in this area. PMID:29109764

PLGA nanoparticles introduction into mitoxantrone-loaded ultrasound-responsive liposomes: In vitro and in vivo investigations.

PubMed

Xin, Yuxuan; Qi, Qi; Mao, Zhenmin; Zhan, Xiaoping

2017-08-07

A novel ultrasound-responsive liposomal system for tumor targeting was prepared in order to increase the antitumor efficacy and decrease serious side effects. In this paper, PLGA nanoparticles were used ultrasound-responsive agents instead of conventional microbubbles. The PLGA-nanoparticles were prepared by an emulsion solvent evaporation method. The liposomes were prepared by a lipid film hydration method. Particle size, zeta potential, encapsulation efficiency and drug loading capacity of the liposomes were studied by light scattering analysis and dialysis. Transmission electron microscopy (TEM) and atomic force microscope (AFM) were used to investigate the morphology of liposomes. The release in vitro was carried out in the pH 7.4 phosphate buffer solutions, as a result, liposome L3 encapsulating PLGA-nanoparticles displayed good stability under simulative physiological conditions and quickly responsive release under the ultrasound. The release in vivo was carried out on the rats, as a result, liposome L3 showed higher bioavailability than traditional intravenous injectable administration, and liposome L3 showed higher elimination ratio after stimulation by ultrasound than L3 without stimulation. Thus, the novel ultrasound-responsive liposome encapsulating PLGA-nanoparticles has a potential to be developed as a new drug delivery system for anti-tumor drug. Copyright © 2017 Elsevier B.V. All rights reserved.

Transdermal drug delivery: from micro to nano

NASA Astrophysics Data System (ADS)

Pegoraro, Carla; MacNeil, Sheila; Battaglia, Giuseppe

2012-03-01

Delivery across skin offers many advantages compared to oral or intravenous routes of drug administration. Skin however is highly impermeable to most molecules on the basis of size, hydrophilicity, lipophilicity and charge. For this reason it is often necessary to temporarily alter the barrier properties of skin for effective administration. This can be done by applying chemical enhancers, which alter the lipid structure of the top layer of skin (the stratum corneum, SC), by applying external forces such as electric currents and ultrasounds, by bypassing the stratum corneum via minimally invasive microneedles or by using nano-delivery vehicles that can cross and deliver their payload to the deeper layers of skin. Here we present a critical summary of the latest technologies used to increase transdermal delivery.

Dual-Functional Nanographene Oxide as Cancer-Targeted Drug-Delivery System to Selectively Induce Cancer-Cell Apoptosis.

PubMed

Zhou, Binwei; Huang, Yanyu; Yang, Fang; Zheng, Wenjie; Chen, Tianfeng

2016-04-05

Construction of bioresponsive drug-delivery nanosystems could enhance the anticancer efficacy of anticancer agents and reduce their toxic side effects. Herein, by using transferrin (Tf) as a surface decorator, we constructed a cancer-targeted nanographene oxide (NGO) nanosystem for use in drug delivery. This nanosystem (Tf-NGO@HPIP) drastically enhanced the cellular uptake, retention, and anticancer efficacy of loaded drugs but showed much lower toxicity to normal cells. The nanosystem was internalized through receptor-mediated endocytosis and triggered pH-dependent drug release in acidic environments and in the presence of cellular enzymes. Moreover, Tf-NGO@HPIP effectively induced cancer-cell apoptosis through activation of superoxide-mediated p53 and MAPK pathways along with inactivation of ERK and AKT. Taken together, this study demonstrates a good strategy for the construction of bioresponsive NGO drug-delivery nanosystems and their use as efficient anticancer drug carriers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

EFSUMB guidelines 2011: comment on emergent indications and visions.

PubMed

Dietrich, C F; Cui, X W; Barreiros, A P; Hocke, M; Ignee, A

2012-07-01

The focus of this article is the emergent and potential indications of contrast-enhanced ultrasound (CEUS). Emergent applications of CEUS techniques include extravascular and intracavitary contrast-enhanced ultrasound, quantitative assessment of microvascular circulation for tumor response assessment, and tumor characterization using dynamic contrast-enhanced ultrasound (DCE-US). Potential indications for microbubble agents include novel molecular imaging and drug and gene delivery techniques, which have been successfully tested in animal models. "Comments and Illustrations of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) Non-Liver Guidelines 2011" which focus more on established applications are published in the same supplement to Ultraschall in der Medizin (European Journal of Ultrasound). © Georg Thieme Verlag KG Stuttgart · New York.

Image-guided ultrasound phased arrays are a disruptive technology for non-invasive therapy

NASA Astrophysics Data System (ADS)

Hynynen, Kullervo; Jones, Ryan M.

2016-09-01

Focused ultrasound offers a non-invasive way of depositing acoustic energy deep into the body, which can be harnessed for a broad spectrum of therapeutic purposes, including tissue ablation, the targeting of therapeutic agents, and stem cell delivery. Phased array transducers enable electronic control over the beam geometry and direction, and can be tailored to provide optimal energy deposition patterns for a given therapeutic application. Their use in combination with modern medical imaging for therapy guidance allows precise targeting, online monitoring, and post-treatment evaluation of the ultrasound-mediated bioeffects. In the past there have been some technical obstacles hindering the construction of large aperture, high-power, densely-populated phased arrays and, as a result, they have not been fully exploited for therapy delivery to date. However, recent research has made the construction of such arrays feasible, and it is expected that their continued development will both greatly improve the safety and efficacy of existing ultrasound therapies as well as enable treatments that are not currently possible with existing technology. This review will summarize the basic principles, current statures, and future potential of image-guided ultrasound phased arrays for therapy.

Image-guided ultrasound phased arrays are a disruptive technology for non-invasive therapy.

PubMed

Hynynen, Kullervo; Jones, Ryan M

2016-09-07

Focused ultrasound offers a non-invasive way of depositing acoustic energy deep into the body, which can be harnessed for a broad spectrum of therapeutic purposes, including tissue ablation, the targeting of therapeutic agents, and stem cell delivery. Phased array transducers enable electronic control over the beam geometry and direction, and can be tailored to provide optimal energy deposition patterns for a given therapeutic application. Their use in combination with modern medical imaging for therapy guidance allows precise targeting, online monitoring, and post-treatment evaluation of the ultrasound-mediated bioeffects. In the past there have been some technical obstacles hindering the construction of large aperture, high-power, densely-populated phased arrays and, as a result, they have not been fully exploited for therapy delivery to date. However, recent research has made the construction of such arrays feasible, and it is expected that their continued development will both greatly improve the safety and efficacy of existing ultrasound therapies as well as enable treatments that are not currently possible with existing technology. This review will summarize the basic principles, current statures, and future potential of image-guided ultrasound phased arrays for therapy.

Image-guided ultrasound phased arrays are a disruptive technology for non-invasive therapy

PubMed Central

Hynynen, Kullervo; Jones, Ryan M.

2016-01-01

Focused ultrasound offers a non-invasive way of depositing acoustic energy deep into the body, which can be harnessed for a broad spectrum of therapeutic purposes, including tissue ablation, the targeting of therapeutic agents, and stem cell delivery. Phased array transducers enable electronic control over the beam geometry and direction, and can be tailored to provide optimal energy deposition patterns for a given therapeutic application. Their use in combination with modern medical imaging for therapy guidance allows precise targeting, online monitoring, and post-treatment evaluation of the ultrasound-mediated bioeffects. In the past there have been some technical obstacles hindering the construction of large aperture, high-power, densely-populated phased arrays and, as a result, they have not been fully exploited for therapy delivery to date. However, recent research has made the construction of such arrays feasible, and it is expected that their continued development will both greatly improve the safety and efficacy of existing ultrasound therapies as well as enable treatments that are not currently possible with existing technology. This review will summarize the basic principles, current statures, and future potential of image-guided ultrasound phased arrays for therapy. PMID:27494561

DELIVERY OF WATER-SOLUBLE DRUGS USING ACOUSTICALLY-TRIGGERED, PERFLUOROCARBON DOUBLE EMULSIONS

PubMed Central

Fabiilli, Mario L.; Lee, James A.; Kripfgans, Oliver D.; Carson, Paul L.; Fowlkes, J. Brian

2010-01-01

Purpose Ultrasound can be used to release a therapeutic payload encapsulated within a perfluorocarbon (PFC) emulsion via acoustic droplet vaporization (ADV), a process whereby the PFC phase is vaporized and the agent is released. ADV-generated microbubbles have been previously used to selectively occlude blood vessels in vivo. The coupling of ADV-generated drug delivery and occlusion has therapeutically, synergistic potentials. Methods Micron-sized, water-in-PFC-in-water (W1/PFC/W2) emulsions were prepared in a two-step process using perfluoropentane (PFP) or perfluorohexane (PFH) as the PFC phase. Fluorescein or thrombin was contained in the W1 phase. Results Double emulsions containing fluorescein in the W1 phase displayed a 5.7±1.4 fold and 8.2±1.3 fold increase in fluorescein mass flux, as measured using a Franz diffusion cell, after ADV for the PFP and PFH emulsions, respectively. Thrombin was stably retained in four out of five double emulsions. For three out of five formulations tested, the clotting time of whole blood decreased, in a statistically significant manner (p < 0.01), when incubated with thrombin-loaded emulsions exposed to ultrasound compared to emulsions not exposed to ultrasound. Conclusions ADV can be used to spatially and temporally control the delivery of water-soluble compounds formulated in PFC double emulsions. Thrombin release could extend the duration of ADV-generated, microbubble occlusions. PMID:20872050

Development and evaluation of perfluorocarbon nanobubbles for apomorphine delivery.

PubMed

Hwang, Tsong-Long; Lin, Yin-Ku; Chi, Chen-Hsien; Huang, Tse-Hung; Fang, Jia-You

2009-10-01

Apomorphine is a dopamine receptor agonist for treating Parkinson's disease. However, its clinical application is limited by its instability and the need for frequent injections. The aim of the present work was to develop acoustically active perfluorocarbon nanobubbles (PNs) for encapsulation of both apomorphine HCl and base forms to circumvent these delivery problems. The PNs were prepared using coconut oil and perfluoropentane as the inner phase, which was emulsified by phospholipids and cholesterol. The morphology, size, zeta potential, and drug release of the PNs were characterized. The particle size ranged from 150 to 380 nm, with differences in the oil or perfluorocarbon ratio in the formulations. Atomic force microscopy confirmed oval- or raisin-shaped particles and a narrow size distribution of these systems (polydispersity index = 0.25-0.28). The stability experimental results indicated that PNs could protect apomorphine from degradation. Evaporation of the PNs at 37 degrees C was also limited. Apomorphine HCl and base in PNs showed retarded and sustained release profiles. Ultrasound imaging confirmed the echogenic activity of PNs developed in this study. The apomorphine HCl release by insonation at 1 MHz showed enhancements of two- to fourfold compared to the non-ultrasound group, illustrating a possible drug-targeting effect. On the contrary, apomorphine base showed a decreased release profile with ultrasound application. Apomorphine-loaded PNs showed promising stability and safety. They were successful in sustaining apomorphine delivery.

Rupture threshold characterization of polymer-shelled ultrasound contrast agents subjected to static overpressure

NASA Astrophysics Data System (ADS)

Chitnis, Parag V.; Lee, Paul; Mamou, Jonathan; Allen, John S.; Böhmer, Marcel; Ketterling, Jeffrey A.

2011-04-01

Polymer-shelled micro-bubbles are employed as ultrasound contrast agents (UCAs) and vesicles for targeted drug delivery. UCA-based delivery of the therapeutic payload relies on ultrasound-induced shell rupture. The fragility of two polymer-shelled UCAs manufactured by Point Biomedical or Philips Research was investigated by characterizing their response to static overpressure. The nominal diameters of Point and Philips UCAs were 3 μm and 2 μm, respectively. The UCAs were subjected to static overpressure in a glycerol-filled test chamber with a microscope-reticule lid. UCAs were reconstituted in 0.1 mL of water and added over the glycerol surface in contact with the reticule. A video-microscope imaged UCAs as glycerol was injected (5 mL/h) to vary the pressure from 2 to 180 kPa over 1 h. Neither UCA population responded to overpressure until the rupture threshold was exceeded, which resulted in abrupt destruction. The rupture data for both UCAs indicated three subclasses that exhibited different rupture behavior, although their mean diameters were not statistically different. The rupture pressures provided a measure of UCA fragility; the Philips UCAs were more resilient than Point UCAs. Results were compared to theoretical models of spherical shells under compression. Observed variations in rupture pressures are attributed to shell imperfections. These results may provide means to optimize polymeric UCAs for drug delivery and elucidate associated mechanisms.

Echogenic Glycol Chitosan Nanoparticles for Ultrasound-Triggered Cancer Theranostics

PubMed Central

Min, Hyun Su; You, Dong Gil; Son, Sejin; Jeon, Sangmin; Park, Jae Hyung; Lee, Seulki; Kwon, Ick Chan; Kim, Kwangmeyung

2015-01-01

Theranostic nanoparticles hold great promise for simultaneous diagnosis of diseases, targeted drug delivery with minimal toxicity, and monitoring of therapeutic efficacy. However, one of the current challenges in developing theranostic nanoparticles is enhancing the tumor-specific targeting of both imaging probes and anticancer agents. Herein, we report the development of tumor-homing echogenic glycol chitosan-based nanoparticles (Echo-CNPs) that concurrently execute cancer-targeted ultrasound (US) imaging and US-triggered drug delivery. To construct this novel Echo-CNPs, an anticancer drug and bioinert perfluoropentane (PFP), a US gas precursor, were simultaneously encapsulated into glycol chitosan nanoparticles using the oil in water (O/W) emulsion method. The resulting Echo-CNPs had a nano-sized particle structure, composing of hydrophobic anticancer drug/PFP inner cores and a hydrophilic glycol chitosan polymer outer shell. The Echo-CNPs had a favorable hydrodynamic size of 432 nm, which is entirely different from the micro-sized core-empty conventional microbubbles (1-10 μm). Furthermore, Echo-CNPs showed the prolonged echogenicity via the sustained microbubble formation process of liquid-phase PFP at the body temperature and they also presented a US-triggered drug release profile through the external US irradiation. Interestingly, Echo-CNPs exhibited significantly increased tumor-homing ability with lower non-specific uptake by other tissues in tumor-bearing mice through the nanoparticle's enhanced permeation and retention (EPR) effect. Conclusively, theranostic Echo-CNPs are highly useful for simultaneous cancer-targeting US imaging and US-triggered delivery in cancer theranostics. PMID:26681985

Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment.

PubMed

Liu, Hao-Li; Hua, Mu-Yi; Chen, Pin-Yuan; Chu, Po-Chun; Pan, Chia-Hsin; Yang, Hung-Wei; Huang, Chiung-Yin; Wang, Jiun-Jie; Yen, Tzu-Chen; Wei, Kuo-Chen

2010-05-01

To demonstrate the feasibility of using focused ultrasound to enhance delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to glioblastomas in rats with induced tumors and determine if such an approach increases treatment efficacy. All animal experiments were approved by the animal committee and adhered to the experimental animal care guidelines. A 400-kHz focused ultrasound generator was used to transcranially disrupt the blood-brain barrier (BBB) in rat brains by delivering burst-tone ultrasound energy in the presence of microbubbles. The process was monitored in vivo by using magnetic resonance (MR) imaging. Cultured C6 glioma cells implanted in Sprague-Dawley rats were used as the tumor model. BCNU (13.5 mg/kg) was administered intravenously and its concentration in brains was quantified by using high-performance liquid chromatography. MR imaging was used to evaluate the effect of treatments longitudinally, including analysis of tumor progression and animal survival, and brain tissues were histologically examined. Methods including the two-tailed unpaired t test and the Mantel-Cox test were used for statistical analyses, with a significance level of .05. Focused ultrasound significantly enhanced the penetration of BCNU through the BBB in normal (by 340%) and tumor-implanted (by 202%) brains without causing hemorrhaging. Treatment of tumor-implanted rats with focused ultrasound alone had no beneficial effect on tumor progression or on animal survival up to 60 days. Administration of BCNU only transiently controlled tumor progression; nevertheless, relative to untreated controls, animal survival was improved by treatment with BCNU alone (increase in median survival time [IST(median)], 15.7%, P = .023). Treatment with focused ultrasound before BCNU administration controlled tumor progression (day 31: 0.05 cm(3) + or - 0.1 [standard deviation] vs 0.28 cm(3) + or - 0.1) and improved animal survival relative to untreated controls (IST(median), 85.9%, P = .0015). This study demonstrates a means of increasing localized chemotherapeutic drug delivery for brain tumor treatment and strongly supports the feasibility of this treatment in a clinical setting.

Transsclera Drug Delivery by Pulsed High-Intensity Focused Ultrasound (HIFU): An Ex Vivo Study.

PubMed

Murugappan, Suresh Kanna; Zhou, Yufeng

2015-01-01

PURPOSE/AIM OF STUDY: Drug delivery to the ocular posterior segment is of importance, but it is a challenge in the treatment of irreversible blindness disease, such as age-related macular degeneration. Although some methods (i.e. intraocular injection, sustained release by polymer and iontophoresis) have been applied, some technical drawbacks, such as slow rate and damage to the eye, need to be overcome for wide use. In this study, the feasibility of high-intensity focused ultrasound (HIFU) to enhance the transsclera drug delivery was tested for the first time. One-hundred HIFU pulses with the driving frequency of 1.1 MHz, acoustic power of 105.6 W, pulse duration of 10-50 ms and pulse repetition frequency of 1 Hz were delivered to the fresh ex vivo porcine sclera specimen. In comparison to the passive diffusion (control), 50-ms HIFU can increase the penetration depth by 2.0 folds (501.7 ± 126.4 µm versus 252.4 ± 29.2 µm) using bicinchoninic acid assay and Rhodamine 6 G fluorescence intensity by 3.1 folds (22.4 ± 12.3 versus 7.1 ± 4.1) and coverage area by 2.6 folds (40.4 ± 9.1% versus 15.8 ± 2.9%). No morphological changes on the sonicated sclera samples were found using a surface electron microscope. In summary, pulsed-HIFU may be an effective modality in the transsclera drug delivery with a high transporting rate and depth. In vivo studies are necessary to further evaluate its performance, including the drug penetration and its possible side effects.

High-Intensity Focused Ultrasound Therapy: an Overview for Radiologists

PubMed Central

Kim, Young-sun; Choi, Min Joo; Lim, Hyo Keun; Choi, Dongil

2008-01-01

High-intensity focused ultrasound therapy is a novel, emerging, therapeutic modality that uses ultrasound waves, propagated through tissue media, as carriers of energy. This completely non-invasive technology has great potential for tumor ablation as well as hemostasis, thrombolysis and targeted drug/gene delivery. However, the application of this technology still has many drawbacks. It is expected that current obstacles to implementation will be resolved in the near future. In this review, we provide an overview of high-intensity focused ultrasound therapy from the basic physics to recent clinical studies with an interventional radiologist's perspective for the purpose of improving the general understanding of this cutting-edge technology as well as speculating on future developments. PMID:18682666

Acoustic Droplet Vaporization and Propulsion of Perfluorocarbon-Loaded Microbullets for Targeted Tissue Penetration and Deformation

PubMed Central

Kagan, Daniel; Benchimol, Michael J.; Claussen, Jonathan C.; Chuluun-Erdene, Erdembileg

2012-01-01

Acoustic droplet vaporization of perfluorocarbon-loaded microbullets triggered by an ultrasound pulse provides the necessary force to penetrate, cleave, and deform cellular tissue for potential targeted drug delivery and precision nanosurgery. PMID:22692791

Dynamics and fragmentation of thick-shelled microbubbles.

PubMed

May, Donovan J; Allen, John S; Ferrara, Katherine W

2002-10-01

Localized delivery could decrease the systemic side effects of toxic chemotherapy drugs. The unique delivery agents we examine consist of microbubbles with an outer lipid coating, an oil layer, and a perfluorobutane gas core. These structures are 0.5-12 microm in radius at rest. Oil layers of these acoustically active lipospheres (AALs) range from 0.3-1.5 microm in thickness and thus the agents can carry a large payload compared to nano-scale drug delivery systems. We show that triacetin-based drug-delivery vehicles can be fragmented using ultrasound. Compared with a lipid-shelled contrast agent, the expansion of the drug-delivery vehicle within the first cycle is similar, and a subharmonic component is demonstrated at an equivalent radius, frequency, and driving pressure. For the experimental conditions explored here, the pulse length required for destruction of the drug-delivery vehicle is significantly greater, with at least five cycles required, compared with one cycle for the contrast agent. For the drug-delivery vehicle, the observed destruction mechanism varies with the initial radius, with microbubbles smaller than resonance size undergoing a symmetric collapse and producing a set of small, equal-sized fragments. Between resonance size and twice resonance size, surface waves become visible, and the oscillations become asymmetrical. For agents larger than twice the resonance radius, the destruction mechanism changes to a pinch-off, with one fragment containing a large fraction of the original volume.

Comparison of high-resolution ultrasonic resonator technology and Raman spectroscopy as novel process analytical tools for drug quantification in self-emulsifying drug delivery systems.

PubMed

Stillhart, Cordula; Kuentz, Martin

2012-02-05

Self-emulsifying drug delivery systems (SEDDS) are complex mixtures in which drug quantification can become a challenging task. Thus, a general need exists for novel analytical methods and a particular interest lies in techniques with the potential for process monitoring. This article compares Raman spectroscopy with high-resolution ultrasonic resonator technology (URT) for drug quantification in SEDDS. The model drugs fenofibrate, indomethacin, and probucol were quantitatively assayed in different self-emulsifying formulations. We measured ultrasound velocity and attenuation in the bulk formulation containing drug at different concentrations. The formulations were also studied by Raman spectroscopy. We used both, an in-line immersion probe for the bulk formulation and a multi-fiber sensor for measuring through hard-gelatin capsules that were filled with SEDDS. Each method was assessed by calculating the relative standard error of prediction (RSEP) as well as the limit of quantification (LOQ) and the mean recovery. Raman spectroscopy led to excellent calibration models for the bulk formulation as well as the capsules. The RSEP depended on the SEDDS type with values of 1.5-3.8%, while LOQ was between 0.04 and 0.35% (w/w) for drug quantification in the bulk. Similarly, the analysis of the capsules led to RSEP of 1.9-6.5% and LOQ of 0.01-0.41% (w/w). On the other hand, ultrasound attenuation resulted in RSEP of 2.3-4.4% and LOQ of 0.1-0.6% (w/w). Moreover, ultrasound velocity provided an interesting analytical response in cases where the drug strongly affected the density or compressibility of the SEDDS. We conclude that ultrasonic resonator technology and Raman spectroscopy constitute suitable methods for drug quantification in SEDDS, which is promising for their use as process analytical technologies. Copyright © 2011 Elsevier B.V. All rights reserved.

Recent Advances in Nanoparticle-Mediated Delivery of Anti-Inflammatory Phytocompounds

PubMed Central

Conte, Raffaele; Marturano, Valentina; Peluso, Gianfranco; Calarco, Anna; Cerruti, Pierfrancesco

2017-01-01

Phytocompounds have been used in medicine for decades owing to their potential in anti-inflammatory applications. However, major difficulties in achieving sustained delivery of phyto-based drugs are related to their low solubility and cell penetration, and high instability. To overcome these disadvantages, nanosized delivery technologies are currently in use for sustained and enhanced delivery of phyto-derived bioactive compounds in the pharmaceutical sector. This review focuses on the recent advances in nanocarrier-mediated drug delivery of bioactive molecules of plant origin in the field of anti-inflammatory research. In particular, special attention is paid to the relationship between structure and properties of the nanocarrier and phytodrug release behavior. PMID:28350317

Intravascular forward-looking ultrasound transducers for microbubble-mediated sonothrombolysis.

PubMed

Kim, Jinwook; Lindsey, Brooks D; Chang, Wei-Yi; Dai, Xuming; Stavas, Joseph M; Dayton, Paul A; Jiang, Xiaoning

2017-06-14

Effective removal or dissolution of large blood clots remains a challenge in clinical treatment of acute thrombo-occlusive diseases. Here we report the development of an intravascular microbubble-mediated sonothrombolysis device for improving thrombolytic rate and thus minimizing the required dose of thrombolytic drugs. We hypothesize that a sub-megahertz, forward-looking ultrasound transducer with an integrated microbubble injection tube is more advantageous for efficient thrombolysis by enhancing cavitation-induced microstreaming than the conventional high-frequency, side-looking, catheter-mounted transducers. We developed custom miniaturized transducers and demonstrated that these transducers are able to generate sufficient pressure to induce cavitation of lipid-shelled microbubble contrast agents. Our technology demonstrates a thrombolysis rate of 0.7 ± 0.15 percent mass loss/min in vitro without any use of thrombolytic drugs.

Mechanism-Based Tumor-Targeting Drug Delivery System. Validation of Efficient Vitamin Receptor-Mediated Endocytosis and Drug Release

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, S.; Wong, S.; Zhao, X.

An efficient mechanism-based tumor-targeting drug delivery system, based on tumor-specific vitamin-receptor mediated endocytosis, has been developed. The tumor-targeting drug delivery system is a conjugate of a tumor-targeting molecule (biotin: vitamin H or vitamin B-7), a mechanism-based self-immolative linker and a second-generation taxoid (SB-T-1214) as the cytotoxic agent. This conjugate (1) is designed to be (i) specific to the vitamin receptors overexpressed on tumor cell surface and (ii) internalized efficiently through receptor-mediated endocytosis, followed by smooth drug release via glutathione-triggered self-immolation of the linker. In order to monitor and validate the sequence of events hypothesized, i.e., receptor-mediated endocytosis of the conjugate,more » drug release, and drug-binding to the target protein (microtubules), three fluorescent/fluorogenic molecular probes (2, 3, and 4) were designed and synthesized. The actual occurrence of these processes was unambiguously confirmed by means of confocal fluorescence microscopy (CFM) and flow cytometry using L1210FR leukemia cells, overexpressing biotin receptors. The molecular probe 4, bearing the taxoid linked to fluorescein, was also used to examine the cell specificity (i.e., efficacy of receptor-based cell targeting) for three cell lines, L1210FR (biotin receptors overexpressed), L1210 (biotin receptors not overexpressed), and WI38 (normal human lung fibroblast, biotin receptor negative). As anticipated, the molecular probe 4 exhibited high specificity only to L1210FR. To confirm the direct correlation between the cell-specific drug delivery and anticancer activity of the probe 4, its cytotoxicity against these three cell lines was also examined. The results clearly showed a good correlation between the two methods. In the same manner, excellent cell-specific cytotoxicity of the conjugate 1 (without fluorescein attachment to the taxoid) against the same three cell lines was confirmed. This mechanism-based tumor-targeting drug delivery system will find a range of applications.« less

Multifunctional PLGA Nanobubbles as Theranostic Agents: Combining Doxorubicin and P-gp siRNA Co-Delivery Into Human Breast Cancer Cells and Ultrasound Cellular Imaging.

PubMed

Yang, Hong; Deng, Liwei; Li, Tingting; Shen, Xue; Yan, Jie; Zuo, Liangming; Wu, Chunhui; Liu, Yiyao

2015-12-01

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. One of the effective approaches to overcome MDR is to use nanoparticle-mediated the gene silence of chemotherapeutic export proteins by RNA interference to increase drug accumulation in drug resistant cancer cells. In this work, a new co-delivery system, DOX-PLGA/PEI/P-gp shRNA nanobubbles (NBs) around 327 nm, to overcome doxorubicin (DOX) resistance in MCF-7 human breast cancer was designed and developed. Positively charged polyethylenimine (PEI) were modified onto the surface of DOX-PLGA NBs through DCC/NHS crosslinking, and could efficiently condense P-gp shRNA into DOX-PLGA/PEI NBs at vector/shRNA weight ratios of 70:1 and above. An in vitro release profile demonstrated an efficient DOX release (more than 80%) from DOX-PLGA/PEI NBs at pH 4.4, suggesting a pH-responsive drug release for the multifunctionalized NBs. Cellular experimental results further showed that DOX-PLGA/PEI/P-gp shRNA NBs could facilitate cellular uptake of DOX into cells and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The IC50 of DOX-PLGA NBs against MCF-7/ADR cells was 2-fold lower than that of free DOX. The increased cellular uptake and nuclear accumulation of DOX delivered by DOX-PLGA/PEI/P-gp shRNA NBs in MCF-7/ADR cells was confirmed by fluorescence microscopy and fluorescence spectrophotometry, and might be owning to the down-regulation of P-gp and reduced the efflux of DOX. The cellular uptake mechanism of DOX-PLGA/PEI/P-gp shRNA NBs indicated that the macropinocytosis was one of the pathways for the uptake of NBs by MCF-7/ADR cells, which was also an energy-dependent process. Furthermore, the in vitro cellular ultrasound imaging suggested that the employment of the DOX-PLGA/PEI/P-gp shRNA NBs could efficiently enhance ultrasound imaging of cancer cells. These results demonstrated that the developed DOX-PLGA/PEI/P-gp shRNA NBs is a potential, safe and efficient theranotic agent for cancer therapy and diagnostics.

Intravenous Delivery of pDNA and siRNA into Muscle with Bubble Liposomes and Ultrasound

NASA Astrophysics Data System (ADS)

Negishi, Yoichi; Sekine, Shohko; Endo, Yoko; Nishijima, Nobuaki; Suzuki, Ryo; Maruyama, Kazuo; Aramaki, Yukihiko

2010-03-01

Skeletal muscle is an attractive target tissue for numerous gene therapy strategies. Gene delivery into muscle has been extensively studied. Of the strategies, intravascular delivery of naked pDNA is desirable. Muscle has a high density of capillaries that are in close contact with myofibers. Previously, we developed polyethylene glycol (PEG)-modified liposomes entrapping echo-contrast gas, known as ultrasound (US) imaging gas. We called the liposomes "Bubble liposomes" (BLs). It has been reported that BLs improve the tissue permeability by cavitation on US exposure. Here, we modified the naked pDNA or siRNA transfer method into hind limb muscle through blood vessels using BLs and US. The intravenous delivery of pDNA into muscle can be markedly enhanced when the pDNA is delivered in combination with BLs and US. In addition, the expression of pDNA is high in the US-focused site. Moreover, efficient gene delivery can be achieved by the intravenous delivery of pDNA into muscle with BLs and US. Expression is also down-regulated by delivering siRNA with BLs and US. Thus, this US-mediated BL technique involving veins may be an effective method for gene therapy.

Acoustic accessibility investigation for ultrasound mediated treatment of glycogen storage disease type Ia patients.

PubMed

Wang, Shutao; Raju, Balasundar I; Leyvi, Evgeniy; Weinstein, David A; Seip, Ralf

2011-09-01

Glycogen storage disease type Ia (GSDIa) is caused by an inherited defect in the glucose-6-phosphatase gene. The recent advent of targeted ultrasound-mediated delivery (USMD) of plasmid DNA (pDNA) to the liver in conjunction with microbubbles may provide an alternative treatment option. This study focuses on determining the acoustically accessible liver volume in GSDIa patients using transducer models of various geometries with an image-based geometry-driven approach. Results show that transducers with longer focal lengths and smaller apertures (up to an f/number of 2) are able to access larger liver volumes in GSDIa patients while still being capable of delivering the required ultrasound dose in situ (2.5 MPa peak negative pressure at the focus). With sufficiently large acoustic windows and the ability to use glucose to easily assess efficacy, GSD appears to be a good model for testing USMD as proof of principle as a potential therapy for liver applications in general. Copyright © 2011 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Classification of stimuli-responsive polymers as anticancer drug delivery systems.

PubMed

Taghizadeh, Bita; Taranejoo, Shahrouz; Monemian, Seyed Ali; Salehi Moghaddam, Zoha; Daliri, Karim; Derakhshankhah, Hossein; Derakhshani, Zaynab

2015-02-01

Although several anticancer drugs have been introduced as chemotherapeutic agents, the effective treatment of cancer remains a challenge. Major limitations in the application of anticancer drugs include their nonspecificity, wide biodistribution, short half-life, low concentration in tumor tissue and systemic toxicity. Drug delivery to the tumor site has become feasible in recent years, and recent advances in the development of new drug delivery systems for controlled drug release in tumor tissues with reduced side effects show great promise. In this field, the use of biodegradable polymers as drug carriers has attracted the most attention. However, drug release is still difficult to control even when a polymeric drug carrier is used. The design of pharmaceutical polymers that respond to external stimuli (known as stimuli-responsive polymers) such as temperature, pH, electric or magnetic field, enzymes, ultrasound waves, etc. appears to be a successful approach. In these systems, drug release is triggered by different stimuli. The purpose of this review is to summarize different types of polymeric drug carriers and stimuli, in addition to the combination use of stimuli in order to achieve a better controlled drug release, and it discusses their potential strengths and applications. A survey of the recent literature on various stimuli-responsive drug delivery systems is also provided and perspectives on possible future developments in controlled drug release at tumor site have been discussed.

Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption.

PubMed

Kobus, Thiele; Zervantonakis, Ioannis K; Zhang, Yongzhi; McDannold, Nathan J

2016-09-28

HER2-targeting antibodies (i.e. trastuzumab and pertuzumab) prolong survival in HER2-positive breast cancer patients with extracranial metastases. However, the response of brain metastases to these drugs is poor, and it is hypothesized that the blood-brain barrier (BBB) limits drug delivery to the brain. We investigated whether we could improve the response by temporary disruption of the BBB using focused ultrasound in combination with microbubbles. To study this, we inoculated 30 nude rats with HER2-positive cells derived from a brain metastasis of a breast cancer patient (MDA-MB-361). The animals were divided into three groups: a control-group that received no treatment; an antibody-only group that received six weekly treatments of trastuzumab and pertuzumab; and an ultrasound+antibody group that received trastuzumab and pertuzumab in combination with six weekly sessions of BBB disruption using focused ultrasound. In two animals, the leakiness of the tumors before disruption was evaluated using contrast-enhanced T1-weighted magnetic resonance imaging and found that the tumors were not leaky. The same technique was used to evaluate the effectiveness of BBB disruption, which was successful in all sessions. The tumor in the control animals grew exponentially with a growth constant of 0.042±0.011mm(3)/day. None of the antibody-only animals responded to the treatment and the growth constant was 0.033±0.009mm(3)/day during the treatment period. Four of the ten animals in the ultrasound+antibody-group showed a response to the treatment with an average growth constant of 0.010±0.007mm(3)/day, compared to a growth constant 0.043±0.013mm(3)/day for the six non-responders. After the treatment period, the tumors in all groups grew at similar rates. As the tumors were not leaky before BBB disruption and there were no responders in the antibody-only group, these results show that at least in some cases disruption of the BBB is necessary for a response to the antibodies in these brain metastases. Interestingly, only some of the rats responded to the treatment. We did not observe a difference in tumor volume at the start of the treatment, nor in HER2 expression or in contrast-enhancement on MRI between the responders and non-responders to explain this. Better understanding of why certain animals respond is needed and will help in translating this technique to the clinic. In conclusion, we demonstrate that BBB disruption using focused ultrasound in combination with antibody therapy can inhibit growth of breast cancer brain metastasis. Copyright © 2016 Elsevier B.V. All rights reserved.

BBB disruption with unfocused ultrasound alone-A paradigm shift

NASA Astrophysics Data System (ADS)

Kyle, Al

2012-10-01

One paradigm for ultrasound-enabled blood brain barrier disruption uses image guided focused ultrasound and preformed microbubble agents to enable drug delivery to the brain. We propose an alternative approach: unguided, unfocused ultrasound with no adjunctive agent. Compared with the focused approach, the proposed method affects a larger region of the brain, and is aimed at treatment of regional neurological disease including glioblastoma multiforme (GBM). Avoidance of image guidance and focusing reduces cost for equipment and staff training. Avoidance of adjunctive agents also lowers cost and is enabled by a longer exposure time. Since 2004, our group has worked with two animal models, three investigators in four laboratories to safely deliver five compounds, increasing the concentration of large molecule markers in brain tissue two fold or more. Safety and effectiveness data for four studies have been presented at the Ultrasound Industry Association meetings in 2007 and 2010. This paper describes new safety and effectiveness results for a fifth study. We present evidence of delivery of large molecules - including Avastin-to the brains of a large animal model correlated with acoustic pressure, and summarize the advantages and disadvantages of this novel approach.

Intein-mediated site-specific synthesis of tumor-targeting protein delivery system: Turning PEG dilemma into prodrug-like feature

PubMed Central

Chen, Yingzhi; Zhang, Meng; Jin, Hongyue; Tang, Yisi; Wang, Huiyuan; Xu, Qin; Li, Yaping; Li, Feng; Huang, Yongzhuo

2017-01-01

Poor tumor-targeted and cytoplasmic delivery is a bottleneck for protein toxin-based cancer therapy. Ideally, a protein toxin drug should remain stealthy in circulation for prolonged half-life and reduced side toxicity, but turn activated at tumor. PEGylation is a solution to achieve the first goal, but creates a hurdle for the second because PEG rejects interaction between the drugs and tumor cells therein. Such PEG dilemma is an unsolved problem in protein delivery. Herein proposed is a concept of turning PEG dilemma into prodrug-like feature. A site-selectively PEGylated, gelatinase-triggered cell-penetrating trichosanthin protein delivery system is developed with three specific aims. The first is to develop an intein-based ligation method for achieving site-specific modification of protein toxins. The second is to develop a prodrug feature that renders protein toxins remaining stealthy in blood for reduced side toxicity and improved EPR effect. The third is to develop a gelatinase activatable cell-penetration strategy for enhanced tumor targeting and cytoplasmic delivery. Of note, site-specific modification is a big challenge in protein drug research, especially for such a complicated, multifunctional protein delivery system. We successfully develop a protocol for constructing a macromolecular prodrug system with intein-mediated ligation synthesis. With an on-column process of purification and intein-mediated cleavage, the site-specific PEGylation then can be readily achieved by conjugation with the activated C-terminus, thus constructing a PEG-capped, cell-penetrating trichosanthin system with a gelatinase-cleavable linker that enables tumor-specific activation of cytoplasmic delivery. It provides a promising method to address the PEG dilemma for enhanced protein drug delivery, and importantly, a facile protocol for site-specific modification of such a class of protein drugs for improving their druggability and industrial translation. PMID:27914267

Nanostructure-mediated drug delivery.

PubMed

Hughes, Gareth A

2005-03-01

Nanotechnology is expected to have an impact on all industries including semiconductors, manufacturing, and biotechnology. Tools that provide the capability to characterize and manipulate materials at the nanoscale level further elucidate nanoscale phenomena and equip researchers and developers with the ability to fabricate novel materials and structures. One of the most promising societal impacts of nanotechnology is in the area of nanomedicine. Personalized health care, rational drug design, and targeted drug delivery are some of the benefits of a nanomedicine-based approach to therapy. This review will focus on the development of nanoscale drug delivery mechanisms. Nanostructured drug carriers allow for the delivery of not only small-molecule drugs but also the delivery of nucleic acids and proteins. Delivery of these molecules to specific areas within the body can be achieved, which will reduce systemic side effects and allow for more efficient use of the drug.

Formulation and Characterization of Echogenic Lipid–Pluronic Nanobubbles

PubMed Central

Krupka, Tianyi M.; Solorio, Luis; Wilson, Robin E.; Wu, Hanping; Azar, Nami; Exner, Agata A.

2012-01-01

The advent of microbubble contrast agents has enhanced the capabilities of ultrasound as a medical imaging modality and stimulated innovative strategies for ultrasound-mediated drug and gene delivery. While the utilization of microbubbles as carrier vehicles has shown encouraging results in cancer therapy, their applicability has been limited by a large size which typically confines them to the vasculature. To enhance their multifunctional contrast and delivery capacity, it is critical to reduce bubble size to the nanometer range without reducing echogenicity. In this work, we present a novel strategy for formulation of nanosized, echogenic lipid bubbles by incorporating the surfactant Pluronic, a triblock copolymer of ethylene oxide copropylene oxide coethylene oxide into the formulation. Five Pluronics (L31, L61, L81, L64 and P85) with a range of molecular weights (Mw: 1100 to 4600 Da) were incorporated into the lipid shell either before or after lipid film hydration and before addition of perfluorocarbon gas. Results demonstrate that Pluronic–lipid interactions lead to a significantly reduced bubble size. Among the tested formulations, bubbles made with Pluronic L61 were the smallest with a mean hydrodynamic diameter of 207.9 ± 74.7 nm compared to the 880.9 ± 127.6 nm control bubbles. Pluronic L81 also significantly reduced bubble size to 406.8 ± 21.0 nm. We conclude that Pluronic is effective in lipid bubble size control, and Pluronic Mw, hydrophilic–lipophilic balance (HLB), and Pluronic/ lipid ratio are critical determinants of the bubble size. Most importantly, our results have shown that although the bubbles are nanosized, their stability and in vitro and in vivo echogenicity are not compromised. The resulting nanobubbles may be better suited for contrast enhanced tumor imaging and subsequent therapeutic delivery. PMID:19957968

Dendrimer advances for the central nervous system delivery of therapeutics.

PubMed

Xu, Leyuan; Zhang, Hao; Wu, Yue

2014-01-15

The effectiveness of noninvasive treatment for central nervous system (CNS) diseases is generally limited by the poor access of therapeutic agents into the CNS. Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier (BBB), and overcoming this has become one of the most significant challenges in the development of CNS therapeutics. Rapid advances in nanotechnology have provided promising solutions to this challenge. This review discusses the latest applications of dendrimers in the treatment of CNS diseases with an emphasis on brain tumors. Dendrimer-mediated drug delivery, imaging, and diagnosis are also reviewed. The toxicity, biodistribution, and transport mechanisms in dendrimer-mediated delivery of CNS therapeutic agents bypassing or crossing the BBB are also discussed. Future directions and major challenges of dendrimer-mediated delivery of CNS therapeutic agents are included.

Dendrimer Advances for the Central Nervous System Delivery of Therapeutics

PubMed Central

2013-01-01

The effectiveness of noninvasive treatment for central nervous system (CNS) diseases is generally limited by the poor access of therapeutic agents into the CNS. Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier (BBB), and overcoming this has become one of the most significant challenges in the development of CNS therapeutics. Rapid advances in nanotechnology have provided promising solutions to this challenge. This review discusses the latest applications of dendrimers in the treatment of CNS diseases with an emphasis on brain tumors. Dendrimer-mediated drug delivery, imaging, and diagnosis are also reviewed. The toxicity, biodistribution, and transport mechanisms in dendrimer-mediated delivery of CNS therapeutic agents bypassing or crossing the BBB are also discussed. Future directions and major challenges of dendrimer-mediated delivery of CNS therapeutic agents are included. PMID:24274162

Contrast agent-free sonoporation: The use of an ultrasonic standing wave microfluidic system for the delivery of pharmaceutical agents

PubMed Central

Carugo, Dario; Ankrett, Dyan N.; Glynne-Jones, Peter; Capretto, Lorenzo; Boltryk, Rosemary J.; Zhang, Xunli; Townsend, Paul A.; Hill, Martyn

2011-01-01

Sonoporation is a useful biophysical mechanism for facilitating the transmembrane delivery of therapeutic agents from the extracellular to the intracellular milieu. Conventionally, sonoporation is carried out in the presence of ultrasound contrast agents, which are known to greatly enhance transient poration of biological cell membranes. However, in vivo contrast agents have been observed to induce capillary rupture and haemorrhage due to endothelial cell damage and to greatly increase the potential for cell lysis in vitro. Here, we demonstrate sonoporation of cardiac myoblasts in the absence of contrast agent (CA-free sonoporation) using a low-cost ultrasound-microfluidic device. Within this device an ultrasonic standing wave was generated, allowing control over the position of the cells and the strength of the acoustic radiation forces. Real-time single-cell analysis and retrospective post-sonication analysis of insonated cardiac myoblasts showed that CA-free sonoporation induced transmembrane transfer of fluorescent probes (CMFDA and FITC-dextran) and that different mechanisms potentially contribute to membrane poration in the presence of an ultrasonic wave. Additionally, to the best of our knowledge, we have shown for the first time that sonoporation induces increased cell cytotoxicity as a consequence of CA-free ultrasound-facilitated uptake of pharmaceutical agents (doxorubicin, luteolin, and apigenin). The US-microfluidic device designed here provides an in vitro alternative to expensive and controversial in vivo models used for early stage drug discovery, and drug delivery programs and toxicity measurements. PMID:22662060

Energy Deposition in the Body from External Sources to Chemically Trigger Cellular Responses in Desired Localized Regions

NASA Astrophysics Data System (ADS)

Ibsen, Stuart Duncan

One of the major challenges of modern chemotherapy is to deliver a therapeutic dose of active drug to the tumor tissue without causing systemic exposure. The realization of this goal could considerably reduce the negative side effects experienced by patients. The work conducted in this thesis looks at two different approaches to trigger drug activation with the use of external energy sources. This avoids the challenges of relying solely on biochemical and environmental differences as triggers. The two triggers used were low intensity focused ultrasound and 365 nm light delivered with a custom designed needle UV LED fiber optic system. Both can be localized within the body to spatially highlight just the tumor tissue creating a stark differentiation between it and the healthy tissue. The 365nm light based delivery scheme developed here was the first demonstration of a photoactivatable doxorubicin (DOX) prodrug called DOX-PCB. DOX-PCB was shown to be 200 times less toxic than DOX and could be activated to a fully therapeutic form upon exposure to 365nm light. The pharmacokinetics showed a circulation half life comparable to that of DOX and stability against in vivo metabolic degradation. The 365 nm light was shown to adequately irradiate a centimeter of tumor tissue and cause localized activation. In vivo tumors exposed to the light had significantly higher doses of DOX than unexposed control tumors in the same individual. The second delivery scheme made use of focused ultrasound to activate echogenic drug delivery vehicles. These vehicles were the first demonstration of encapsulating microbubbles within liposomes. Specially designed optical equipment documented that the microbubble was ultrasound responsive. The microbubble was shown to violently cavitate and rupture the outer liposome membrane releasing the payload contents. The three dimensional localization of activation was demonstrated in tissue phantoms. The strengths of these two delivery schemes could complement each other when used together. The delivery vehicle could achieve high doses of DOX-PCB within the tumor while the low toxicity prevents harm to the liver and spleen. The 365 nm light could then activate just the DOX-PCB found within the tumor itself causing localized cell death.

Acoustic Droplet Vaporization in Biology and Medicine

PubMed Central

Pitt, William G.

2013-01-01

This paper reviews the literature regarding the use of acoustic droplet vaporization (ADV) in clinical applications of imaging, embolic therapy, and therapeutic delivery. ADV is a physical process in which the pressure waves of ultrasound induce a phase transition that causes superheated liquid nanodroplets to form gas bubbles. The bubbles provide ultrasonic imaging contrast and other functions. ADV of perfluoropentane was used extensively in imaging for preclinical trials in the 1990s, but its use declined rapidly with the advent of other imaging agents. In the last decade, ADV was proposed and explored for embolic occlusion therapy, drug delivery, aberration correction, and high intensity focused ultrasound (HIFU) sensitization. Vessel occlusion via ADV has been explored in rodents and dogs and may be approaching clinical use. ADV for drug delivery is still in preclinical stages with initial applications to treat tumors in mice. Other techniques are still in preclinical studies but have potential for clinical use in specialty applications. Overall, ADV has a bright future in clinical application because the small size of nanodroplets greatly reduces the rate of clearance compared to larger contrast agent bubbles and yet provides the advantages of ultrasonographic contrast, acoustic cavitation, and nontoxicity of conventional perfluorocarbon contrast agent bubbles. PMID:24350267

Microbubbles and Ultrasound: A Bird's Eye View.

PubMed Central

Kaul, Sanjiv

2004-01-01

Gas-filled microbubbles were initially used as ultrasound contrast agent because of their intravascular rheology, which is similar to that of red blood cells. Their transit through tissue can thus be quantified with ultrasound. More recently, these bubbles have been successfully used for molecular imaging by incorporating ligands on their surfaces that will adhere to cellular and other components within the microvasculature and can be detected by ultrasound. These bubbles have also been used for delivery of genes and drugs which can be released locally by disruption of the bubbles with high-energy ultrasound. Finally, bioeffects produced by localized ultrasound disruption of microbubbles have been shown to induce angiogenesis. This brief review will provide a bird's eye view of these applications. Images Fig. 1 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 PMID:17060963

Tumor Penetrating Theranostic Nanoparticles for Enhancement of Targeted and Image-guided Drug Delivery into Peritoneal Tumors following Intraperitoneal Delivery.

PubMed

Gao, Ning; Bozeman, Erica N; Qian, Weiping; Wang, Liya; Chen, Hongyu; Lipowska, Malgorzata; Staley, Charles A; Wang, Y Andrew; Mao, Hui; Yang, Lily

2017-01-01

The major obstacles in intraperitoneal (i.p.) chemotherapy of peritoneal tumors are fast absorption of drugs into the blood circulation, local and systemic toxicities, inadequate drug penetration into large tumors, and drug resistance. Targeted theranostic nanoparticles offer an opportunity to enhance the efficacy of i.p. therapy by increasing intratumoral drug delivery to overcome resistance, mediating image-guided drug delivery, and reducing systemic toxicity. Herein we report that i.p. delivery of urokinase plasminogen activator receptor (uPAR) targeted magnetic iron oxide nanoparticles (IONPs) led to intratumoral accumulation of 17% of total injected nanoparticles in an orthotopic mouse pancreatic cancer model, which was three-fold higher compared with intravenous delivery. Targeted delivery of near infrared dye labeled IONPs into orthotopic tumors could be detected by non-invasive optical and magnetic resonance imaging. Histological analysis revealed that a high level of uPAR targeted, PEGylated IONPs efficiently penetrated into both the peripheral and central tumor areas in the primary tumor as well as peritoneal metastatic tumor. Improved theranostic IONP delivery into the tumor center was not mediated by nonspecific macrophage uptake and was independent from tumor blood vessel locations. Importantly, i.p. delivery of uPAR targeted theranostic IONPs carrying chemotherapeutics, cisplatin or doxorubicin, significantly inhibited the growth of pancreatic tumors without apparent systemic toxicity. The levels of proliferating tumor cells and tumor vessels in tumors treated with the above theranostic IONPs were also markedly decreased. The detection of strong optical signals in residual tumors following i.p. therapy suggested the feasibility of image-guided surgery to remove drug-resistant tumors. Therefore, our results support the translational development of i.p. delivery of uPAR-targeted theranostic IONPs for image-guided treatment of peritoneal tumors.

Magnetic Luminescent Porous Silicon Microparticles for Localized Delivery of Molecular Drug Payloads

PubMed Central

Gu, Luo; Park, Ji-Ho; Duong, Kim H.; Ruoslahti, Erkki; Sailor, Michael J.

2011-01-01

Magnetic manipulation, fluorescent tracking, and localized delivery of a drug payload to cancer cells in vitro is demonstrated, using nanostructured porous silicon microparticles as a carrier. The multifunctional microparticles are prepared by electrochemical porosification of a silicon wafer in a hydrofluoric acid-containing electrolyte, followed by removal and fracture of the porous layer into particles using ultrasound. The intrinsically luminescent particles are loaded with superparamagnetic iron oxide nanoparticles and the anti-cancer drug doxorubicin. The drug-containing particles are delivered to human cervical cancer (HeLa) cells in vitro, under the guidance of a magnetic field. The high concentration of particles in the proximity of the magnetic field results in a high concentration of drug being released in that region of the Petri dish, and localized cell death is confirmed by cellular viability assay (Calcein AM). PMID:20814923

Magnetic luminescent porous silicon microparticles for localized delivery of molecular drug payloads.

PubMed

Gu, Luo; Park, Ji-Ho; Duong, Kim H; Ruoslahti, Erkki; Sailor, Michael J

2010-11-22

Magnetic manipulation, fluorescent tracking, and localized delivery of a drug payload to cancer cells in vitro is demonstrated, using nanostructured porous silicon microparticles as a carrier. The multifunctional microparticles are prepared by electrochemical porosification of a silicon wafer in a hydrofluoric acid-containing electrolyte, followed by removal and fracture of the porous layer into particles using ultrasound. The intrinsically luminescent particles are loaded with superparamagnetic iron oxide nanoparticles and the anti-cancer drug doxorubicin. The drug-containing particles are delivered to human cervical cancer (HeLa) cells in vitro, under the guidance of a magnetic field. The high concentration of particles in the proximity of the magnetic field results in a high concentration of drug being released in that region of the Petri dish, and localized cell death is confirmed by cellular viability assay (Calcein AM).

Role of the Na(+)/K(+)-ATPase beta-subunit in peptide-mediated transdermal drug delivery.

PubMed

Wang, Changli; Ruan, Renquan; Zhang, Li; Zhang, Yunjiao; Zhou, Wei; Lin, Jun; Ding, Weiping; Wen, Longping

2015-04-06

In this work, we discovered that the Na(+)/K(+)-ATPase beta-subunit (ATP1B1) on epidermal cells plays a key role in the peptide-mediated transdermal delivery of macromolecular drugs. First, using a yeast two-hybrid assay, we screened candidate proteins that have specific affinity for the short peptide TD1 (ACSSSPSKHCG) identified in our previous work. Then, we verified the specific binding of TD1 to ATP1B1 in yeast and mammalian cells by a pull-down ELISA and an immunoprecipitation assay. Finally, we confirmed that TD1 mainly interacted with the C-terminus of ATP1B1. Our results showed that the interaction between TD1 and ATP1B1 affected not only the expression and localization of ATP1B1, but also the epidermal structure. In addition, this interaction could be antagonized by the exogenous competitor ATP1B1 or be inhibited by ouabain, which results in the decreased delivery of macromolecular drugs across the skin. The discovery of a critical role of ATP1B1 in the peptide-mediated transdermal drug delivery is of great significance for the future development of new transdermal peptide enhancers.

Receptor-Mediated Drug Delivery to Macrophages in Chemotherapy of Leishmaniasis

NASA Astrophysics Data System (ADS)

Mukhopadhyay, Amitabha; Chaudhuri, Gautam; Arora, Sunil K.; Sehgal, Shobha; Basu, Sandip K.

1989-05-01

Methotrexate coupled to maleylated bovine serum albumin was taken up efficiently through the ``scavenger'' receptors present on macrophages and led to selective killing of intracellular Leishmania mexicana amazonensis amastigotes in cultured hamster peritoneal macrophages. The drug conjugate was nearly 100 times as effective as free methotrexate in eliminating the intracellular parasites. Furthermore, in a model of experimental cutaneous leishmaniasis in hamsters, the drug conjugate brought about more than 90% reduction in the size of footpad lesions within 11 days. In contrast, the free drug at a similar concentration did not significantly affect lesion size. These studies demonstrate the potential of receptor-mediated drug delivery in the therapy of macrophage-associated diseases.

Improved luciferase gene expression using ultrasound targeted microbubble destruction therapy in swine

NASA Astrophysics Data System (ADS)

Noble, Misty L.; Song, Shuxian; Sun, Ryan R.; Fan, Luping; DiBlasi, Robert M.; O'Kelly-Priddy, Colleen; Loeb, Keith R.; Miao, Carol H.

2012-11-01

Ultrasound (US) targeted microbubble (MB) destruction (UTMD) has been shown to be an effective method in delivering drugs and plasmid DNA (pDNA) into cells. We previously reported successful gene transfection of a reporter luciferase gene, pGL4, into livers of mice and rats using UTMD. The challenge is to translate and achieve similar gene expression in large animals, like swine, where the treated tissue volume is substantially larger. The scale-up study requires proportionally increased amount of pDNA/MBs delivered to tissues and an equivalent increase in US energy. We use different MBs and surgical strategies to retain most of pDNA/MB locally during US application in order to maximize the effect of UTMD in gene transfection. Our results show significant increase in luciferase expression in swine injected with MBs and exposed to 2.7 MPa US. We obtained up to 1800-fold enhancement in the pig experiment using Definity® MBs, and 2000-fold and 6300-fold enhancement in two pig studies using RN18 MBs compared to sham. These results represent an important developmental step towards US mediated gene delivery in large animals and clinical trials.

Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain.

PubMed

Patel, Mayur M; Patel, Bhoomika M

2017-02-01

CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood-brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting. Several approaches have been investigated to allow therapeutics to cross the BBB. As the molecular structure of the BBB is better elucidated, several key approaches for brain targeting include physiological transport mechanisms such as adsorptive-mediated transcytosis, inhibition of active efflux pumps, receptor-mediated transport, cell-mediated endocytosis, and the use of peptide vectors. Drug-delivery approaches comprise delivery from microspheres, biodegradable wafers, and colloidal drug-carrier systems (e.g., liposomes, nanoparticles, nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots). The current review discusses the latest advancements in these approaches, with a major focus on articles published in 2015 and 2016. In addition, we also cover the alternative delivery routes, such as intranasal and convection-enhanced diffusion methods, and disruption of the BBB for brain targeting.

Stimulus-responsive liposomes as smart nanoplatforms for drug delivery applications.

PubMed

Zangabad, Parham Sahandi; Mirkiani, Soroush; Shahsavari, Shayan; Masoudi, Behrad; Masroor, Maryam; Hamed, Hamid; Jafari, Zahra; Taghipour, Yasamin Davatgaran; Hashemi, Hura; Karimi, Mahdi; Hamblin, Michael R

2018-02-01

Liposomes are known to be promising nanoparticles (NPs) for drug delivery applications. Among different types of self-assembled NPs, liposomes stand out for their non-toxic nature, and their possession of dual hydrophilic-hydrophobic domains. Advantages of liposomes include the ability to solubilize hydrophobic drugs, the ability to incorporate different hydrophilic and lipophilic drugs at the same time, lessening the exposure of host organs to potentially toxic drugs and allowing modification of the surface by a variety of different chemical groups. This modification of the surface, or of the individual constituents, may be used to achieve two important goals. Firstly, ligands for active targeting can be attached that are recognized by cognate receptors over-expressed on the target cells of tissues. Secondly, modification can be used to impart a stimulus-responsive or "smart" character to the liposomes, whereby the cargo is released on demand only when certain internal stimuli (pH, reducing agents, specific enzymes) or external stimuli (light, magnetic field or ultrasound) are present. Here, we review the field of smart liposomes for drug delivery applications.

Nonspherical dynamics and shape mode stability of ultrasound contrast agent microbubbles

NASA Astrophysics Data System (ADS)

Calvisi, Michael

2016-11-01

Ultrasound contrast agents (UCAs) are shell encapsulated microbubbles developed originally for ultrasound imaging enhancement. UCAs are more recently being exploited for therapeutic applications, such as for drug delivery, gene therapy, and tissue ablation. Ultrasound transducer pulses can induce spherical (radial) UCA oscillations, translation, and nonspherical shape oscillations, the dynamics of which are highly coupled. If driven sufficiently strongly, the ultrasound can induce breakup of UCAs, which can facilitate drug or gene delivery but should be minimized for imaging purposes to increase residence time and maximize diagnostic effect. Therefore, an understanding of the interplay between the acoustic driving and nonspherical shape mode stability of UCAs is essential for both diagnostic and therapeutic applications. In this work, we use both analytical and numerical methods to analyze shape mode stability for cases of small and large nonspherical oscillations, respectively. To analyze shape mode stability in the limit of small nonspherical perturbations, we couple a radial model of a lipid-coated microbubble with a model for bubble translation and nonspherical shape oscillation. This hybrid model is used to predict shape mode stability for ultrasound driving frequencies and pressure amplitudes of clinical interest. In addition, calculations of the stability of individual shape modes, residence time, maximum radius, and translation are provided with respect to acoustic driving parameters and compared to an unshelled bubble. The effects of shell elasticity, shell viscosity, and initial radius on stability are investigated. Furthermore, the well-established boundary element method (BEM) is used to investigate the dynamics and shape stability of large amplitude nonspherical oscillations of an ultrasonically-forced, polymer-coated microbubble near a rigid boundary. Different instability modes are identified based on the degree of jetting and proximity to the boundary. This insight is used to develop diagrams that delineate regions of stability from instability based on the breakup mechanism, in parameter ranges of ultrasound frequency and amplitude relevant to medical applications.

Tracking delivery of a drug surrogate in the porcine heart using photoacoustic imaging and spectroscopy

NASA Astrophysics Data System (ADS)

Furdella, Kenneth J.; Witte, Russell S.; Vande Geest, Jonathan P.

2017-04-01

Although the drug-eluting stent (DES) has dramatically reduced the rate of coronary restenosis, it still occurs in up to 20% of patients with a DES. Monitoring drug delivery could be one way to decrease restenosis rates. We demonstrate real-time photoacoustic imaging and spectroscopy (PAIS) using a wavelength-tunable visible laser and clinical ultrasound scanner to track cardiac drug delivery. The photoacoustic signal was initially calibrated using porcine myocardial samples soaked with a known concentration of a drug surrogate (DiI). Next, an in situ coronary artery was perfused with DiI for 20 min and imaged to monitor dye transport in the tissue. Finally, a partially DiI-coated stent was inserted into the porcine brachiocephalic trunk for imaging. The photoacoustic signal was proportional to the DiI concentration between 2.4 and 120 μg/ml, and the dye was detected over 1.5 mm from the targeted coronary vessel. Photoacoustic imaging was also able to differentiate the DiI-coated portion of the stent from the uncoated region. These results suggest that PAIS can track drug delivery to cardiac tissue and detect drugs loaded onto a stent with sub-mm precision. Future work using PAIS may help improve DES design and reduce the probability of restenosis.

Intravascular ultrasound catheter to enhance microbubble-based drug delivery via acoustic radiation force.

PubMed

Kilroy, Joseph P; Klibanov, Alexander L; Wamhoff, Brian R; Hossack, John A

2012-10-01

Previous research has demonstrated that acoustic radiation force enhances intravascular microbubble adhesion to blood vessels in the presence of flow for moleculartargeted ultrasound imaging and drug delivery. A prototype acoustic radiation force intravascular ultrasound (ARFIVUS) catheter was designed and fabricated to displace a microbubble contrast agent in flow representative of conditions encountered in the human carotid artery. The prototype ARFIVUS transducer was designed to match the resonance frequency of 1.4- to 2.6-μm-diameter microbubbles modeled by an experimentally verified 1-D microbubble acoustic radiation force translation model. The transducer element was an elongated Navy Type I (hard) lead zirconate titanate (PZT) ceramic designed to operate at 3 MHz. Fabricated devices operated with center frequencies of 3.3 and 3.6 MHz with -6-dB fractional bandwidths of 55% and 50%, respectively. Microbubble translation velocities as high as 0.86 m/s were measured using a high-speed streak camera when insonating with the ARFIVUS transducer. Finally, the prototype was used to displace microbubbles in a flow phantom while imaging with a commercial 45-MHz imaging IVUS transducer. A sustained increase of 31 dB in average video intensity was measured following insonation with the ARFIVUS, indicating microbubble accumulation resulting from the application of acoustic radiation force.

Modeling and Characterization of Encapsulated Microbubbles for Ultrasound Imaging and Drug Delivery

NASA Astrophysics Data System (ADS)

Sarkar, Kausik; Jain, Pankaj; Chatterjee, Dhiman

2008-07-01

Intravenously injected encapsulated microbubbles improve the contrast of an ultrasound image. Their destruction is used in measuring blood flow, stimulating arteriogenesis, and drug delivery. We measure attenuation and scattering of ultrasound through solution of commercial contrast agents such as Optison (GE Health Care, Princeton, NJ) and Definity (Bristol Meyer-Squibb Imaging, North Ballerina, MA). We have developed an interfacial rheology model for the encapsulation of such microbubbles. By matching with experimental data, we obtain the characteristic rheological parameters. We compare model predictions with other experiments. We also investigate microbubble destruction under acoustic excitation by measuring time-varying attenuation data. Three regions of acoustic pressure amplitudes are found: at low pressure, there is no destruction; at slightly higher pressure bubbles are destroyed, and the rate of destruction depends on a combination of PRF and amplitude. At a still higher pressure amplitude, the attenuation decreases catastrophically. The last two regimes correspond respectively to 1) slow destruction of bubbles due to increased gas diffusion and 2) complete bubble destruction leading to release of free bubbles. An analytical model for the bubble growth and dissolution will be presented. The effects of membrane permeability and elasticity on the stability of microbubbles are investigated. (Supported by DOD, NSF and NIH).

Spatio-temporal control of gene expression and cancer treatment using magnetic resonance imaging-guided focused ultrasound.

PubMed

Moonen, Chrit T W

2007-06-15

Local temperature elevation may be used for tumor ablation, gene expression, drug activation, and gene and/or drug delivery. High-intensity focused ultrasound (HIFU) is the only clinically viable technology that can be used to achieve a local temperature increase deep inside the human body in a noninvasive way. Magnetic resonance imaging (MRI) guidance of the procedure allows in situ target definition and identification of nearby healthy tissue to be spared. In addition, MRI can be used to provide continuous temperature mapping during HIFU for spatial and temporal control of the heating procedure and prediction of the final lesion based on the received thermal dose. The primary purpose of the development of MRI-guided HIFU was to achieve safe noninvasive tissue ablation. The technique has been tested extensively in preclinical studies and is now accepted in the clinic for ablation of uterine fibroids. MRI-guided HIFU for ablation shows conceptual similarities with radiation therapy. However, thermal damage generally shows threshold-like behavior, with necrosis above the critical thermal dose and full recovery below. MRI-guided HIFU is being clinically evaluated in the cancer field. The technology also shows great promise for a variety of advanced therapeutic methods, such as gene therapy. MR-guided HIFU, together with the use of a temperature-sensitive promoter, provides local, physical, and spatio-temporal control of transgene expression. Specially designed contrast agents, together with the combined use of MRI and ultrasound, may be used for local gene and drug delivery.

Photo-mediated ultrasound therapy (PUT): a novel method of selectively treating neovascularization (Conference Presentation)

NASA Astrophysics Data System (ADS)

Zhang, Haonan; Hu, Zi Zhong; Li, Jia; Mordovanakis, Aghapi G.; Yang, Xinmai; Paulus, Yannis M.; Wang, Xueding

2017-02-01

Retinal and choroidal neovascularization play a pivotal role in the leading causes of blindness including macular degeneration and diabetic retinopathy (DR). Current therapy by focal laser photocoagulation can damage the normal surrounding cells, such as the photoreceptor inner and outer segments which are adjacent to the retinal pigment epithelium (RPE), due to the use of high laser energy and millisecond pulse duration. Therapies with pharmaceutical agents involve systemic administration of drugs, which can cause adverse effects and patients may become drug-resistant. We have developed a noninvasive photo-mediated ultrasound therapy (PUT) technique as a localized antivascular method, and applied it to remove micro blood vessels in the retina. PUT takes advantage of the high native optical contrast among biological tissues, and has the unique capability to self-target microvessels without causing unwanted damages to the surrounding tissues. This technique promotes cavitation activity in blood vessels by synergistically applying nanosecond laser pulses and ultrasound bursts. Through the interaction between cavitation and blood vessel wall, blood clots in microvessels and vasoconstriction can be induced. As a result, microvessels can be occluded. In comparison with other techniques that involves cavitation, both laser and ultrasound energy needed in PUT is significantly lower, and hence improves the safety in therapy.

Labour analgesia: Recent advances

PubMed Central

Pandya, Sunil T

2010-01-01

Advances in the field of labour analgesia have tread a long journey from the days of ether and chloroform in 1847 to the present day practice of comprehensive programme of labour pain management using evidence-based medicine. Newer advances include introduction of newer techniques like combined spinal epidurals, low-dose epidurals facilitating ambulation, pharmacological advances like introduction of remifentanil for patient-controlled intravenous analgesia, introduction of newer local anaesthetics and adjuvants like ropivacaine, levobupivacaine, sufentanil, clonidine and neostigmine, use of inhalational agents like sevoflourane for patient-controlled inhalational analgesia using special vaporizers, all have revolutionized the practice of pain management in labouring parturients. Technological advances like use of ultrasound to localize epidural space in difficult cases minimizes failed epidurals and introduction of novel drug delivery modalities like patient-controlled epidural analgesia (PCEA) pumps and computer-integrated drug delivery pumps have improved the overall maternal satisfaction rate and have enabled us to customize a suitable analgesic regimen for each parturient. Recent randomized controlled trials and Cochrane studies have concluded that the association of epidurals with increased caesarean section and long-term backache remains only a myth. Studies have also shown that the newer, low-dose regimes do not have a statistically significant impact on the duration of labour and breast feeding and also that these reduce the instrumental delivery rates thus improving maternal and foetal safety. Advances in medical technology like use of ultrasound for localizing epidural space have helped the clinicians to minimize the failure rates, and many novel drug delivery modalities like PCEA and computer-integrated PCEA have contributed to the overall maternal satisfaction and safety. PMID:21189877

Public-private partnerships in translational medicine: concepts and practical examples.

PubMed

Luijten, Peter R; van Dongen, Guus A M S; Moonen, Chrit T; Storm, Gert; Crommelin, Daan J A

2012-07-20

The way forward in multidisciplinary research according to former NIH's director Elias Zerhouni is to engage in predictive, personalized, preemptive and participatory medicine. For the creation of the optimal innovation climate that would allow for such a strategy, public-private partnerships have been widely proposed as an important instrument. Public-private partnerships have become an important instrument to expedite translational research in medicine. The Netherlands have initiated three large public-private partnerships in the life sciences and health area to facilitate the translation of valuable basic scientific concepts to new products and services in medicine. The focus of these partnerships has been on drug development, improved diagnosis and regenerative medicine. The Dutch model of public-private partnership forms the blueprint of a much larger European initiative called EATRIS. This paper will provide practical examples of public-private partnerships initiated to expedite the translation of new technology for drug development towards the clinic. Three specific technologies are in focus: companion diagnostics using nuclear medicine, the use of ultra high field MRI to generate sensitive surrogate endpoints based on endogenous contrast, and MRI guidance for High Intensity Focused Ultrasound mediated drug delivery. Copyright © 2012 Elsevier B.V. All rights reserved.

Acoustically accessible window determination for ultrasound mediated treatment of glycogen storage disease type Ia patients

NASA Astrophysics Data System (ADS)

Wang, Shutao; Raju, Balasundar I.; Leyvi, Evgeniy; Weinstein, David A.; Seip, Ralf

2012-10-01

Glycogen storage disease type Ia (GSDIa) is caused by an inherited single-gene defect resulting in an impaired glycogen to glucose conversion pathway. Targeted ultrasound mediated delivery (USMD) of plasmid DNA (pDNA) to liver in conjunction with microbubbles may provide a potential treatment for GSDIa patients. As the success of USMD treatments is largely dependent on the accessibility of the targeted tissue by the focused ultrasound beam, this study presents a quantitative approach to determine the acoustically accessible liver volume in GSDIa patients. Models of focused ultrasound beam profiles for transducers of varying aperture and focal lengths were applied to abdomen models reconstructed from suitable CT and MRI images. Transducer manipulations (simulating USMD treatment procedures) were implemented via transducer translations and rotations with the intent of targeting and exposing the entire liver to ultrasound. Results indicate that acoustically accessible liver volumes can be as large as 50% of the entire liver volume for GSDIa patients and on average 3 times larger compared to a healthy adult group due to GSDIa patients' increased liver size. Detailed descriptions of the evaluation algorithm, transducer-and abdomen models are presented, together with implications for USMD treatments of GSDIa patients and transducer designs for USMD applications.

Therapeutic efficacy of the combination of doxorubicin-loaded liposomes with inertial cavitation generated by confocal ultrasound in AT2 Dunning rat tumour model.

PubMed

Mestas, Jean-Louis; Fowler, R Andrew; Evjen, Tove J; Somaglino, Lucie; Moussatov, Alexei; Ngo, Jacqueline; Chesnais, Sabrina; Røgnvaldsson, Sibylla; Fossheim, Sigrid L; Nilssen, Esben A; Lafon, Cyril

2014-09-01

The combination of liposomal doxorubicin (DXR) and confocal ultrasound (US) was investigated for the enhancement of drug delivery in a rat tumour model. The liposomes, based on the unsaturated phospholipid dierucoylphosphocholine, were designed to be stable during blood circulation in order to maximize accumulation in tumour tissue and to release drug content upon US stimulation. A confocal US setup was developed for delivering inertial cavitation to tumours in a well-controlled and reproducible manner. In vitro studies confirm drug release from liposomes as a function of inertial cavitation dose, while in vivo pharmacokinetic studies show long blood circulation times and peak tumour accumulation at 24-48 h post intravenous administration. Animals injected 6 mg kg(-1) liposomal DXR exposed to US treatment 48 h after administration show significant tumour growth delay compared to control groups. A liposomal DXR dose of 3 mg kg(-1), however, did not induce any significant therapeutic response. This study demonstrates that inertial cavitation can be generated in such a fashion as to disrupt drug carrying liposomes which have accumulated in the tumour, and thereby increase therapeutic effect with a minimum direct effect on the tissue. Such an approach is an important step towards a therapeutic application of cavitation-induced drug delivery and reduced chemotherapy toxicity.

Laser-ultrasonic technologies for medicine

NASA Astrophysics Data System (ADS)

Zharov, Vladimir P.; Latyshev, Alexei S.

1999-06-01

This review tackles the problem of further developing laser- ultrasonic medical technologies and gives the comparison of different laser and ultrasound combinations. The features of combined influence on biotissue are explicated with due regard for mechanic, ultrasonic (US), and thermal effects. The review present the effect of self-cleaning an optical fiber tip from the laser destruction products of biotissue, the result of research on the possibility of laser-US technology applications in endoscopy, and the ways of suppressing unwanted bending oscillations. Various spheres and peculiarities of applying laser-US technologies are discussed, including microsurgery, cosmetology, transcutaneous drug delivery, and the treatment of chronic prostatitis and infected wounds. Furthermore, the analysis of transcutaneous drug delivery methods employing a portable pulsed Er:YAG laser is presented. Drug diffusion has been shown to be enhanced under acoustic and US effects. The photo-vacuum drug injection mechanism recently suggested is discussed. It turned out that laser-US technology can be suitable for both impregnating the photosensitizer in local photodynamic therapy procedures and conducting microsurgery operations involving drug injection. Treatment of infectious processes based on the bactericidal action of photosensitizers and ultrasound due to the cavitation effect in solutions is described. An additional therapeutic effect can be achieved via the US intermingling of solutions with their simulations illumination by a matrix of red lasers or light diodes. An outlook on further developing laser-US technology and the ways of its apparatus realization are considered.

Enhancing the transdermal delivery of rigid nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate

PubMed Central

Lopez, Renata F.V.; Seto, Jennifer E.; Blankschtein, Daniel; Langer, Robert

2010-01-01

The potential of rigid nanoparticles to serve as transdermal drug carriers can be greatly enhanced by improving their skin penetration. Therefore, the simultaneous application of ultrasound and sodium lauryl sulfate (referred to as US/SLS) was evaluated as a skin pre-treatment method for enhancing the passive transdermal delivery of nanoparticles. We utilized inductively-coupled plasma mass spectrometry and an improved application of confocal microscopy to compare the delivery of 10- and 20-nm cationic, neutral, and anionic quantum dots (QDs) into US/SLS-treated and untreated pig split-thickness skin. Our findings include: (a) ~0.01% of the QDs penetrate the dermis of untreated skin (which we quantify for the first time), (b) the QDs fully permeate US/SLS-treated skin, (c) the two cationic QDs studied exhibit different extents of skin penetration and dermal clearance, and (d) the QD skin penetration is heterogeneous. We discuss routes of nanoparticle skin penetration and the application of the methods described herein to address conflicting literature reports on nanoparticle skin penetration. We conclude that US/SLS treatment significantly enhances QD transdermal penetration by 500–1300%. Our findings suggest that an optimum surface charge exists for nanoparticle skin penetration, and motivate the application of nanoparticle carriers to US/SLS-treated skin for enhanced transdermal drug delivery. PMID:20971504

Enhancing the transdermal delivery of rigid nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate.

PubMed

Lopez, Renata F V; Seto, Jennifer E; Blankschtein, Daniel; Langer, Robert

2011-01-01

The potential of rigid nanoparticles to serve as transdermal drug carriers can be greatly enhanced by improving their skin penetration. Therefore, the simultaneous application of ultrasound and sodium lauryl sulfate (referred to as US/SLS) was evaluated as a skin pre-treatment method for enhancing the passive transdermal delivery of nanoparticles. We utilized inductively coupled plasma mass spectrometry and an improved application of confocal microscopy to compare the delivery of 10- and 20-nm cationic, neutral, and anionic quantum dots (QDs) into US/SLS-treated and untreated pig split-thickness skin. Our findings include: (a) ∼0.01% of the QDs penetrate the dermis of untreated skin (which we quantify for the first time), (b) the QDs fully permeate US/SLS-treated skin, (c) the two cationic QDs studied exhibit different extents of skin penetration and dermal clearance, and (d) the QD skin penetration is heterogeneous. We discuss routes of nanoparticle skin penetration and the application of the methods described herein to address conflicting literature reports on nanoparticle skin penetration. We conclude that US/SLS treatment significantly enhances QD transdermal penetration by 500-1300%. Our findings suggest that an optimum surface charge exists for nanoparticle skin penetration, and motivate the application of nanoparticle carriers to US/SLS-treated skin for enhanced transdermal drug delivery. Copyright © 2010 Elsevier Ltd. All rights reserved.

Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

PubMed

Abdullahi, Wazir; Davis, Thomas P; Ronaldson, Patrick T

2017-07-01

Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.

Comparative study of the Ar and He atmospheric pressure plasmas on E-cadherin protein regulation for plasma-mediated transdermal drug delivery

NASA Astrophysics Data System (ADS)

Lee, Hyun Young; Hae Choi, Jeong; Hong, Jin Woo; Kim, Gyoo Cheon; Lee, Hae June

2018-05-01

The effects of argon plasma (ArP) and helium plasma (HeP) jets on E-cadherin protein function have been tested in order to choose the working gas for a better plasma-mediated transdermal drug delivery. The plasma-mediated changes of the E-cadherin function and the skin penetration efficacies of epidermal growth factor (EGF) were monitored in vitro using HaCaT human keratinocytes and in vivo using hairless mice. The ArP showed higher efficacy for E-cadherin regulation and EGF absorption than HeP under the same applied voltage and the same gas flow rate. The ArP generates higher volume power density, higher discharge current peak, and more reactive species than HeP, especially for OH with the same operating parameters. Moreover, the effect of ArP on E-cadherin function was blocked by the use of a grounded metal mesh. Taken together, this study presents the possibility that the synergetic effect of negative charges with radicals plays an important role in plasma-mediated E-cadherin regulation, which leads to enhanced transdermal drug delivery.

Peptide and protein delivery using new drug delivery systems.

PubMed

Jain, Ashish; Jain, Aviral; Gulbake, Arvind; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K

2013-01-01

Pharmaceutical and biotechnological research sorts protein drug delivery systems by importance based on their various therapeutic applications. The effective and potent action of the proteins/peptides makes them the drugs of choice for the treatment of numerous diseases. Major research issues in protein delivery include the stabilization of proteins in delivery devices and the design of appropriate target-specific protein carriers. Many efforts have been made for effective delivery of proteins/peptidal drugs through various routes of administrations for successful therapeutic effects. Nanoparticles made of biodegradable polymers such as poly lactic acid, polycaprolactone, poly(lactic-co-glycolic acid), the poly(fumaric-co-sebacic) anhydride chitosan, and modified chitosan, as well as solid lipids, have shown great potential in the delivery of proteins/peptidal drugs. Moreover, scientists also have used liposomes, PEGylated liposomes, niosomes, and aquasomes, among others, for peptidal drug delivery. They also have developed hydrogels and transdermal drug delivery systems for peptidal drug delivery. A receptor-mediated delivery system is another attractive strategy to overcome the limitation in drug absorption that enables the transcytosis of the protein across the epithelial barrier. Modification such as PEGnology is applied to various proteins and peptides of the desired protein and peptides also increases the circulating life, solubility and stability, pharmacokinetic properties, and antigenicity of protein. This review focuses on various approaches for effective protein/peptidal drug delivery, with special emphasis on insulin delivery.

Drug transport across the blood–brain barrier

PubMed Central

Pardridge, William M

2012-01-01

The blood–brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. This property arises from the epithelial-like tight junctions within the brain capillary endothelium. The BBB is anatomically and functionally distinct from the blood–cerebrospinal fluid barrier at the choroid plexus. Certain small molecule drugs may cross the BBB via lipid-mediated free diffusion, providing the drug has a molecular weight <400 Da and forms <8 hydrogen bonds. These chemical properties are lacking in the majority of small molecule drugs, and all large molecule drugs. Nevertheless, drugs can be reengineered for BBB transport, based on the knowledge of the endogenous transport systems within the BBB. Small molecule drugs can be synthesized that access carrier-mediated transport (CMT) systems within the BBB. Large molecule drugs can be reengineered with molecular Trojan horse delivery systems to access receptor-mediated transport (RMT) systems within the BBB. Peptide and antisense radiopharmaceuticals are made brain-penetrating with the combined use of RMT-based delivery systems and avidin–biotin technology. Knowledge on the endogenous CMT and RMT systems expressed at the BBB enable new solutions to the problem of BBB drug transport. PMID:22929442

Environmentally Responsive Systems for Drug Delivery.

PubMed

Bruschi, Marcos L; Borghi-Pangoni, Fernanda B; Junqueira, Mariana V; de Souza Ferreira, Sabrina B; da Silva, Jessica B

2017-01-01

In recent decades, the development of the environmentally responsive systems for drug delivery has been well regarded, with enormous potential in different applications. <P><P> Methods: These environmentally sensitive, smart, intelligent formulations have the ability to alter their physical properties in response to small changes in physical or chemical conditions, such as temperature, glucose, pH, ultrasound, light, electric field and redox potential with a huge potential in drug delivery systems. The use of formulations containing smart materials enables to carry the drug to the target tissue, cells and release in a triggered way. Consequently, they have demonstrated several advantages like decreased dose frequency, ease of preparation and administration, prolonged release with reduced side effects, as well as, reduced costs when compared to conventional processes for industrial applications. In this sense, many patents have deposited, displaying different pharmaceutical devices using responsive systems. <P><P> Results: There are more than twenty-five patents deposited about thermoresponsive systems. Furthermore, a few number of patents within glucose responsive, ultrasound responsive and light responsive deposited. There also are about eight patents that are pH-responsive, four as electric-field responsive. Most of them cover more than one type of stimuli. <P><P> Conclusion: Therefore, in this review, since 1975 to 2016, we have categorized, reviewed and discussed the patents, applications, pharmaceutical dosage forms, the importance and perspectives of this environmentally responsive approach as potentially useful therapeutic modality. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Driving Circuitry for Focused Ultrasound Noninvasive Surgery and Drug Delivery Applications

PubMed Central

El-Desouki, Munir M.; Hynynen, Kullervo

2011-01-01

Recent works on focused ultrasound (FUS) have shown great promise for cancer therapy. Researchers are continuously trying to improve system performance, which is resulting in an increased complexity that is more apparent when using multi-element phased array systems. This has led to significant efforts to reduce system size and cost by relying on system integration. Although ideas from other fields such as microwave antenna phased arrays can be adopted in FUS, the application requirements differ significantly since the frequency range used in FUS is much lower. In this paper, we review recent efforts to design efficient power monitoring, phase shifting and output driving techniques used specifically for high intensity focused ultrasound (HIFU). PMID:22346589

Driving circuitry for focused ultrasound noninvasive surgery and drug delivery applications.

PubMed

El-Desouki, Munir M; Hynynen, Kullervo

2011-01-01

Recent works on focused ultrasound (FUS) have shown great promise for cancer therapy. Researchers are continuously trying to improve system performance, which is resulting in an increased complexity that is more apparent when using multi-element phased array systems. This has led to significant efforts to reduce system size and cost by relying on system integration. Although ideas from other fields such as microwave antenna phased arrays can be adopted in FUS, the application requirements differ significantly since the frequency range used in FUS is much lower. In this paper, we review recent efforts to design efficient power monitoring, phase shifting and output driving techniques used specifically for high intensity focused ultrasound (HIFU).

Modified titanium implant as a gateway to the human body: the implant mediated drug delivery system.

PubMed

Park, Young-Seok; Cho, Joo-Youn; Lee, Shin-Jae; Hwang, Chee Il

2014-01-01

The aim of this study was to investigate the efficacy of a proposed new implant mediated drug delivery system (IMDDS) in rabbits. The drug delivery system is applied through a modified titanium implant that is configured to be implanted into bone. The implant is hollow and has multiple microholes that can continuously deliver therapeutic agents into the systematic body. To examine the efficacy and feasibility of the IMDDS, we investigated the pharmacokinetic behavior of dexamethasone in plasma after a single dose was delivered via the modified implant placed in the rabbit tibia. After measuring the plasma concentration, the areas under the curve showed that the IMDDS provided a sustained release for a relatively long period. The result suggests that the IMDDS can deliver a sustained release of certain drug components with a high bioavailability. Accordingly, the IMDDS may provide the basis for a novel approach to treating patients with chronic diseases.

Anti-transferrin receptor-modified amphotericin B-loaded PLA-PEG nanoparticles cure Candidal meningitis and reduce drug toxicity.

PubMed

Tang, Xiaolong; Liang, Yong; Zhu, Yongqiang; Xie, Chunmei; Yao, Aixia; Chen, Li; Jiang, Qinglin; Liu, Tingting; Wang, Xiaoyu; Qian, Yunyun; Wei, Jia; Ni, Wenxuan; Dai, Jingjing; Jiang, Zhenyou; Hou, Wei

2015-01-01

Fatal fungal infections in central nervous system (CNS) can occur through hematogenous spread or direct extension. At present, hydrophobic amphotericin B (AMB) is the most effective antifungal drug in clinical trials. However, AMB is hydrophobic and therefore penetrates poorly into the CNS, and therapeutic levels of AMB are hard to achieve. The transferrin receptor (TfR/CD71) located at the blood-brain barrier mediates transferrin transcytosis. In order to enhance the receptor-mediated delivery of AMB into CNS with therapeutic level, an anti-TfR antibody (OX26)-modified AMB-loaded PLA (poly[lactic acid])-PEG (polyethylene glycol)-based micellar drug delivery system was constructed. The prepared OX26-modified AMB-loaded nanoparticles (OX26-AMB-NPs) showed significant reduction of CNS fungal burden and an increase of mouse survival time. In conclusion, OX26-AMB-NPs represent a promising novel drug delivery system for intracerebral fungal infection.

Ultrasound: medical imaging and beyond (an invited review).

PubMed

Azhari, Haim

2012-09-01

Medical applications of ultrasound were first investigated about seventy years ago. It has rapidly evolved since then, becoming an essential tool in medical imaging. Ultrasound ability to provide real time images with frame rates exceeding several hundred frames per second allows one to view rapid anatomical changes as well as to guide minimal invasive procedures. By, combining Doppler techniques with anatomical images ultrasound provides real time quantitative flow information as well. It is portable, versatile, cost effective and considered sufficiently hazardless to monitor pregnancy. Moreover, ultrasound has the unique capacity to offer therapeutic capabilities in addition to its outstanding imaging abilities. It can be used for physiotherapy, lithotripsy, and thermal ablation, and recent studies have demonstrated its usefulness in drug delivery, gene therapy and molecular imaging. The purpose of this article is to provide an introductory review of the field covering briefly topics from basic physics through current imaging methods to therapeutic applications.

Controlled drug release by polymer dissolution. II: Enzyme-mediated delivery device.

PubMed

Heller, J; Trescony, P V

1979-07-01

A novel, closed-loop drug delivery system was developed where the presence or absence of an external compound controls drug delivery from a bioerodible polymer. In the described delivery system, hydrocortisone was incorporated into a n-hexyl half-ester of a methyl vinyl ehter-maleic anhydride copolymer, and the polymer-drug mixture was fabricated into disks. These disks were then coated with a hydrogel containing immobilized urease. In a medium of constant pH and in the absence of external urea, the hydrocortisone release was that normally expected for that polymer at the given pH. With external urea, ammonium bicarbonate and ammonium hydroxide were generated within the hydrogel, which accelerated polymer erosion and drug release. The drug delivery rate increase was proportional to the amount of external urea and was reversible; that is, when external urea was removed, the drug release rate gradually returned to its original value.

Glutathione-responsive nano-transporter-mediated siRNA delivery: silencing the mRNA expression of Ras.

PubMed

Doss, C George Priya; Debottam, S; Debajyoti, C

2013-06-01

Gene therapy through antisense technology via intracellular delivery of a gene-silencing element is a promising approach to treat critical diseases like cancers. Ras acts as molecular switch, considered as one of the proto-oncogenes whose modification or mutation may promote tumor formation. The recent trends of nano-carrier-based drug delivery have gained superiority and proved to be 100 times more potent in drug delivery compared to standard therapies. The nano-based drug delivery has provided the basis of achieving successful target-specific drug delivery. Glutathione (GSH) is considered as one of the best and ubiquitous internal stimulus for swift destabilization of nano-transporters inside cells to accomplish proficient intracellular drug release. This concept has given a new hope to oncologists of modifying the existing drugs to be delivered to their desired destination. RNA interference is a primary tool in functional genomics to selectively silence messenger RNA (mRNA) expression, which can be exploited quickly to develop novel drugs against lethal disease target. Silencing of mRNA molecules using siRNA has also come of age to become one of the latest weapons developed in the concept of gene therapy. However, this strategy has severely failed to achieve target specificity especially to a tumor cell. In this context, we have proposed the incorporation of an antisense siRNA packed inside a GSH-responsive nano-transporter to be delivered specifically to a tumor cell against the sense mRNA of the Ras protein. It will limit the Ras-mediated activation of other proteins and transcription factors. Thus, it will knock down several differential gene expressions being regulated by Ras-activated pathways like enzyme-linked receptor kinase pathway. Henceforth, gene silencing technology through nano-drug delivery can be combined as a single weapon to terminate malignancy.

Drug delivery systems with modified release for systemic and biophase bioavailability.

PubMed

Leucuta, Sorin E

2012-11-01

This review describes the most important new generations of pharmaceutical systems: medicines with extended release, controlled release pharmaceutical systems, pharmaceutical systems for the targeted delivery of drug substances. The latest advances and approaches for delivering small molecular weight drugs and other biologically active agents such as proteins and nucleic acids require novel delivery technologies, the success of a drug being many times dependent on the delivery method. All these dosage forms are qualitatively superior to medicines with immediate release, in that they ensure optimal drug concentrations depending on specific demands of different disease particularities of the body. Drug delivery of these pharmaceutical formulations has the benefit of improving product efficacy and safety, as well as patient convenience and compliance. This paper describes the biopharmaceutical, pharmacokinetic, pharmacologic and technological principles in the design of drug delivery systems with modified release as well as the formulation criteria of prolonged and controlled release drug delivery systems. The paper presents pharmaceutical prolonged and controlled release dosage forms intended for different routes of administration: oral, ocular, transdermal, parenteral, pulmonary, mucoadhesive, but also orally fast dissolving tablets, gastroretentive drug delivery systems, colon-specific drug delivery systems, pulsatile drug delivery systems and carrier or ligand mediated transport for site specific or receptor drug targeting. Specific technologies are given on the dosage forms with modified release as well as examples of marketed products, and current research in these areas.

Stimuli-Responsive Polymeric Systems for Controlled Protein and Peptide Delivery: Future Implications for Ocular Delivery.

PubMed

Mahlumba, Pakama; Choonara, Yahya E; Kumar, Pradeep; du Toit, Lisa C; Pillay, Viness

2016-07-30

Therapeutic proteins and peptides have become notable in the drug delivery arena for their compatibility with the human body as well as their high potency. However, their biocompatibility and high potency does not negate the existence of challenges resulting from physicochemical properties of proteins and peptides, including large size, short half-life, capability to provoke immune responses and susceptibility to degradation. Various delivery routes and delivery systems have been utilized to improve bioavailability, patient acceptability and reduce biodegradation. The ocular route remains of great interest, particularly for responsive delivery of macromolecules due to the anatomy and physiology of the eye that makes it a sensitive and complex environment. Research in this field is slowly gaining attention as this could be the breakthrough in ocular drug delivery of macromolecules. This work reviews stimuli-responsive polymeric delivery systems, their use in the delivery of therapeutic proteins and peptides as well as examples of proteins and peptides used in the treatment of ocular disorders. Stimuli reviewed include pH, temperature, enzymes, light, ultrasound and magnetic field. In addition, it discusses the current progress in responsive ocular drug delivery. Furthermore, it explores future prospects in the use of stimuli-responsive polymers for ocular delivery of proteins and peptides. Stimuli-responsive polymers offer great potential in improving the delivery of ocular therapeutics, therefore there is a need to consider them in order to guarantee a local, sustained and ideal delivery of ocular proteins and peptides, evading tissue invasion and systemic side-effects.

Materials to clinical devices: technologies for remotely triggered drug delivery.

PubMed

Timko, Brian P; Kohane, Daniel S

2012-11-01

Technologies in which a remote trigger is used to release drug from an implanted or injected device could enable on-demand release profiles that enhance therapeutic effectiveness or reduce systemic toxicity. A number of new materials have been developed that exhibit sensitivity to light, ultrasound, or electrical or magnetic fields. Delivery systems that incorporate these materials might be triggered externally by the patient, parent or physician to provide flexible control of dose magnitude and timing. To review injectable or implantable systems that are candidates for translation to the clinic, or ones that have already undergone clinical trials. Also considered are applicability in pediatrics and prospects for the future of drug delivery systems. We performed literature searches of the PubMed and Science Citation Index databases for articles in English that reported triggerable drug delivery devices, and for articles reporting related materials and concepts. Approaches to remotely-triggered systems that have clinical potential were identified. Ideally, these systems have been engineered to exhibit controlled on-state release kinetics, low baseline leak rates, and reproducible dosing across multiple cycles. Advances in remotely-triggered drug delivery have been brought about by the convergence of numerous scientific and engineering disciplines, and this convergence is likely to play an important part in the current trend to develop systems that provide more than one therapeutic modality. Preclinical systems must be carefully assessed for biocompatibility, and engineered to ensure pharmacokinetics within the therapeutic window. Future drug delivery systems may incorporate additional modalities, such as closed-loop sensing or onboard power generation, enabling more sophisticated drug delivery regimens. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Evaluation of 18F-labeled targeted perfluorocarbon-filled albumin microbubbles as a probe for microUS and microPET in tumor-bearing mice.

PubMed

Liao, Ai-Ho; Wu, Shih-Yen; Wang, Hsin-Ell; Weng, Chien-Hsiu; Wu, Ming-Fang; Li, Pai-Chi

2013-02-01

In this study, albumin-shelled, targeted MBs (tMBs) were first demonstrated with the expectation of visualization of biodistribution of albumin-shelled tMBs. The actual biodistribution of albumin-shelled tMBs is of vital importance either for molecular imaging or for drug delivery. Recently, albumin microbubbles (MBs) have been studied for drug and gene delivery in vitro and in vivo through cavitation. Targeted lipid-shelled MBs have been applied for ultrasound molecular imaging and conjugated with radiolabeled antibodies for whole-body biodistribution evaluations. The novelty of the work is that, in addition to the lipid tMBs, the albumin tMBs was also applied in biodistribution detection. Multimodality albumin-shelled, (18)F-SFB-labeled VEGFR2 tMBs were synthesized, and their characteristics in mice bearing MDA-MB-231 human breast cancer were investigated with micro-positron-emission tomography (microPET) and high-frequency ultrasound (microUS). Albumin-shelled MBs can be labeled with (18)F-SFB directly and conjugated with antibodies for dual molecular imaging. The albumin-shelled tMBs show a lifetime in 30min in the blood pool and a highly specific adherence to tumor vessels in mice bearing human breast cancer. From the evaluations of whole-body biodistribution, the potential of the dual molecular imaging probe for drug or gene delivery in animal experiments with albumin shelled MBs has been investigated. Copyright © 2012 Elsevier B.V. All rights reserved.

Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping.

PubMed

Wu, Shih-Ying; Aurup, Christian; Sanchez, Carlos Sierra; Grondin, Julien; Zheng, Wenlan; Kamimura, Hermes; Ferrera, Vincent P; Konofagou, Elisa E

2018-05-22

Brain diseases including neurological disorders and tumors remain under treated due to the challenge to access the brain, and blood-brain barrier (BBB) restricting drug delivery which, also profoundly limits the development of pharmacological treatment. Focused ultrasound (FUS) with microbubbles is the sole method to open the BBB noninvasively, locally, and transiently and facilitate drug delivery, while translation to the clinic is challenging due to long procedure, targeting limitations, or invasiveness of current systems. In order to provide rapid, flexible yet precise applications, we have designed a noninvasive FUS and monitoring system with the protocol tested in monkeys (from in silico preplanning and simulation, real-time targeting and acoustic mapping, to post-treatment assessment). With a short procedure (30 min) similar to current clinical imaging duration or radiation therapy, the achieved targeting (both cerebral cortex and subcortical structures) and monitoring accuracy was close to the predicted 2-mm lower limit. This system would enable rapid clinical transcranial FUS applications outside of the MRI system without a stereotactic frame, thereby benefiting patients especially in the elderly population.

MR-Guided Unfocused Ultrasound Disruption of the Rat Blood-Brain Barrier

NASA Astrophysics Data System (ADS)

Townsend, Kelly A.; King, Randy L.; Zaharchuk, Greg; Pauly, Kim Butts

2011-09-01

Therapeutic ultrasound with microbubbles can temporarily disrupt the blood-brain barrier (BBB) for drug delivery. Contrast-enhanced MRI (CE-MRI) can visualize gadolinium passage into the brain, indicating BBB opening. Previous studies used focused ultrasound, which is appropriate for the targeted delivery of drugs. The purpose of this study was to investigate unfocused ultrasound for BBB opening across the whole brain. In 10 rats, gadolinium-based MR contrast agent (Gd; 0.25 ml) was administered concurrent with ultrasound microbubbles (Optison, 0.25 ml) and circulated for 20 sec before sonication. A 753 kHz planar PZT transducer, diameter 1.8 cm, sonicated each rat brain with supplied voltage of 300, 400, or 500 mVpp for 10 sec in continuous wave mode, or at 500 mVpp at 20% duty cycle at 10 Hz for 30-300 sec. After sonication, coronal T1-weighted FSE CE-MRI images were acquired with a 3in surface coil. The imaging protocol was repeated 3-5 times after treatment. One control animal was given Gd and microbubbles, but not sonicated, and the other was given Gd and sonicated without microbubbles. Signal change in ROIs over the muscle, mesencephalon/ventricles, and the cortex/striatum were measured at 3-5 time points up to 36 min after sonication. Signal intensity was converted to % signal change compared to the initial image. In the controls, CE-MRI showed brightening of surrounding structures, but not the brain. In the continuous wave subjects, cortex/striatum signal did not increase, but ventricle/mesenchephalon signal did. Those that received pulsed sonications showed signal increases in both the cortex/striatum and ventricles/mesenchephalon. In conclusion, after pulsed unfocused ultrasound sonication, the BBB is disrupted across the whole brain, including cortex and deep grey matter, while continuous wave sonication affects only the ventricles and possibly deeper structures, without opening the cortex BBB. As time passes, the timeline of Gd passage into the brain can be visualized.

Molecular modeling of transmembrane delivery of paclitaxel by shock waves with nanobubbles

NASA Astrophysics Data System (ADS)

Lu, Xue-mei; Yuan, Bing; Zhang, Xian-ren; Yang, Kai; Ma, Yu-qiang

2017-01-01

The development of advanced delivery strategies for anticancer drugs that can permeate through cellular membranes is urgently required for biomedical applications. In this work, we investigated the dynamic transmembrane behavior of paclitaxel (PTX), a powerful anticancer drug, under the combined impact of shock waves and nanobubbles, by using atomistic molecular dynamics simulations. Our simulations show that the PTX molecule experiences complicated motion modes during the action process with the membrane, as a consequence of its interplay with the lipid bilayer and water, under the joint effect of the shock wave and nanobubble. Moreover, it was found that the transmembrane movement of PTX is closely associated with the conformation changes of PTX, as well as the structural changes of the membrane (e.g., compression and poration in membrane). The nanobubble collapse induced by the shock wave, the proper PTX location with respect to the nanobubble, and a suitable nanobubble size and shock impulse are all necessary for the delivery of PTX into the cell. This work provides a molecular understanding of the interaction mechanism between drug molecules and cell membranes under the influence of shock waves and nanobubbles, and paves the way for exploiting targeted drug delivery systems that combine nanobubbles and ultrasound.

Cavitation-enhanced extravasation for drug delivery.

PubMed

Arvanitis, Costas D; Bazan-Peregrino, Miriam; Rifai, Bassel; Seymour, Leonard W; Coussios, Constantin C

2011-11-01

A flow-through tissue-mimicking phantom composed of a biocompatible hydro-gel with embedded tumour cells was used to assess and optimize the role of ultrasound-induced cavitation on the extravasation of a macromolecular compound from a channel mimicking vessel in the gel, namely a non-replicating luciferase-expressing adenovirus (Ad-Luc). Using a 500 KHz therapeutic ultrasound transducer confocally aligned with a focussed passive cavitation detector, different exposure conditions and burst mode timings were selected by performing time and frequency domain analysis of passively recorded acoustic emissions, in the absence and in the presence of ultrasound contrast agents acting as cavitation nuclei. In the presence of Sonovue, maximum ultraharmonic emissions were detected for peak rarefactional pressures of 360 kPa, and maximum broadband emissions occurred at 1250 kPa. The energy of the recorded acoustic emissions was used to optimise the pulse repetition frequency and duty cycle in order to maximize either ultraharmonic or broadband emissions while keeping the acoustic energy delivered to the focus constant. Cell viability measurements indicated that none of the insonation conditions investigated induces cell death in the absence of a therapeutic agent (i.e. virus). Phase contrast images of the tissue-mimicking phantom showed that short range vessel disruption can occur when ultra-harmonic emissions (nf0/2) are maximised whereas formation of a micro-channel perpendicular to the flow can be obtained in the presence of broadband acoustic emissions. Following Ad-Luc delivery, luciferase expression measurements showed that a 60-fold increase in its bioavailability can be achieved when broadband noise emissions are present during insonation, even for modest contrast agent concentrations. The findings of the present study suggest that drug delivery systems based on acoustic cavitation may help enhance the extravasation of anticancer agents, thus increasing their penetration distance to hypoxic regions and poorly vascularised tumour regions. Copyright © 2011 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

The use of 5-fluorouracil-loaded nanobubbles combined with low-frequency ultrasound to treat hepatocellular carcinoma in nude mice.

PubMed

Li, Qiaoya; Li, Hongyang; He, Chengjun; Jing, Zhouhong; Liu, Changan; Xie, Juan; Ma, Wenwen; Deng, Huisheng

2017-11-21

This study aimed to investigate the therapeutic effects of 5-fluorouracil (5-FU)-loaded nanobubbles irradiated with low-intensity, low-frequency ultrasound in nude mice with hepatocellular carcinoma (HCC). A transplanted tumor model of HCC in nude mice was established in 40 mice, which were then randomly divided equally into four groups: group A (saline), group B (5-FU-loaded nanobubbles), group C (5-FU-loaded nanobubbles with non-low-frequency ultrasound), and group D (5-FU-loaded nanobubbles with low-frequency ultrasound). The tumor size in each mouse was observed via ultrasound before and after the treatments. Inhibition of the tumor growth in each group was compared, and survival curves were generated. Tumor tissues were removed to determine the apoptotic index using the TUNEL method and quantitative analysis. Tumor tissues with CD34-positive microvessels were observed by immunohistochemistry, and the tumor microvessel densities were calculated. The growth rate of the tumor volumes in group D was significantly slower than that in the other groups, while the tumor inhibition rates and apoptotic index in group D were significantly higher than those of the other groups. The number of microvessels staining positive for CD34 was decreased in group D. Therefore, group D presented the most significant inhibitory effects. Therefore, 5-FU-loaded nanobubbles subjected to irradiation with low-frequency ultrasound could further improve drug targeting and effectively inhibit the growth of transplanted tumors, which is expected to become an ideal drug carrier and targeted drug delivery system for the treatment of HCC in the future.

Development of controlled drug delivery systems for bone fracture-targeted therapeutic delivery: A review.

PubMed

Wang, Yuchen; Newman, Maureen R; Benoit, Danielle S W

2018-06-01

Impaired fracture healing is a major clinical problem that can lead to patient disability, prolonged hospitalization, and significant financial burden. Although the majority of fractures heal using standard clinical practices, approximately 10% suffer from delayed unions or non-unions. A wide range of factors contribute to the risk for nonunions including internal factors, such as patient age, gender, and comorbidities, and external factors, such as the location and extent of injury. Current clinical approaches to treat nonunions include bone grafts and low-intensity pulsed ultrasound (LIPUS), which realizes clinical success only to select patients due to limitations including donor morbidities (grafts) and necessity of fracture reduction (LIPUS), respectively. To date, therapeutic approaches for bone regeneration rely heavily on protein-based growth factors such as INFUSE, an FDA-approved scaffold for delivery of bone morphogenetic protein 2 (BMP-2). Small molecule modulators and RNAi therapeutics are under development to circumvent challenges associated with traditional growth factors. While preclinical studies has shown promise, drug delivery has become a major hurdle stalling clinical translation. Therefore, this review overviews current therapies employed to stimulate fracture healing pre-clinically and clinically, including a focus on drug delivery systems for growth factors, parathyroid hormone (PTH), small molecules, and RNAi therapeutics, as well as recent advances and future promise of fracture-targeted drug delivery. Copyright © 2018 Elsevier B.V. All rights reserved.

Polymeric micelles with stimuli-triggering systems for advanced cancer drug targeting.

PubMed

Nakayama, Masamichi; Akimoto, Jun; Okano, Teruo

2014-08-01

Since the 1990s, nanoscale drug carriers have played a pivotal role in cancer chemotherapy, acting through passive drug delivery mechanisms and subsequent pharmaceutical action at tumor tissues with reduction of adverse effects. Polymeric micelles, as supramolecular assemblies of amphiphilic polymers, have been considerably developed as promising drug carrier candidates, and a number of clinical studies of anticancer drug-loaded polymeric micelle carriers for cancer chemotherapy applications are now in progress. However, these systems still face several issues; at present, the simultaneous control of target-selective delivery and release of incorporated drugs remains difficult. To resolve these points, the introduction of stimuli-responsive mechanisms to drug carrier systems is believed to be a promising approach to provide better solutions for future tumor drug targeting strategies. As possible trigger signals, biological acidic pH, light, heating/cooling and ultrasound actively play significant roles in signal-triggering drug release and carrier interaction with target cells. This review article summarizes several molecular designs for stimuli-responsive polymeric micelles in response to variation of pH, light and temperature and discusses their potentials as next-generation tumor drug targeting systems.

Nano-based theranostics for chronic obstructive lung diseases: challenges and therapeutic potential.

PubMed

Vij, Neeraj

2011-09-01

The major challenges in the delivery and therapeutic efficacy of nano-delivery systems in chronic obstructive airway conditions are airway defense, severe inflammation and mucous hypersecretion. Chronic airway inflammation and mucous hypersecretion are hallmarks of chronic obstructive airway diseases, including asthma, COPD (chronic obstructive pulmonary disease) and CF (cystic fibrosis). Distinct etiologies drive inflammation and mucous hypersecretion in these diseases, which are further induced by infection or components of cigarette smoke. Controlling chronic inflammation is at the root of treatments such as corticosteroids, antibiotics or other available drugs, which pose the challenge of sustained delivery of drugs to target cells or tissues. In spite of the wide application of nano-based drug delivery systems, very few are tested to date. Targeted nanoparticle-mediated sustained drug delivery is required to control inflammatory cell chemotaxis, fibrosis, protease-mediated chronic emphysema and/or chronic lung obstruction in COPD. Moreover, targeted epithelial delivery is indispensable for correcting the underlying defects in CF and targeted inflammatory cell delivery for controlling other chronic inflammatory lung diseases. We propose that the design and development of nano-based targeted theranostic vehicles with therapeutic, imaging and airway-defense penetrating capability, will be invaluable for treating chronic obstructive lung diseases. This paper discusses a novel nano-theranostic strategy that we are currently evaluating to treat the underlying cause of CF and COPD lung disease.

Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood-Brain Barrier.

PubMed

Georgieva, Julia V; Hoekstra, Dick; Zuhorn, Inge S

2014-11-17

The blood-brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the brain. This concept relies on the application of natural or genetically engineered proteins or small peptides, capable of specifically ferrying a drug-payload that is either directly coupled or encapsulated in an appropriate nanocarrier, across the blood-brain barrier via receptor-mediated transcytosis. Specifically, in this process the nanocarrier-drug system ("Trojan horse complex") is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by a native receptor. Naturally, only certain properties would favor a receptor to serve as a transporter for nanocarriers, coated with appropriate ligands. Here we briefly discuss brain microvascular endothelial receptors that have been explored until now, highlighting molecular features that govern the efficiency of nanocarrier-mediated drug delivery into the brain.

Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release

PubMed Central

Bult, Wouter; Bos, Mariska; Storm, Gert; Nijsen, J. Frank W.; Hennink, Wim E.

2010-01-01

ABSTRACT Micelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a ‘magic bullet’ a major step forward. PMID:20725771

Intrapartum ultrasound: A useful method for evaluating labor progress and predicting operative vaginal delivery

PubMed Central

Ahn, Ki Hoon

2014-01-01

The last step of a successful pregnancy is the safe delivery of the fetus. An important question is if the delivery should vaginal or operative. In addition to the use of conventional antenatal ultrasound, the use of intrapartum ultrasound to evaluate fetal head station, position, cervical ripening, and placental separation is promising. This review evaluates and summarizes the usefulness of intrapartum ultrasound for the evaluation of labor progress and predicting successful operative vaginal delivery. PMID:25469329

Influence of ultrasound induced cavitation on magnetic resonance imaging contrast in the rat liver in the presence of macromolecular contrast agent.

PubMed

Frulio, Nora; Trillaud, Hervé; Deckers, Roel; Lepreux, Sébastien; Moonen, Chrit; Quesson, Bruno

2010-05-01

Local drug delivery by ultrasound (US)-induced cavitation is a promising strategy for increasing the drug concentration at the target location and for decreasing the systemic toxicity effects. The presence of microbubbles during sonication at the targeted location improves the likelihood for cavitation that can be exploited to increase the capillary permeability. The objective of this work was to evaluate the magnetic resonance imaging (MRI) contrast changes in hepatic tissue in vivo, induced by US-triggered cavitation and destruction of microbubbles (Sonovue), in the presence of a coinjected blood pool MRI contrast agent (Vistarem) used as a reporter macromolecule. The potential tissue damage induced by microbubbles destruction was also evaluated by histology. The change in the hepatic distribution of the macromolecular MRI contrast agent associated with cavitation was monitored at 1.5 T with a look-locker fast inversion recovery sequence to map the longitudinal relaxation rates, before and during 1 hour after intravenous administration of Vistarem and Sonovue. In 1 group of rats (n = 5), these microbubbles were immediately destroyed with a clinical echograph, using a high mechanical index (MI = 1.5) at low frequency (2 MHz). The control group (n = 7) received identical injections without application of US. The parametric relaxation rate images were computed, and the changes in time were analyzed to account for the potential effect of microbubble destruction by US on the permeability of the hepatic vessels. The animals were killed 1 day after the experiment for routine histology of the liver. For both groups of animals, after an initial increase, a transient decay of the longitudinal relaxation rate was observed, followed by a constant plateau after 20 minutes. The analysis of the mean relaxation rates in the liver showed significant (P < 0.01) higher values for the group with destruction of microbubbles as compared with the control group. The US-triggered cavitation and destruction of microbubble with the proposed protocol suggests an increased concentration of Vistarem of a factor 2 in the hepatic tissue. No tissue damage was observed at the microscopic analysis. The absence of tissue alterations indicates that the destruction of this US contrast agent could be safe in vivo under an appropriate choice of the sonication parameters. This approach opens new perspectives for translation toward clinical applications of local drug delivery. Ultrasound-mediated microbubble destruction may help in increasing the local concentration of a drug currently limited by the endothelial barrier. In addition, it may help in reducing the systemic toxicity to normal cells in standard chemotherapies, because the enhanced capillary permeability effect can be spatially adjusted by selecting the sonicated region.

Chitosan-functionalised single-walled carbon nanotube-mediated drug delivery of SNX-2112 in cancer cells.

PubMed

Zheng, Lixia; Wu, Shao; Tan, Li; Tan, Huo; Yu, Baodan

2016-09-01

Delivery of amphiphobic drugs (insoluble in both water and oil) has been a great challenge in drug delivery. SNX-2112, a novel inhibitor of Hsp90, is a promising drug candidate for treating various types of cancers; however, the insolubility greatly limits its clinical application. This study aimed to build a new type of drug delivery system using single-walled carbon nanotubes (SWNTs) for controllable release of SNX-2112; chitosan (CHI) was non-covalently added to SWNTs to improve their biocompatibility. SWNTs-CHI demonstrated high drug-loading capability; the release of SNX-2112 was pH triggered and time related. The intracellular reactive oxygen species of SWNTs-CHI increased, compared with that of SWNTs, leading to higher mitogen-activated protein kinase and cell apoptosis. The results of western-blotting, lactate dehydrogenase (LDH) release assay, and cell viability assay analyses indicated that apoptosis-related proteins were abundantly expressed in K562 cells and that the drug delivery system significantly inhibited K562 cells. Thus, SWNT-CHI/SNX-2112 shows great potential as a drug delivery system for cancer therapy. © The Author(s) 2016.

Calcium Binding-Mediated Sustained Release of Minocycline from Hydrophilic Multilayer Coatings Targeting Infection and Inflammation

PubMed Central

Zhang, Zhiling; Nix, Camilla A.; Ercan, Utku K.; Gerstenhaber, Jonathan A.; Joshi, Suresh G.; Zhong, Yinghui

2014-01-01

Infection and inflammation are common complications that seriously affect the functionality and longevity of implanted medical implants. Systemic administration of antibiotics and anti-inflammatory drugs often cannot achieve sufficient local concentration to be effective, and elicits serious side effects. Local delivery of therapeutics from drug-eluting coatings presents a promising solution. However, hydrophobic and thick coatings are commonly used to ensure sufficient drug loading and sustained release, which may limit tissue integration and tissue device communications. A calcium-mediated drug delivery mechanism was developed and characterized in this study. This novel mechanism allows controlled, sustained release of minocycline, an effective antibiotic and anti-inflammatory drug, from nanoscale thin hydrophilic polyelectrolyte multilayers for over 35 days at physiologically relevant concentrations. pH-responsive minocycline release was observed as the chelation between minocycline and Ca2+ is less stable at acidic pH, enabling ‘smart’ drug delivery in response to infection and/or inflammation-induced tissue acidosis. The release kinetics of minocycline can be controlled by varying initial loading, Ca2+ concentration, and Ca2+ incorporation into different layers, enabling facile development of implant coatings with versatile release kinetics. This drug delivery platform can potentially be used for releasing any drug that has high Ca2+ binding affinity, enabling its use in a variety of biomedical applications. PMID:24409292

Focused ultrasound-mediated bbb disruption is associated with an increase in activation of AKT: experimental study in rats

PubMed Central

2010-01-01

Background The Blood Brain Barrier (BBB) maintains the homeostasis of central nervous system by preventing the free passage of macromolecules from the systemic circulation into the brain. This normal physiological function of the BBB presents a challenge for delivery of therapeutic compounds into the brain. Recent studies have shown that the application of focused ultrasound together with ultrasound contrast agent (microbubbles) temporarily increases the permeability of the BBB. This effect is associated with breakdown of tight junctions, the structures that regulate the paracellular permeability of the endothelial cell layer. The influence of this ultrasound effect on the activation of intracellular signaling proteins is currently not well understood. Therefore, the aim of this study was to investigate the activation of cell survival signaling molecules in response to ultrasound-mediated BBB opening; Methods The BBB was disrupted in two four-spot lines (1-1.5 mm spacing) along the right hemisphere of rat brain with ultrasound beams (0.3 MPa, 120 s, 10 ms bursts, repetition frequency = 1 Hz) in the presence Definity microbubbles. Contrast-enhanced MRI images were acquired to assess the extent of BBB opening upon which the animals were sacrificed and the brains removed and processed for biochemical and immunohistochemical analyses; Results Immunoblotting of sonicated brain lysates resolved by SDS-PAGE demonstrated an increase in phosphorylation of Akt and its downstream signaling molecule, GSK3β, while the phosphorylation of MAPK remained unchanged. The elevated levels of pAkt and pGSK3β are still evident after 24 hours post-sonication, a time point where the integrity of the BBB is known to be re-established. Furthermore, immunofluoresence staining localized this increase in pAkt and pGSK3β levels to neuronal cells flanking the region of the disrupted BBB; Conclusions Our data demonstrates that ultrasound-mediated BBB disruption causes an activation of the Akt signaling pathway in neuronal cells surrounding the disrupted BBB. PMID:21078165

Introduction for the special issue on recent advances in drug delivery across tissue barriers.

PubMed

Mrsny, Randall J; Brayden, David J

2016-01-01

This special issue of Tissue Barriers contains a series of reviews with the common theme of how biological barriers established at epithelial tissues limit the uptake of macromolecular therapeutics. By improving our functional understanding of these barriers, the majority of the authors have highlighted potential strategies that might be applied to the non-invasive delivery of biopharmaceuticals that would otherwise require an injection format for administration. Half of the articles focus on the potential of particular technologies to assist oral delivery of peptides, proteins and other macromolecules. These include use of prodrug chemistry to improve molecule stability and permeability, and the related potential for oral delivery of poorly permeable agents by cell-penetrating peptides and dendrimers. Safety aspects of intestinal permeation enhancers are discussed, along with the more recent foray into drug-device combinations as represented by intestinal microneedles and externally-applied ultrasound. Other articles highlight the crossover between food research and oral delivery based on nanoparticle technology, while the final one provides a fascinating interpretation of the physiological problems associated with subcutaneous insulin delivery and how inefficient it is at targeting the liver.

Blood-brain barrier transport machineries and targeted therapy of brain diseases

PubMed Central

Barar, Jaleh; Rafi, Mohammad A.; Pourseif, Mohammad M.; Omidi, Yadollah

2016-01-01

Introduction: Desired clinical outcome of pharmacotherapy of brain diseases largely depends upon the safe drug delivery into the brain parenchyma. However, due to the robust blockade function of the blood-brain barrier (BBB), drug transport into the brain is selectively controlled by the BBB formed by brain capillary endothelial cells and supported by astrocytes and pericytes. Methods: In the current study, we have reviewed the most recent literature on the subject to provide an insight upon the role and impacts of BBB on brain drug delivery and targeting. Results: All drugs, either small molecules or macromolecules, designated to treat brain diseases must adequately cross the BBB to provide their therapeutic properties on biological targets within the central nervous system (CNS). However, most of these pharmaceuticals do not sufficiently penetrate into CNS, failing to meet the intended therapeutic outcomes. Most lipophilic drugs capable of penetrating BBB are prone to the efflux functionality of BBB. In contrast, all hydrophilic drugs are facing severe infiltration blockage imposed by the tight cellular junctions of the BBB. Hence, a number of strategies have been devised to improve the efficiency of brain drug delivery and targeted therapy of CNS disorders using multimodal nanosystems (NSs). Conclusions: In order to improve the therapeutic outcomes of CNS drug transfer and targeted delivery, the discriminatory permeability of BBB needs to be taken under control. The carrier-mediated transport machineries of brain capillary endothelial cells (BCECs) can be exploited for the discovery, development and delivery of small molecules into the brain. Further, the receptor-mediated transport systems can be recruited for the delivery of macromolecular biologics and multimodal NSs into the brain. PMID:28265539

Blood-brain barrier transport machineries and targeted therapy of brain diseases.

PubMed

Barar, Jaleh; Rafi, Mohammad A; Pourseif, Mohammad M; Omidi, Yadollah

2016-01-01

Introduction: Desired clinical outcome of pharmacotherapy of brain diseases largely depends upon the safe drug delivery into the brain parenchyma. However, due to the robust blockade function of the blood-brain barrier (BBB), drug transport into the brain is selectively controlled by the BBB formed by brain capillary endothelial cells and supported by astrocytes and pericytes. Methods: In the current study, we have reviewed the most recent literature on the subject to provide an insight upon the role and impacts of BBB on brain drug delivery and targeting. Results: All drugs, either small molecules or macromolecules, designated to treat brain diseases must adequately cross the BBB to provide their therapeutic properties on biological targets within the central nervous system (CNS). However, most of these pharmaceuticals do not sufficiently penetrate into CNS, failing to meet the intended therapeutic outcomes. Most lipophilic drugs capable of penetrating BBB are prone to the efflux functionality of BBB. In contrast, all hydrophilic drugs are facing severe infiltration blockage imposed by the tight cellular junctions of the BBB. Hence, a number of strategies have been devised to improve the efficiency of brain drug delivery and targeted therapy of CNS disorders using multimodal nanosystems (NSs). Conclusions: In order to improve the therapeutic outcomes of CNS drug transfer and targeted delivery, the discriminatory permeability of BBB needs to be taken under control. The carrier-mediated transport machineries of brain capillary endothelial cells (BCECs) can be exploited for the discovery, development and delivery of small molecules into the brain. Further, the receptor-mediated transport systems can be recruited for the delivery of macromolecular biologics and multimodal NSs into the brain.

Cavitation and contrast: the use of bubbles in ultrasound imaging and therapy.

PubMed

Stride, E P; Coussios, C C

2010-01-01

Microbubbles and cavitation are playing an increasingly significant role in both diagnostic and therapeutic applications of ultrasound. Microbubble ultrasound contrast agents have been in clinical use now for more than two decades, stimulating the development of a range of new contrast-specific imaging techniques which offer substantial benefits in echocardiography, microcirculatory imaging, and more recently, quantitative and molecular imaging. In drug delivery and gene therapy, microbubbles are being investigated/developed as vehicles which can be loaded with the required therapeutic agent, traced to the target site using diagnostic ultrasound, and then destroyed with ultrasound of higher intensity energy burst to release the material locally, thus avoiding side effects associated with systemic administration, e.g. of toxic chemotherapy. It has moreover been shown that the motion of the microbubbles increases the permeability of both individual cell membranes and the endothelium, thus enhancing therapeutic uptake, and can locally increase the activity of drugs by enhancing their transport across biologically inaccessible interfaces such as blood clots or solid tumours. In high-intensity focused ultrasound (HIFU) surgery and lithotripsy, controlled cavitation is being investigated as a means of increasing the speed and efficacy of the treatment. The aim of this paper is both to describe the key features of the physical behaviour of acoustically driven bubbles which underlie their effectiveness in biomedical applications and to review the current state of the art.

Folate-conjugated boron nitride nanospheres for targeted delivery of anticancer drugs.

PubMed

Feng, Shini; Zhang, Huijie; Yan, Ting; Huang, Dandi; Zhi, Chunyi; Nakanishi, Hideki; Gao, Xiao-Dong

With its unique physical and chemical properties and structural similarity to carbon, boron nitride (BN) has attracted considerable attention and found many applications. Biomedical applications of BN have recently started to emerge, raising great hopes in drug and gene delivery. Here, we developed a targeted anticancer drug delivery system based on folate-conjugated BN nanospheres (BNNS) with receptor-mediated targeting. Folic acid (FA) was successfully grafted onto BNNS via esterification reaction. In vitro cytotoxicity assay showed that BNNS-FA complexes were non-toxic to HeLa cells up to a concentration of 100 μg/mL. Then, doxorubicin hydrochloride (DOX), a commonly used anticancer drug, was loaded onto BNNS-FA complexes. BNNS-FA/DOX complexes were stable at pH 7.4 but effectively released DOX at pH 5.0, which exhibited a pH sensitive and sustained release pattern. BNNS-FA/DOX complexes could be recognized and specifically internalized by HeLa cells via FA receptor-mediated endocytosis. BNNS-FA/DOX complexes exhibited greater cytotoxicity to HeLa cells than free DOX and BNNS/DOX complexes due to the increased cellular uptake of DOX mediated by the FA receptor. Therefore, BNNS-FA complexes had strong potential for targeted cancer therapy.

Influence of peptide dendrimers and sonophoresis on the transdermal delivery of ketoprofen.

PubMed

Manikkath, Jyothsna; Hegde, Aswathi R; Kalthur, Guruprasad; Parekh, Harendra S; Mutalik, Srinivas

2017-04-15

The aim of this study was to determine the individual and combined effects of peptide dendrimers and low frequency ultrasound on the transdermal permeation of ketoprofen. Arginine terminated peptide dendrimers of varying charges (4 + , 8 + and 16 + , named as A4. A8 and A16 respectively) were synthesized and characterized. Ketoprofen was subjected to passive, peptide dendrimer-assisted and sonophoretic permeation studies (with and without dendrimer application) across Swiss albino mouse skin, both in vitro and in vivo. The studies revealed that the synthesized peptide dendrimers considerably increased the transdermal permeation of ketoprofen and displayed enhancement ratios of up to 3.25 (with A16 dendrimer), compared to passive diffusion of drug alone in vitro. Moreover, the combination of peptide dendrimer treatment and ultrasound application worked in synergy and gave enhancement ratios of up to 1369.15 (with ketoprofen-A16 dendrimer complex). In vivo studies demonstrated that dendrimer and ultrasound-assisted permeation of drug achieved much higher plasma concentration of drug, compared to passive diffusion. Comparison of transdermal and oral absorption studies revealed that transdermal administration of ketoprofen with A8 dendrimer showed comparable absorption and plasma drug levels with oral route. The excised mouse skin after in vivo permeation study with dendrimers and ultrasound did not show major toxic reactions. This study demonstrates that arginine terminated peptide dendrimers combined with sonophoresis can effectively improve the transdermal permeation of ketoprofen. Copyright © 2017 Elsevier B.V. All rights reserved.

Silk-Based Biomaterials for Sustained Drug Delivery

PubMed Central

Yucel, Tuna; Lovett, Michael L.; Kaplan, David L.

2014-01-01

Silk presents a rare combination of desirable properties for sustained drug delivery, including aqueous-based purification and processing options without chemical cross-linkers, compatibility with common sterilization methods, controllable and surface-mediated biodegradation into non-inflammatory by-products, biocompatibility, utility in drug stabilization, and robust mechanical properties. A versatile silk-based toolkit is currently available for sustained drug delivery formulations of small molecule through macromolecular drugs, with a promise to mitigate several drawbacks associated with other degradable sustained delivery technologies in the market. Silk-based formulations utilize silk’s well-defined nano- through microscale structural hierarchy, stimuli-responsive self-assembly pathways and crystal polymorphism, as well as sequence and genetic modification options towards targeted pharmaceutical outcomes. Furthermore, by manipulating the interactions between silk and drug molecules, near-zero order sustained release may be achieved through diffusion- and degradation-based release mechanisms. Because of these desirable properties, there has been increasing industrial interest in silk-based drug delivery systems currently at various stages of the developmental pipeline from pre-clinical to FDA-approved products. Here, we discuss the unique aspects of silk technology as a sustained drug delivery platform and highlight the current state of the art in silk-based drug delivery. We also offer a potential early development pathway for silk-based sustained delivery products. PMID:24910193

Albumin-based drug delivery: harnessing nature to cure disease.

PubMed

Larsen, Maja Thim; Kuhlmann, Matthias; Hvam, Michael Lykke; Howard, Kenneth A

2016-01-01

The effectiveness of a drug is dependent on accumulation at the site of action at therapeutic levels, however, challenges such as rapid renal clearance, degradation or non-specific accumulation requires drug delivery enabling technologies. Albumin is a natural transport protein with multiple ligand binding sites, cellular receptor engagement, and a long circulatory half-life due to interaction with the recycling neonatal Fc receptor. Exploitation of these properties promotes albumin as an attractive candidate for half-life extension and targeted intracellular delivery of drugs attached by covalent conjugation, genetic fusions, association or ligand-mediated association. This review will give an overview of albumin-based products with focus on the natural biological properties and molecular interactions that can be harnessed for the design of a next-generation drug delivery platform.

Correlation of acoustic emissions associated with effects from diagnostic and therapeutic ultrasound

NASA Astrophysics Data System (ADS)

Samuel, Stanley

2007-12-01

This research has investigated the correlation of acoustic emissions with associated contrast-mediated ultrasound bio-effects. The hypothesis that motivated this study was that during exposure with ultrasound, the cavitation occurring in tissue emits acoustical signals, which if correlated with specific bio-effects, could provide a way to monitor the potential bio-effects of exposure. A good bio-effects indicator would find immediate use in research on drug and gene delivery, and could have clinical application in avoiding bio-effects in diagnosis. Studies conducted to test the hypothesis involved investigation of (i) the influence of pulse repetition frequency (PRF) and number of exposures on cell damage, (ii) the effect of total exposure duration and pulse-to-pulse bubble distribution on acoustic emissions and corresponding cell damage, and (iii) the translation of in vitro effects to an in situ environment. Exposures were primarily conducted at a peak rarefactional pressure of 2 MPa, 2.25 MHz insonating frequency and pulse length of 46 cycles. PRFs of 1-, 10-, 100-, 500-, and 1000 Hz were compared. High speed photography (2000 fps) was employed for the investigation of pulse-to-pulse bubble distribution while intravital microscopy was used for in situ studies. A strong correlation was observed between acoustic emissions and bio-effects with the availability of bubbles of resonant size serving as a key link between the two. It was observed that total exposure duration may play an important role in cell damage. Damage increased with increasing total exposure duration from 0 ms to 100 ms with a plateau at above 100 ms. These results were consistent for all studies. There is, therefore, an implication that manipulating these parameters may allow for measurement and control of the extent of bioeffects. Moreover, the correlation of acoustic emission and extravasation observed in in situ studies reveals that cumulative function of the relative integrated power spectrum (CRIPS) of the emissions may find use as a monitoring method related to tissue damage due to contrast-mediated ultrasound in vivo.

On ultrasound-induced microbubble oscillation in a capillary blood vessel and its implications for the blood-brain barrier

NASA Astrophysics Data System (ADS)

Wiedemair, W.; Tuković, Ž.; Jasak, H.; Poulikakos, D.; Kurtcuoglu, V.

2012-02-01

The complex interaction between an ultrasound-driven microbubble and an enclosing capillary microvessel is investigated by means of a coupled, multi-domain numerical model using the finite volume formulation. This system is of interest in the study of transient blood-brain barrier disruption (BBBD) for drug delivery applications. The compliant vessel structure is incorporated explicitly as a distinct domain described by a dedicated physical model. Red blood cells (RBCs) are taken into account as elastic solids in the blood plasma. We report the temporal and spatial development of transmural pressure (Ptm) and wall shear stress (WSS) at the luminal endothelial interface, both of which are candidates for the yet unknown mediator of BBBD. The explicit introduction of RBCs shapes the Ptm and WSS distributions and their derivatives markedly. While the peak values of these mechanical wall parameters are not affected considerably by the presence of RBCs, a pronounced increase in their spatial gradients is observed compared to a configuration with blood plasma alone. The novelty of our work lies in the explicit treatment of the vessel wall, and in the modelling of blood as a composite fluid, which we show to be relevant for the mechanical processes at the endothelium.

Stable Encapsulated Air Nanobubbles in Water.

PubMed

Wang, Yu; Liu, Guojun; Hu, Heng; Li, Terry Yantian; Johri, Amer M; Li, Xiaoyu; Wang, Jian

2015-11-23

The dispersion into water of nanocapsules bearing a highly hydrophobic fluorinated internal lining yielded encapsulated air nanobubbles. These bubbles, like their micrometer-sized counterparts (microbubbles), effectively reflected ultrasound. More importantly, the nanobubbles survived under ultrasonication 100-times longer than a commercial microbubble sample that is currently in clinical use. We justify this unprecedented stability theoretically. These nanobubbles, owing to their small size and potential ability to permeate the capillary networks of tissues, may expand the applications of microbubbles in diagnostic ultrasonography and find new applications in ultrasound-regulated drug delivery. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Strategies to improve drug delivery across the blood-brain barrier.

PubMed

de Boer, Albertus G; Gaillard, Pieter J

2007-01-01

The blood-brain barrier (BBB), together with the blood-cerebrospinal-fluid barrier, protects and regulates the homeostasis of the brain. However, these barriers also limit the transport of small-molecule and, particularly, biopharmaceutical drugs such as proteins, genes and interference RNA to the brain, thereby limiting the treatment of many brain diseases. As a result, various drug delivery and targeting strategies are currently being developed to enhance the transport and distribution of drugs into the brain. In this review, we discuss briefly the biology and physiology of the BBB as the most important barrier for drug transport to the brain and, in more detail, the possibilities for delivering large-molecule drugs, particularly genes, by receptor-mediated nonviral drug delivery to the (human) brain. In addition, the systemic and intracellular pharmacokinetics of nonviral gene delivery, together with targeted brain imaging, are reviewed briefly.

Experiment on the factors for enhancing the susceptibility of cancer cells to chemotherapeutic drug by ultrasound microbubbles.

PubMed

Zhao, Ying-Zheng; Gao, Hui-Sheng; Zhou, Zhi-Cai; Tang, Qin-Qin; Lu, Cui-Tao; Jin, Zhuo; Tian, Ji-Lai; Xu, Yan-Yan; Tian, Xin-Qiao; Wang, Lee; Kong, Fan-Lei; Li, Xiao-Kun; Huang, Pin-Tong; He, Hui-Liao; Wu, Yan

2010-07-01

The objective of this study was to investigate the factors for enhancing the susceptibility of cancer cells to chemotherapeutic drug by ultrasound microbubbles. Ultrasound (US) combined with phospholipid-based microbubbles (MB) was used to enhance the susceptibility of colon cancer cell line SWD-620 to anticancer drugs Topotecan hydrochloride (TOP). Experiments were designed to investigate the influence of main factors on cell viability and cell inhibition, such as US intensity, MB concentration, drug combination with MB, asynchronous action between US triggered cavitation and drug entering cell, MB particle size. US exposure for 10 sec with US probe power at 0.6 W/cm(2) had satisfied cell viability. Treated with US combined with 15% MB, cell viability maintained more than 85% and cell inhibition 86.16%. Under optimal US combined with MB, TOP showed much higher cell inhibition than that of only TOP group. Cell inhibition under short delayed time (<2 h) for TOP addition did not show obvious difference. In terms of MB particle size, the order of cell inhibition was: Mixture > Micron bubble part > Nanometer bubble part. US combined with MB can enhance the susceptibility of cancer cells to chemotherapeutic drug, which may provide a potential method for US-mediated tumor chemotherapy.

Cavitation in ultrasound and shockwave therapy

NASA Astrophysics Data System (ADS)

Colonius, Tim

2014-11-01

Acoustic waves, especially high-intensity ultrasound and shock waves, are used for medical imaging and intra- and extra-corporeal manipulation of cells, tissue, and urinary calculi. Waves are currently used to treat kidney stone disease, plantar fasciitis, and bone nonunion, and they are being investigated as a technique to ablate cancer tumors and mediate drug delivery. In many applications, acoustic waves induce the expansion and collapse of preexisting or newly cavitating bubbles whose presence can either mediate the generation of localized stresses or lead to collateral damage, depending on how effectively they can be controlled. We describe efforts aimed at simulating the collapse of bubbles, both individually and in clusters, with the aim to characterize the induced mechanical stresses and strains. To simulate collapse of one or a few bubbles, compressible Euler and Navier-Stokes simulations of multi-component materials are performed with WENO-based shock and interface capturing schemes. Repetitive insonification generates numerous bubbles that are difficult to resolve numerically. Such clouds are also important in traditional engineering applications such as caveating hydrofoils. Models that incorporate the dynamics of an unresolved dispersed phase consisting of the bubble cloud are also developed. The results of several model problems including bubble collapse near rigid surfaces, bubble collapse near compliant surfaces and in small capillaries are analyzed. The results are processed to determine the potential for micron-sized preexisting gas bubbles to damage capillaries. The translation of the fundamental fluid dynamics into improvements in the design and clinical application of shockwave lithotripters will be discussed. NIH Grant PO1-DK043881.

Targeted nanobubbles in low-frequency ultrasound-mediated gene transfection and growth inhibition of hepatocellular carcinoma cells.

PubMed

Wu, Bolin; Qiao, Qiang; Han, Xue; Jing, Hui; Zhang, Hao; Liang, Hongjian; Cheng, Wen

2016-09-01

The use of SonoVue combined with ultrasound exposure increases the transfection efficiency of short interfering RNA (siRNA). The objective of this study was to prepare targeted nanobubbles (TNB) conjugated with NET-1 siRNA and an antibody GPC3 to direct nanobubbles to hepatocellular carcinoma cells. SMMC-7721 human hepatocellular carcinoma cells were treated with six different groups. The transfection efficiency and cellular apoptosis were measured by flow cytometry. The protein and messenger RNA (mRNA) expression were measured by Western blot and quantitative real-time PCR, respectively. The migration and invasion potential of the cells were determined by Transwell analysis. The results show that US-guided siRNA-TNB transfection effectively enhanced gene silencing. In summary, siRNA-TNB may be an effective delivery vector to mediate highly effective RNA interference in tumor treatment.

Enzyme-activated intracellular drug delivery with tubule clay nanoformulation

PubMed Central

Dzamukova, Maria R.; Naumenko, Ekaterina A.; Lvov, Yuri M.; Fakhrullin, Rawil F.

2015-01-01

Fabrication of stimuli-triggered drug delivery vehicle s is an important milestone in treating cancer. Here we demonstrate the selective anticancer drug delivery into human cells with biocompatible 50-nm diameter halloysite nanotube carriers. Physically-adsorbed dextrin end stoppers secure the intercellular release of brilliant green. Drug-loaded nanotubes penetrate through the cellular membranes and their uptake efficiency depends on the cells growth rate. Intercellular glycosyl hydrolases-mediated decomposition of the dextrin tube-end stoppers triggers the release of the lumen-loaded brilliant green, which allowed for preferable elimination of human lung carcinoma cells (А549) as compared with hepatoma cells (Hep3b). The enzyme-activated intracellular delivery of brilliant green using dextrin-coated halloysite nanotubes is a promising platform for anticancer treatment. PMID:25976444

Poly (amidoamine) (PAMAM) dendrimer mediated delivery of drug and pDNA/siRNA for cancer therapy.

PubMed

Li, Jun; Liang, Huamin; Liu, Jing; Wang, Ziyuan

2018-07-30

Poly (amidoamine) (PAMAM) dendrimers are well-defined, highly branched macromolecules with numerous active amine groups on the surface. Because of their unique properties, PAMAM dendrimers have steadily grown in popularity in drug delivery, gene therapy, medical imaging and diagnostic application. This review focuses on the recent developments on the application in PAMAM dendrimers as effective carriers for drug and gene (pDNA, siRNA) delivery in cancer therapy, including: a) PAMAM for anticancer drug delivery; b) PAMAM and gene therapy; c) PAMAM used in overcoming tumor multidrug resistance; d) PAMAM used for hybrid nanoparticles; and e) PAMAM linked or loaded in other nanoparticles. Copyright © 2018 Elsevier B.V. All rights reserved.

Advances in bioresponsive closed-loop drug delivery systems.

PubMed

Yu, Jicheng; Zhang, Yuqi; Yan, Junjie; Kahkoska, Anna R; Gu, Zhen

2017-11-27

Controlled drug delivery systems are able to improve efficacy and safety of therapeutics by optimizing the duration and kinetics of release. Among them, closed-loop delivery strategies, also known as self-regulated administration, have proven to be a practical tool for homeostatic regulation, by tuning drug release as a function of biosignals relevant to physiological and pathological processes. A typical example is glucose-responsive insulin delivery system, which can mimic the pancreatic beta cells to release insulin with a proper dose at a proper time point by responding to plasma glucose levels. Similar self-regulated systems are also important in the treatment of other diseases including thrombosis and bacterial infection. In this review, we survey the recent advances in bioresponsive closed-loop drug delivery systems, including glucose-responsive, enzyme-activated, and other biosignal-mediated delivery systems. We also discuss the future opportunities and challenges in this field. Copyright © 2017 Elsevier B.V. All rights reserved.

Fabrication and characterization of an inorganic gold and silica nanoparticle mediated drug delivery system for nitric oxide

NASA Astrophysics Data System (ADS)

Das, Amitava; Mukherjee, Priyabrata; Singla, Sumit K.; Guturu, Praveen; Frost, Megan C.; Mukhopadhyay, Debabrata; Shah, Vijay H.; Ranjan Patra, Chitta

2010-07-01

Nitric oxide (NO) plays an important role in inhibiting the development of hepatic fibrosis and its ensuing complication of portal hypertension by inhibiting human hepatic stellate cell (HSC) activation. Here we have developed a gold nanoparticle and silica nanoparticle mediated drug delivery system containing NO donors, which could be used for potential therapeutic application in chronic liver disease. The gold nanoconjugates were characterized using several physico-chemical techniques such as UV-visible spectroscopy and transmission electron microscopy. Silica nanoconjugates were synthesized and characterized as reported previously. NO released from gold and silica nanoconjugates was quantified under physiological conditions (pH = 7.4 at 37 °C) for a substantial period of time. HSC proliferation and the vascular tube formation ability, manifestations of their activation, were significantly attenuated by the NO released from these nanoconjugates. This study indicates that gold and silica nanoparticle mediated drug delivery systems for introducing NO could be used as a strategy for the treatment of hepatic fibrosis or chronic liver diseases, by limiting HSC activation.

Gold Nanorods as Nanodevices for Bioimaging, Photothermal Therapeutics, and Drug Delivery.

PubMed

Haine, Aung Thu; Niidome, Takuro

2017-01-01

Gold nanorods are promising metals in several biomedical applications such as bioimaging, thermal therapy, and drug delivery. Gold nanorods have strong absorption bands in near-infrared (NIR) light region and show photothermal effects. Since NIR light can penetrate deeply into tissues, their unique optical, chemical, and biological properties have attracted considerable clinical interest. Gold nanorods are expected to act not only as on-demand thermal converters for photothermal therapy but also as mediators of a controlled drug-release system responding to light irradiation. In this review, we discuss current progress using gold nanorods as bioimaging platform, phototherapeutic agents, and drug delivery vehicles.

Rat model of blood-brain barrier disruption to allow targeted neurovascular therapeutics.

PubMed

Martin, Jacob A; Maris, Alexander S; Ehtesham, Moneeb; Singer, Robert J

2012-11-30

Endothelial cells with tight junctions along with the basement membrane and astrocyte end feet surround cerebral blood vessels to form the blood-brain barrier(1). The barrier selectively excludes molecules from crossing between the blood and the brain based upon their size and charge. This function can impede the delivery of therapeutics for neurological disorders. A number of chemotherapeutic drugs, for example, will not effectively cross the blood-brain barrier to reach tumor cells(2). Thus, improving the delivery of drugs across the blood-brain barrier is an area of interest. The most prevalent methods for enhancing the delivery of drugs to the brain are direct cerebral infusion and blood-brain barrier disruption(3). Direct intracerebral infusion guarantees that therapies reach the brain; however, this method has a limited ability to disperse the drug(4). Blood-brain barrier disruption (BBBD) allows drugs to flow directly from the circulatory system into the brain and thus more effectively reach dispersed tumor cells. Three methods of barrier disruption include osmotic barrier disruption, pharmacological barrier disruption, and focused ultrasound with microbubbles. Osmotic disruption, pioneered by Neuwelt, uses a hypertonic solution of 25% mannitol that dehydrates the cells of the blood-brain barrier causing them to shrink and disrupt their tight junctions. Barrier disruption can also be accomplished pharmacologically with vasoactive compounds such as histamine(5) and bradykinin(6). This method, however, is selective primarily for the brain-tumor barrier(7). Additionally, RMP-7, an analog of the peptide bradykinin, was found to be inferior when compared head-to-head with osmotic BBBD with 25% mannitol(8). Another method, focused ultrasound (FUS) in conjunction with microbubble ultrasound contrast agents, has also been shown to reversibly open the blood-brain barrier(9). In comparison to FUS, though, 25% mannitol has a longer history of safety in human patients that makes it a proven tool for translational research(10-12). In order to accomplish BBBD, mannitol must be delivered at a high rate directly into the brain's arterial circulation. In humans, an endovascular catheter is guided to the brain where rapid, direct flow can be accomplished. This protocol models human BBBD as closely as possible. Following a cut-down to the bifurcation of the common carotid artery, a catheter is inserted retrograde into the ECA and used to deliver mannitol directly into the internal carotid artery (ICA) circulation. Propofol and N2O anesthesia are used for their ability to maximize the effectiveness of barrier disruption(13). If executed properly, this procedure has the ability to safely, effectively, and reversibly open the blood-brain barrier and improve the delivery of drugs that do not ordinarily reach the brain (8,13,14).

Noninvasive Drug Delivery Using Ultrasound: Targeting Melanoma Using siRNA Against Mutant (V600E) B-Raf

NASA Astrophysics Data System (ADS)

Tran, Melissa A.; Gowda, Raghavendra; Park, Eun-Joo; Adair, James; Smith, Nadine; Kester, Mark; Robertson, Gavin P.

2009-04-01

Melanoma is the most deadly form of skin cancer. Currently early surgical removal is the best treatment option for melanoma patients with little hope of successful treatment of late stage melanoma. Clearly new treatment options must be explored. Topical administration of drugs provides the advantage of being able to apply large quantities of drug in close proximity to the tumor without the issue of systemic side effects. However, the natural barrier formed by the skin must first be overcome for topical treatment to become a viable option. With this in mind we have sought to use low-frequency ultrasound to transiently permeabilize the stratum corneum and successfully deliver liposomal siRNA to melanoma cells residing at the basement membrane. B-Raf is one of the most frequently activated genes in melanoma, making it an ideal candidate for targeting via siRNA. The novel liposomes used in this study load siRNA, protect if from the outside environment and lead to knockdown of target message. Combining ultrasound with liposomal siRNA we show that siRNA can be delivered into melanoma cells. Additionally, we show that siRNA to mutant B-Raf can effectively inhibit melanoma growth in reconstructs and in mice by 60% and 30% respectively. Therefore, ultrasound with liposomal siRNA is a potentially valuable treatment option for melanoma patients.

From nose to brain: understanding transport capacity and transport rate of drugs.

PubMed

Wu, Hongbing; Hu, Kaili; Jiang, Xinguo

2008-10-01

The unique relationship between nasal cavity and cranial cavity tissues in anatomy and physiology makes intranasal delivery to the brain feasible. An intranasal delivery provides some drugs with short channels to bypass the blood-brain barrier (BBB), especially for those with fairly low brain concentrations after a routine delivery, thus greatly enhancing the therapeutic effect on brain diseases. In the past two decades, a good number of encouraging outcomes have been reported in the treatment of diseases of the brain or central nervous system (CNS) through nasal administration. In spite of the significant merit of bypassing the BBB, direct nose-to-brain delivery still bears the problems of low efficiency and volume for capacity due to the limited volume of the nasal cavity, the small area ratio of olfactory mucosa to nasal mucosa and the limitations of low dose and short retention time of drug absorption. It is crucial that selective distribution and retention time of drugs or preparations on olfactory mucosa should be enhanced so as to increase the direct delivery efficiency. In this article, we first briefly review the nose-to-brain transport pathways, before detailing the impacts on them, followed by a comprehensive summary of effective methods, including formulation modification, agglutinant-mediated transport and a brain-homing, peptide-mediated delivery based on phage display screening technique, with a view to providing a theoretic reference for elevating the therapeutic effects on brain diseases.

Process evaluation and in vitro selectivity analysis of aptamer-drug polymeric formulation for targeted pharmaceutical delivery.

PubMed

Tan, Kei X; Lau, Sie Yon; Danquah, Michael K

2018-05-01

Targeted drug delivery is a promising strategy to promote effective delivery of conventional and emerging pharmaceuticals. The emergence of aptamers as superior targeting ligands to direct active drug molecules specifically to desired malignant cells has created new opportunities to enhance disease therapies. The application of biodegradable polymers as delivery carriers to develop aptamer-navigated drug delivery system is a promising approach to effectively deliver desired drug dosages to target cells. This study reports the development of a layer-by-layer aptamer-mediated drug delivery system (DPAP) via a w/o/w double emulsion technique homogenized by ultrasonication or magnetic stirring. Experimental results showed no significant differences in the biophysical characteristics of DPAP nanoparticles generated using the two homogenization techniques. The DPAP formulation demonstrated a strong targeting performance and selectivity towards its target receptor molecules in the presence of non-targets. The DPAP formulation demonstrated a controlled and sustained drug release profile under the conditions of pH 7 and temperature 37 °C. Also, the drug release rate of DPAP formulation was successfully accelerated under an endosomal acidic condition of ∼pH 5.5, indicating the potential to enhance drug delivery within the endosomal micro-environment. The findings from this work are useful to understanding polymer-aptamer-drug relationship and their impact on developing effective targeted delivery systems. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Novel chitosan derivative for temperature and ultrasound dual-sensitive liposomal microbubble gel.

PubMed

Chen, Daquan; Yu, Hongyun; Mu, Hongjie; Wei, Junhua; Song, Zhenkun; Shi, Hong; Liang, Rongcai; Sun, Kaoxiang; Liu, Wanhui

2013-04-15

In this study, a novel liposome-loaded microbubble gel based on N-cholesteryl hemisuccinate-O-sulfate chitosan (NCHOSC) was designed. The structure of the NCHOSC was characterized by FTIR and (1)H NMR. The liposomal microbubble gel based on NCHOSC with a high encapsulation efficiency of curcumin was formed and improved the solubility of curcumin. The diameter of most liposomal microbubble was about 950 nm. The temperature-sensitive CS/GP gel could be formulated at room temperature and would form a gel at body temperature. Simultaneously, the ultrasound-sensitive induced release of curcumin was 85% applying ultrasound. The results of cytotoxicity assay indicated that encapsulated curcumin in Cur-LM or Cur-LM-G was less toxic. The anti-tumor efficacy in vivo suggested that Cur-LM-G by ultrasound suppressed tumor growth most efficiently. These findings have shed some light on the potential NCHOSC material used to liposome-loaded microbubble gel for temperature and ultrasound dual-sensitive drug delivery. Copyright © 2013 Elsevier Ltd. All rights reserved.

Co-formulation of P-glycoprotein Substrate and Inhibitor in Nanocarriers: An Emerging Strategy for Cancer Chemotherapy.

PubMed

Saneja, Ankit; Dubey, Ravindra Dhar; Alam, Noor; Khare, Vaibhav; Gupta, Prem N

2014-01-01

Scientific community is striving to understand the role of P-glycoprotein (P-gp) in drug discovery programs due to its impact on pharmacokinetic and multi-drug resistance (MDR) of anticancer drugs. A number of efforts to resolve the crystal structure and understanding the mechanism of P-gp mediated efflux have been made. Several generations of Pgp inhibitors have been developed to tackle this multi-specific efflux protein. Unfortunately, these inhibitors lack selectivity, exhibit poor solubility and severe pharmacokinetic interactions restricting their clinical use. The nanocarrier drug delivery systems (NDDS) are receiving increasing attention for P-gp modulating activity of pharmaceutical excipients which are used in their fabrication. In addition, NDDS can enhance the solubility and exhibited ability to bypass P-gp mediated efflux. The co-formulation of P-gp inhibitors and substrate anticancer drugs in single drug delivery system offers the advantage of bypassing P-gp mediated drug efflux as well as inhibiting the P-gp. Moreover, severe pharmacokinetic interactions between P-gp inhibitor and substrate anticancer drugs could be avoided by using this strategy. In this article we describe the co-formulation strategies using nanocarriers for modulation of pharmacokinetics as well as multi-drug resistance of anticancer drugs along with the challenges in this area.

Genetically engineered nanocarriers for drug delivery.

PubMed

Shi, Pu; Gustafson, Joshua A; MacKay, J Andrew

2014-01-01

Cytotoxicity, low water solubility, rapid clearance from circulation, and off-target side-effects are common drawbacks of conventional small-molecule drugs. To overcome these shortcomings, many multifunctional nanocarriers have been proposed to enhance drug delivery. In concept, multifunctional nanoparticles might carry multiple agents, control release rate, biodegrade, and utilize target-mediated drug delivery; however, the design of these particles presents many challenges at the stage of pharmaceutical development. An emerging solution to improve control over these particles is to turn to genetic engineering. Genetically engineered nanocarriers are precisely controlled in size and structure and can provide specific control over sites for chemical attachment of drugs. Genetically engineered drug carriers that assemble nanostructures including nanoparticles and nanofibers can be polymeric or non-polymeric. This review summarizes the recent development of applications in drug and gene delivery utilizing nanostructures of polymeric genetically engineered drug carriers such as elastin-like polypeptides, silk-like polypeptides, and silk-elastin-like protein polymers, and non-polymeric genetically engineered drug carriers such as vault proteins and viral proteins.

Genetically engineered nanocarriers for drug delivery

PubMed Central

Shi, Pu; Gustafson, Joshua A; MacKay, J Andrew

2014-01-01

Cytotoxicity, low water solubility, rapid clearance from circulation, and off-target side-effects are common drawbacks of conventional small-molecule drugs. To overcome these shortcomings, many multifunctional nanocarriers have been proposed to enhance drug delivery. In concept, multifunctional nanoparticles might carry multiple agents, control release rate, biodegrade, and utilize target-mediated drug delivery; however, the design of these particles presents many challenges at the stage of pharmaceutical development. An emerging solution to improve control over these particles is to turn to genetic engineering. Genetically engineered nanocarriers are precisely controlled in size and structure and can provide specific control over sites for chemical attachment of drugs. Genetically engineered drug carriers that assemble nanostructures including nanoparticles and nanofibers can be polymeric or non-polymeric. This review summarizes the recent development of applications in drug and gene delivery utilizing nanostructures of polymeric genetically engineered drug carriers such as elastin-like polypeptides, silk-like polypeptides, and silk-elastin-like protein polymers, and non-polymeric genetically engineered drug carriers such as vault proteins and viral proteins. PMID:24741309

Drug Delivery to the Brain by Focused Ultrasound Induced Blood-Brain Barrier Disruption: Quantitative Evaluation of Enhanced Permeability of Cerebral Vasculature Using Two-Photon Microscopy

PubMed Central

Nhan, Tam; Burgess, Alison; Cho, Eunice E.; Stefanovic, Bojana; Lilge, Lothar; Hynynen, Kullervo

2013-01-01

Reversible and localized blood-brain barrier disruption (BBBD) using focused ultrasound (FUS) in combination with intravascularly administered microbubbles (MBs) has been established as a non-invasive method for drug delivery to the brain. Using two-photon fluorescence microscopy (2PFM), we imaged the cerebral vasculature during BBBD and observed the extravasation of fluorescent dye in real-time in vivo. We measured the enhanced permeability upon BBBD for both 10kDa and 70kDa dextran conjugated Texas Red (TR) at the acoustic pressure range of 0.2-0.8 MPa and found permeability constants of TR10kDa and TR70kDa vary from 0.0006 to 0.0359 min−1 and 0.0003 to 0.0231 min−1, respectively. For both substances, a linear regression was applied on the permeability constant against the acoustic pressure and the slope from best-fit was found to be 0.039±0.005 min−1/MPa and 0.018±0.005 min−1/MPa, respectively. In addition, the pressure threshold for successfully induced BBBD was confirmed to be 0.4-0.6 MPa. Finally, we identified two types of leakage kinetics (fast and slow) that exhibit distinct permeability constants and temporal disruption onsets, as well as demonstrated their correlations with the applied acoustic pressure and vessel diameter. Direct assessment of vascular permeability and insights on its dependency on acoustic pressure, vessel size and leakage kinetics are important for treatment strategies of BBBD-based drug delivery. PMID:24008151

Aptamer-conjugated and drug-loaded acoustic droplets for ultrasound theranosis.

PubMed

Wang, Chung-Hsin; Kang, Shih-Tsung; Lee, Ya-Hsuan; Luo, Yun-Ling; Huang, Yu-Fen; Yeh, Chih-Kuang

2012-02-01

Tumor therapy requires multi-functional treatment strategies with specific targeting of therapeutics to reduce general toxicity and increase efficacy. In this study we fabricated and functionally tested aptamer-conjugated and doxorubicin (DOX)-loaded acoustic droplets comprising cores of liquid perfluoropentane compound and lipid-based shell materials. Conjugation of sgc8c aptamers provided the ability to specifically target CCRF-CEM cells for both imaging and therapy. High-intensity focused ultrasound (HIFU) was introduced to trigger targeted acoustic droplet vaporization (ADV) which resulted in both mechanical cancer cell destruction by inertial cavitation and chemical treatment through localized drug release. HIFU insonation showed a 56.8% decrease in cell viability with aptamer-conjugated droplets, representing a 4.5-fold increase in comparison to non-conjugated droplets. In addition, the fully-vaporized droplets resulted in the highest DOX uptake by cancer cells, compared to non-vaporized or partially vaporized droplets. Optical studies clearly illustrated the transient changes that occurred upon ADV of droplet-targeted CEM cells, and B-mode ultrasound imaging revealed contrast enhancement by ADV in ultrasound images. In conclusion, our fabricated droplets functioned as a hybrid chemical and mechanical strategy for the specific destruction of cancer cells upon ultrasound-mediated ADV, while simultaneously providing ultrasound imaging capability. Copyright © 2011 Elsevier Ltd. All rights reserved.

Liposomes and nanotechnology in drug development: focus on ocular targets

PubMed Central

Honda, Miki; Asai, Tomohiro; Oku, Naoto; Araki, Yoshihiko; Tanaka, Minoru; Ebihara, Nobuyuki

2013-01-01

Poor drug delivery to lesions in patients’ eyes is a major obstacle to the treatment of ocular diseases. The accessibility of these areas to drugs is highly restricted by the presence of barriers, including the corneal barrier, aqueous barrier, and the inner and outer blood–retinal barriers. In particular, the posterior segment is difficult to reach for drugs because of its structural peculiarities. This review discusses various barriers to drug delivery and provides comprehensive information for designing nanoparticle-mediated drug delivery systems for the treatment of ocular diseases. Nanoparticles can be designed to improve penetration, controlled release, and drug targeting. As highlighted in this review, the therapeutic efficacy of drugs in ocular diseases has been reported to be enhanced by the use of nanoparticles such as liposomes, micro/nanospheres, microemulsions, and dendrimers. Our recent data show that intravitreal injection of targeted liposomes encapsulating an angiogenesis inhibitor caused significantly greater suppression of choroidal neovascularization than did the injection of free drug. Recent progress in ocular drug delivery systems research has provided new insights into drug development, and the use of nanoparticles for drug delivery is thus a promising approach for advanced therapy of ocular diseases. PMID:23439842

Using exosomes, naturally-equipped nanocarriers, for drug delivery.

PubMed

Batrakova, Elena V; Kim, Myung Soo

2015-12-10

Exosomes offer distinct advantages that uniquely position them as highly effective drug carriers. Comprised of cellular membranes with multiple adhesive proteins on their surface, exosomes are known to specialize in cell-cell communications and provide an exclusive approach for the delivery of various therapeutic agents to target cells. In addition, exosomes can be amended through their parental cells to express a targeting moiety on their surface, or supplemented with desired biological activity. Development and validation of exosome-based drug delivery systems are the focus of this review. Different techniques of exosome isolation, characterization, drug loading, and applications in experimental disease models and clinic are discussed. Exosome-based drug formulations may be applied to a wide variety of disorders such as cancer, various infectious, cardiovascular, and neurodegenerative disorders. Overall, exosomes combine benefits of both synthetic nanocarriers and cell-mediated drug delivery systems while avoiding their limitations. Published by Elsevier B.V.

Sonoporation at Small and Large Length Scales: Effect of Cavitation Bubble Collapse on Membranes.

PubMed

Fu, Haohao; Comer, Jeffrey; Cai, Wensheng; Chipot, Christophe

2015-02-05

Ultrasound has emerged as a promising means to effect controlled delivery of therapeutic agents through cell membranes. One possible mechanism that explains the enhanced permeability of lipid bilayers is the fast contraction of cavitation bubbles produced on the membrane surface, thereby generating large impulses, which, in turn, enhance the permeability of the bilayer to small molecules. In the present contribution, we investigate the collapse of bubbles of different diameters, using atomistic and coarse-grained molecular dynamics simulations to calculate the force exerted on the membrane. The total impulse can be computed rigorously in numerical simulations, revealing a superlinear dependence of the impulse on the radius of the bubble. The collapse affects the structure of a nearby immobilized membrane, and leads to partial membrane invagination and increased water permeation. The results of the present study are envisioned to help optimize the use of ultrasound, notably for the delivery of drugs.

Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance in vitro.

PubMed

Khdair, Ayman; Handa, Hitesh; Mao, Guangzhao; Panyam, Jayanth

2009-02-01

Drug resistance limits the success of many anticancer drugs. Reduced accumulation of the drug at its intracellular site of action because of overexpression of efflux transporters such as P-glycoprotein (P-gp) is a major mechanism of drug resistance. In this study, we investigated whether photodynamic therapy (PDT) using methylene blue, also a P-gp inhibitor, can be used to enhance doxorubicin-induced cytotoxicity in drug-resistant tumor cells. Aerosol OT (AOT)-alginate nanoparticles were used as a carrier for the simultaneous cellular delivery of doxorubicin and methylene blue. Methylene blue was photoactivated using light of 665 nm wavelength. Induction of apoptosis and necrosis following treatment with combination chemotherapy and PDT was investigated in drug-resistant NCI/ADR-RES cells using flow cytometry and fluorescence microscopy. Effect of encapsulation in nanoparticles on the intracellular accumulation of doxorubicin and methylene blue was investigated qualitatively using fluorescence microscopy and was quantitated using HPLC. Encapsulation in AOT-alginate nanoparticles significantly enhanced the cytotoxicity of combination therapy in resistant tumor cells. Nanoparticle-mediated combination therapy resulted in a significant induction of both apoptosis and necrosis. Improvement in cytotoxicity could be correlated with enhanced intracellular and nuclear delivery of the two drugs. Further, nanoparticle-mediated combination therapy resulted in significantly elevated reactive oxygen species (ROS) production compared to single drug treatment. In conclusion, nanoparticle-mediated combination chemotherapy and PDT using doxorubicin and methylene blue was able to overcome resistance mechanisms and resulted in improved cytotoxicity in drug-resistant tumor cells.

MSN anti-cancer nanomedicines: chemotherapy enhancement, overcoming of drug resistance, and metastasis inhibition.

PubMed

He, Qianjun; Shi, Jianlin

2014-01-22

In the anti-cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti-cancer drugs to normal tissues due to the lack of tumor-selectivity, the multi-drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state-of-art nanomedicines based on mesoporous silica nanoparticles (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti-cancer strategy, this review highlights the most recent advances of MSN anti-cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs-based anti-cancer nanomedicines, and propose several innovative and forward-looking anti-cancer strategies, including tumor tissue-cell-nuclear successionally targeted drug delivery strategy, tumor cell-selective nuclear-targeted drug delivery strategy, multi-targeting and multi-drug strategy, chemo-/radio-/photodynamic-/ultrasound-/thermo-combined multi-modal therapy by virtue of functionalized hollow/rattle-structured MSNs. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effect of lipophilicity on microneedle-mediated iontophoretic transdermal delivery across human skin in vitro.

PubMed

Pawar, Kasturi R; Smith, Forrest; Kolli, Chandra Sekhar; Babu, R Jayachandra

2013-10-01

The effect of lipophilicity of drug on the microneedle (MN)-mediated iontophoretic delivery across dermatomed human skin was studied. Beta blockers with similar pKa but varied log P values were selected as model drugs in this study. Iontophoresis (ITP) or MNs, when used independently, increased the transdermal flux of beta blockers as compared with passive delivery (PD). ITP across the MN-treated skin (MN + ITP) increased the permeation rate of all beta blockers as compared with PD (p < 0.001). The enhancement ratios (ER) for hydrophilic molecules (atenolol and sotalol) were 71- and 78-fold higher for ITP + MN as compared with PD. However, for lipophilic molecule such as propranolol, there was 10-fold increase in the ER as compared with PD. These observations were further substantiated by the skin retention data; an inverse relationship between the skin retention and the hydrophilicity of the drug was observed. The results in the present study point out that the lipophilicity of the molecule plays a significant role on the electrically assisted transdermal delivery of drugs across the microporated skin. Using the combination of ITP + MN, hydrophilic drugs (atenolol and sotalol) were delivered at a much higher rate as compared with lipophilic molecules (propranolol and acebutolol). © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Exosomes: Nanoparticulate tools for RNA interference and drug delivery.

PubMed

Shahabipour, Fahimeh; Barati, Nastaran; Johnston, Thomas P; Derosa, Giuseppe; Maffioli, Pamela; Sahebkar, Amirhossein

2017-07-01

Exosomes are naturally occurring extracellular vesicles released by most mammalian cells in all body fluids. Exosomes are known as key mediators in cell-cell communication and facilitate the transfer of genetic and biochemical information between distant cells. Structurally, exosomes are composed of lipids, proteins, and also several types of RNAs which enable these vesicles to serve as important disease biomarkers. Moreover, exosomes have emerged as novel drug and gene delivery tools owing to their multiple advantages over conventional delivery systems. Recently, increasing attention has been focused on exosomes for the delivery of drugs, including therapeutic recombinant proteins, to various target tissues. Exosomes are also promising vehicles for the delivery of microRNAs and small interfering RNAs, which is usually hampered by rapid degradation of these RNAs, as well as inefficient tissue specificity of currently available delivery strategies. This review highlights the most recent accomplishments and trends in the use of exosomes for the delivery of drugs and therapeutic RNA molecules. © 2017 Wiley Periodicals, Inc.

Focused ultrasound facilitated thermo-chemotherapy for targeted retinoblastoma treatment: a modeling study.

PubMed

Wang, Shutao; Mahesh, Sankaranarayana P; Liu, Ji; Geist, Craig; Zderic, Vesna

2012-07-01

Retinoblastoma is the most common type of intraocular tumors in children. Currently, with early detection and improved systemic chemo-adjuvant therapies, treatment paradigm has shifted from survival to globe salvation/vision preservation. The objective of our work has been to explore the possible application of focused ultrasound (FUS) for targeted drug delivery in the posterior pole retinoblastoma. Specifically, theoretical models were implemented to evaluate the feasibility of using FUS to generate localized hyperthermia in retinal tumor areas, for potential triggering the chemotherapeutic agent deployment from heat-sensitive drug carriers. In-vitro experiments were conducted in tissue-mimicking phantoms with embedded excised rabbit eyes to validate the reliability of the modeling results. After confirming the reliability of our model, various FUS transducer parameters were investigated to induce maximal hyperthermia coverage in the tumor, while sparing adjacent eye structures (e.g. the lens). The evaluated FUS parameters included operating frequency, total acoustic power, geometric dimensions, transducer f-number, standoff distance, as well as different pulsing scenarios. Our modeling results suggest that the most suitable ultrasound frequency for this type of treatments was in the range of 2-3.5 MHz depending on the size of retinoblastoma. Appropriate transducer f-number (close to 1) and standoff distance could be selected to minimize the risks of over-heating undesired regions. With the total acoustic power of 0.4 W, 56.3% of the tumor was heated to hyperthermic temperature range (39-44 °C) while the temperature in lens was maintained below 41 °C. In conclusion, FUS-induced hyperthermia for targeted drug delivery may be a viable option in treatments of juxta-foveal or posterior pole retinoblastomas. Future in-vivo studies will allow us to determine the effectiveness and safety of the proposed approach. Copyright © 2012 Elsevier Ltd. All rights reserved.

Stent-mediated gene and drug delivery for cardiovascular disease and cancer: A brief insight.

PubMed

Krishnagopal, Akshaya; Reddy, Aakash; Sen, Dwaipayan

2017-05-01

This review concisely recapitulates the different existing modes of stent-mediated gene/drug delivery, their considerable advancement in clinical trials and a rationale for other merging new technologies such as nanotechnology and microRNA-based therapeutics, in addition to addressing the limitations in each of these perpetual stent platforms. Over the past decade, stent-mediated gene/drug delivery has materialized as a hopeful alternative for cardiovascular disease and cancer in contrast to routine conventional treatment modalities. Regardless of the phenomenal recent developments achieved by coronary interventions and cancer therapies that employ gene and drug-eluting stents, practical hurdles still remain a challenge. The present review highlights the limitations that each of the existing stent-based gene/drug delivery system encompasses and therefore provides a vision for the future with respect to discovering an ideal stent therapeutic platform that would circumvent all the practical hurdles witnessed with the existing technology. Further study of the improvisation of next-generation drug-eluting stents has helped to overcome the issue of restenosis to some extent. However, current stent formulations fall short of the anticipated clinically meaningful outcomes and there is an explicit need for more randomized trials aiming to further evaluate stent platforms in favour of enhanced safety and clinical value. Gene-eluting stents may hold promise in contributing new ideas for stent-based prevention of in-stent restenosis through genetic interventions by capitalizing on a wide variety of molecular targets. Therefore, the central consideration directs us toward finding an ideal stent therapeutic platform that would tackle all of the gaps in the existing technology. Copyright © 2017 John Wiley & Sons, Ltd.

Phase Transitions of Nanoemulsions Using Ultrasound: Experimental Observations

PubMed Central

Singh, Ram; Husseini, Ghaleb A.; Pitt, William G.

2012-01-01

The ultrasound-induced transformation of perfluorocarbon liquids to gases is of interest in the area of drug and gene delivery. In this study, three independent parameters (temperature, size, and perfluorocarbon species) were selected to investigate the effects of 476-kHz and 20-kHz ultrasound on nanoemulsion phase transition. Two levels of each factor (low and high) were considered at each frequency. The acoustic intensities at gas bubble formation and at the onset of inertial cavitation were recorded and subsequently correlated with the acoustic parameters. Experimental data showed that low frequencies are more effective in forming and collapsing a bubble. Additionally, as the size of the emulsion droplet increased, the intensity required for bubble formation decreased. As expected, perfluorohexane emulsions require greater intensity to form cavitating bubbles than perfluoropentane emulsions. PMID:22444691

Acid-mediated Lipinski's second rule: application to drug design and targeting in cancer.

PubMed

Omran, Ziad; Rauch, Cyril

2014-05-01

With a predicted 382.4 per 100,000 people expected to suffer from some form of malignant neoplasm by 2015, and a current death toll of 1 out of 8 deaths worldwide, improving treatment and/or drug design is an essential focus of cancer research. Multi-drug resistance is the leading cause of chemotherapeutic failure, and delivery of anticancer drugs to the inside of cancerous cells is another major challenge. Fifteen years ago, in a completely different field in which improving drug delivery is the objective, the bioavailability of oral compounds, Christopher Lipinski formulated some rules that are still used by the pharmaceutical industry as rules of thumb to improve drug delivery to their target. Although Lipinski's rules were not formulated to improve delivery of antineoplastic drugs to the inside of cancer cells, it is interesting to note that the problems are similar. On the basis of the strong similarity between the fields, we discuss how they can be connected and how new drug targets can be defined in cancer.

Recent advances in galactose-engineered nanocarriers for the site-specific delivery of siRNA and anticancer drugs.

PubMed

Jain, Ashay; Jain, Atul; Parajuli, Prahlad; Mishra, Vijay; Ghoshal, Gargi; Singh, Bhupinder; Shivhare, Uma Shankar; Katare, Om Prakash; Kesharwani, Prashant

2018-05-01

Galactosylated nanocarriers have recently emerged as viable and versatile tools to deliver drugs at an optimal rate specifically to their target tissues or cells, thus maximizing their therapeutic benefits while circumventing off-target effects. The abundance of lectin receptors on cell surfaces makes the galactosylated carriers suitable for the targeted delivery of bioactives. Additionally, tethering of galactose (GAL) to various carriers, including micelles, liposomes, and nanoparticles (NPs), might also be appropriate for drug delivery. Here, we review recent advances in the development of galactosylated nanocarriers for active tumor targeting. We also provide a brief overview of the targeting mechanisms and cell receptor theory involved in the ligand-receptor-mediated delivery of drug carriers. Copyright © 2017 Elsevier Ltd. All rights reserved.

Understanding causal pathways within health systems policy evaluation through mediation analysis: an application to payment for performance (P4P) in Tanzania.

PubMed

Anselmi, Laura; Binyaruka, Peter; Borghi, Josephine

2017-02-02

The evaluation of payment for performance (P4P) programmes has focused mainly on understanding contributions to health service coverage, without unpacking causal mechanisms. The overall aim of the paper is to test the causal pathways through which P4P schemes may (or may not) influence maternal care outcomes. We used data from an evaluation of a P4P programme in Tanzania. Data were collected from a sample of 3000 women who delivered in the 12 months prior to interview and 200 health workers at 150 health facilities from seven intervention and four comparison districts in Tanzania in January 2012 and in February 2013. We applied causal mediation analysis using a linear structural equation model to identify direct and indirect effects of P4P on institutional delivery rates and on the uptake of two doses of an antimalarial drug during pregnancy. We first ran a series of linear difference-in-difference regression models to test the effect of P4P on potential mediators, which we then included in a linear difference-in-difference model evaluating the impact of P4P on the outcome. We tested the robustness of our results to unmeasured confounding using semi-parametric methods. P4P reduced the probability of women paying for delivery care (-4.5 percentage points) which mediates the total effect of P4P on institutional deliveries (by 48%) and on deliveries in a public health facility (by 78%). P4P reduced the stock-out rate for some essential drugs, specifically oxytocin (-36 percentage points), which mediated the total effect of P4P on institutional deliveries (by 22%) and deliveries in a public health facility (by 30%). P4P increased kindness at delivery (5 percentage points), which mediated the effect of P4P on institutional deliveries (by 48%) and on deliveries in a public health facility (by 49%). P4P increased the likelihood of supervision visits taking place within the last 90 days (18 percentage points), which mediated 15% of the total P4P effect on the uptake of two antimalarial doses during antenatal care (IPT2). Kindness during deliveries and the probability of paying out of pocket for delivery care were the mediators most robust to unmeasured confounding. The effect of P4P on institutional deliveries is mediated by financing and human resources factors, while uptake of antimalarials in pregnancy is mediated by governance factors. Further research is required to explore additional and more complex causal pathways.

Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer.

PubMed

Ota, Shinichi; Geschwind, Jean-Francois H; Buijs, Manon; Wijlemans, Joost W; Kwak, Byung Kook; Ganapathy-Kanniappan, Shanmugasundaram

2013-06-01

Studies in animal models of cancer have demonstrated that targeting tumor metabolism can be an effective anticancer strategy. Previously, we showed that inhibition of glucose metabolism by the pyruvate analog, 3-bromopyruvate (3-BrPA), induces anticancer effects both in vitro and in vivo. We have also documented that intratumoral delivery of 3-BrPA affects tumor growth in a subcutaneous tumor model of human liver cancer. However, the efficacy of such an approach in a clinically relevant orthotopic tumor model has not been reported. Here, we investigated the feasibility of ultrasound (US) image-guided delivery of 3-BrPA in an orthotopic mouse model of human pancreatic cancer and evaluated its therapeutic efficacy. In vitro, treatment of Panc-1 cells with 3-BrPA resulted in a dose-dependent decrease in cell viability. The loss of viability correlated with a dose-dependent decrease in the intracellular ATP level and lactate production confirming that disruption of energy metabolism underlies these 3-BrPA-mediated effects. In vivo, US-guided delivery of 3-BrPA was feasible and effective as demonstrated by a marked decrease in tumor size on imaging. Further, the antitumor effect was confirmed by (1) a decrease in the proliferative potential by Ki-67 immunohistochemical staining and (2) the induction of apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphospate nick end labeling staining. We therefore demonstrate the technical feasibility of US-guided intratumoral injection of 3-BrPA in a mouse model of human pancreatic cancer as well as its therapeutic efficacy. Our data suggest that this new therapeutic approach consisting of a direct intratumoral injection of antiglycolytic agents may represent an exciting opportunity to treat patients with pancreas cancer.

The Endoplasmic Reticulum Stress Protein Calreticulin in Diabetic Chronic Kidney Disease

DTIC Science & Technology

2016-07-01

AWARD NUMBER: W81XWH-14-1-0203 TITLE: The Endoplasmic Reticulum Stress Protein Calreticulin in Diabetic Chronic Kidney Disease PRINCIPAL...1 July 2015- 30 June 2016 4. TITLE AND SUBTITLE The Endoplasmic Reticulum Stress Protein Calreticulin in Diabetic Chronic Kidney Disease 5a... kidney targeted microbubble/ultrasound-mediated plasmid delivery. We will also examine non-targeted CRT knockdown in these mice. Aim 2.b: We will

Pulsed magnetic field induced fast drug release from magneto liposomes via ultrasound generation.

PubMed

Podaru, George; Ogden, Saralyn; Baxter, Amanda; Shrestha, Tej; Ren, Shenqiang; Thapa, Prem; Dani, Raj Kumar; Wang, Hongwang; Basel, Matthew T; Prakash, Punit; Bossmann, Stefan H; Chikan, Viktor

2014-10-09

Fast drug delivery is very important to utilize drug molecules that are short-lived under physiological conditions. Techniques that can release model molecules under physiological conditions could play an important role to discover the pharmacokinetics of short-lived substances in the body. Here an experimental method is developed for the fast release of the liposomes' payload without a significant increase in (local) temperatures. This goal is achieved by using short magnetic pulses to disrupt the lipid bilayer of liposomes loaded with magnetic nanoparticles. The drug release has been tested by two independent assays. The first assay relies on the AC impedance measurements of MgSO4 released from the magnetic liposomes. The second standard release assay is based on the increase of the fluorescence signal from 5(6)-carboxyfluorescein dye when the dye is released from the magneto liposomes. The efficiency of drug release ranges from a few percent to up to 40% in the case of the MgSO4. The experiments also indicate that the magnetic nanoparticles generate ultrasound, which is assumed to have a role in the release of the model drugs from the magneto liposomes.

Initial observations of cell-mediated drug delivery to the deep lung.

PubMed

Kumar, Arun; Glaum, Mark; El-Badri, Nagwa; Mohapatra, Shyam; Haller, Edward; Park, Seungjoo; Patrick, Leslie; Nattkemper, Leigh; Vo, Dawn; Cameron, Don F

2011-01-01

Using current methodologies, drug delivery to small airways, terminal bronchioles, and alveoli (deep lung) is inefficient, especially to the lower lungs. Urgent lung pathologies such as acute respiratory distress syndrome (ARDS) and post-lung transplantation complications are difficult to treat, in part due to the methodological limitations in targeting the deep lung with high efficiency drug distribution to the site of pathology. To overcome drug delivery limitations inhibiting the optimization of deep lung therapy, isolated rat Sertoli cells preloaded with chitosan nanoparticles were use to obtain a high-density distribution and concentration (92%) of the nanoparticles in the lungs of mice by way of the peripheral venous vasculature rather than the more commonly used pulmonary route. Additionally, Sertoli cells were preloaded with chitosan nanoparticles coupled with the anti-inflammatory compound curcumin and then injected intravenously into control or experimental mice with deep lung inflammation. By 24 h postinjection, most of the curcumin load (∼90%) delivered in the injected Sertoli cells was present and distributed throughout the lungs, including the perialveloar sac area in the lower lungs. This was based on the high-density, positive quantification of both nanoparticles and curcumin in the lungs. There was a marked positive therapeutic effect achieved 24 h following curcumin treatment delivered by this Sertoli cell nanoparticle protocol (SNAP). Results identify a novel and efficient protocol for targeted delivery of drugs to the deep lung mediated by extratesticular Sertoli cells. Utilization of SNAP delivery may optimize drug therapy for conditions such as ARDS, status asthmaticus, pulmonary hypertension, lung cancer, and complications following lung transplantation where the use of high concentrations of anti-inflammatory drugs is desirable, but often limited by risks of systemic drug toxicity.

Folate-conjugated boron nitride nanospheres for targeted delivery of anticancer drugs

PubMed Central

Feng, Shini; Zhang, Huijie; Yan, Ting; Huang, Dandi; Zhi, Chunyi; Nakanishi, Hideki; Gao, Xiao-Dong

2016-01-01

With its unique physical and chemical properties and structural similarity to carbon, boron nitride (BN) has attracted considerable attention and found many applications. Biomedical applications of BN have recently started to emerge, raising great hopes in drug and gene delivery. Here, we developed a targeted anticancer drug delivery system based on folate-conjugated BN nanospheres (BNNS) with receptor-mediated targeting. Folic acid (FA) was successfully grafted onto BNNS via esterification reaction. In vitro cytotoxicity assay showed that BNNS-FA complexes were non-toxic to HeLa cells up to a concentration of 100 μg/mL. Then, doxorubicin hydrochloride (DOX), a commonly used anticancer drug, was loaded onto BNNS-FA complexes. BNNS-FA/DOX complexes were stable at pH 7.4 but effectively released DOX at pH 5.0, which exhibited a pH sensitive and sustained release pattern. BNNS-FA/DOX complexes could be recognized and specifically internalized by HeLa cells via FA receptor-mediated endocytosis. BNNS-FA/DOX complexes exhibited greater cytotoxicity to HeLa cells than free DOX and BNNS/DOX complexes due to the increased cellular uptake of DOX mediated by the FA receptor. Therefore, BNNS-FA complexes had strong potential for targeted cancer therapy. PMID:27695318

Polysaccharide-based Noncovalent Assembly for Targeted Delivery of Taxol

NASA Astrophysics Data System (ADS)

Yang, Yang; Zhang, Ying-Ming; Chen, Yong; Chen, Jia-Tong; Liu, Yu

2016-01-01

The construction of synthetic straightforward, biocompatible and biodegradable targeted drug delivery system with fluorescent tracking abilities, high anticancer activities and low side effects is still a challenge in the field of biochemistry and material chemistry. In this work, we constructed targeted paclitaxel (Taxol) delivery nanoparticles composed of permethyl-β-cyclodextrin modified hyaluronic acid (HApCD) and porphyrin modified paclitaxel prodrug (PorTaxol), through host-guest and amphiphilic interactions. The obtained nanoparticles (HATXP) were biocompatible and enzymatic biodegradable due to their hydrophilic hyaluronic acid (HA) shell and hydrophobic Taxol core, and exhibited specific targeting internalization into cancer cells via HA receptor mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities to, but much lower side effects than commercial anticancer drug Taxol. The present work would provide a platform for targeted paclitaxel drug delivery and a general protocol for the design of advanced multifunctional nanoscale biomaterials for targeted drug/gene delivery.

Biological Functionalization of Drug Delivery Carriers to Bypass Size Restrictions of Receptor-Mediated Endocytosis Independently from Receptor Targeting

PubMed Central

Ansar, Maria; Serrano, Daniel; Papademetriou, Iason; Bhowmick, Tridib Kumar; Muro, Silvia

2014-01-01

Targeting of drug carriers to cell-surface receptors involved in endocytosis is commonly used for intracellular drug delivery. However, most endocytic receptors mediate uptake via clathrin or caveolar pathways associated with ≤200-nm vesicles, restricting carrier design. We recently showed that endocytosis mediated by intercellular adhesion molecule 1 (ICAM-1), which differs from clathrin- and caveolar-mediated pathways, allows uptake of nano- and micro-carriers in cell culture and in vivo due to recruitment of cellular sphingomyelinases to the plasmalemma. This leads to ceramide generation at carrier binding sites and formation of actin stress-fibers, enabling engulfment and uptake of a wide size-range of carriers. Here we adapted this paradigm to enhance uptake of drug carriers targeted to receptors associated with size-restricted pathways. We coated sphingomyelinase onto model (polystyrene) submicro- and micro-carriers targeted to clathrin-associated mannose-6-phosphate receptor. In endothelial cells, this provided ceramide enrichment at the cell surface and actin stress-fiber formation, modifying the uptake pathway and enhancing carrier endocytosis without affecting targeting, endosomal transport, cell-associated degradation, or cell viability. This improvement depended on the carrier size and enzyme dose, and similar results were observed for other receptors (transferrin receptor) and cell types (epithelial cells). This phenomenon also enhanced tissue accumulation of carriers after intravenous injection in mice. Hence, it is possible to maintain targeting toward a selected receptor while bypassing natural size-restrictions of its associated endocytic route by functionalization of drug carriers with biological elements mimicking the ICAM-1 pathway. This strategy holds considerable promise to enhance flexibility of design of targeted drug delivery systems. PMID:24237309

Biological functionalization of drug delivery carriers to bypass size restrictions of receptor-mediated endocytosis independently from receptor targeting.

PubMed

Ansar, Maria; Serrano, Daniel; Papademetriou, Iason; Bhowmick, Tridib Kumar; Muro, Silvia

2013-12-23

Targeting of drug carriers to cell-surface receptors involved in endocytosis is commonly used for intracellular drug delivery. However, most endocytic receptors mediate uptake via clathrin or caveolar pathways associated with ≤200-nm vesicles, restricting carrier design. We recently showed that endocytosis mediated by intercellular adhesion molecule 1 (ICAM-1), which differs from clathrin- and caveolae-mediated pathways, allows uptake of nano- and microcarriers in cell culture and in vivo due to recruitment of cellular sphingomyelinases to the plasmalemma. This leads to ceramide generation at carrier binding sites and formation of actin stress-fibers, enabling engulfment and uptake of a wide size-range of carriers. Here we adapted this paradigm to enhance uptake of drug carriers targeted to receptors associated with size-restricted pathways. We coated sphingomyelinase onto model (polystyrene) submicro- and microcarriers targeted to clathrin-associated mannose-6-phosphate receptor. In endothelial cells, this provided ceramide enrichment at the cell surface and actin stress-fiber formation, modifying the uptake pathway and enhancing carrier endocytosis without affecting targeting, endosomal transport, cell-associated degradation, or cell viability. This improvement depended on the carrier size and enzyme dose, and similar results were observed for other receptors (transferrin receptor) and cell types (epithelial cells). This phenomenon also enhanced tissue accumulation of carriers after intravenous injection in mice. Hence, it is possible to maintain targeting toward a selected receptor while bypassing natural size restrictions of its associated endocytic route by functionalization of drug carriers with biological elements mimicking the ICAM-1 pathway. This strategy holds considerable promise to enhance flexibility of design of targeted drug delivery systems.

Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells.

PubMed

Saari, Heikki; Lázaro-Ibáñez, Elisa; Viitala, Tapani; Vuorimaa-Laukkanen, Elina; Siljander, Pia; Yliperttula, Marjo

2015-12-28

Extracellular vesicles (EVs) are naturally occurring membrane particles that mediate intercellular communication by delivering molecular information between cells. In this study, we investigated the effectiveness of two different populations of EVs (microvesicle- and exosome-enriched) as carriers of Paclitaxel to autologous prostate cancer cells. EVs were isolated from LNCaP- and PC-3 prostate cancer cell cultures using differential centrifugation and characterized by electron microscopy, nanoparticle tracking analysis, and Western blot. The uptake of microvesicles and exosomes by the autologous prostate cancer cells was assessed by flow cytometry and confocal microscopy. The EVs were loaded with Paclitaxel and the effectiveness of EV-mediated drug delivery was assessed with viability assays. The distribution of EVs and EV-delivered Paclitaxel in cells was inspected by confocal microscopy. Our main finding was that the loading of Paclitaxel to autologous prostate cancer cell-derived EVs increased its cytotoxic effect. This capacity was independent of the EV population and the cell line tested. Although the EVs without the drug increased cancer cell viability, the net effect of enhanced cytotoxicity remained. Both EV populations delivered Paclitaxel to the recipient cells through endocytosis, leading to the release of the drug from within the cells. The removal of EV surface proteins did not affect exosomes, while the drug delivery mediated by microvesicles was partially inhibited. Cancer cell-derived EVs can be used as effective carriers of Paclitaxel to their parental cells, bringing the drug into the cells through an endocytic pathway and increasing its cytotoxicity. However, due to the increased cell viability, the use of cancer cell-derived EVs must be further investigated before any clinical applications can be designed. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Tumor-penetrating codelivery of siRNA and paclitaxel with ultrasound-responsive nanobubbles hetero-assembled from polymeric micelles and liposomes.

PubMed

Yin, Tinghui; Wang, Ping; Li, Jingguo; Wang, Yiru; Zheng, Bowen; Zheng, Rongqin; Cheng, Du; Shuai, Xintao

2014-07-01

Drug resistance is a big problem in systemic chemotherapy of hepatocellular carcinoma (HCC), and nanomedicines loaded with both chemotherapeutic agents (e.g. paclitaxel, PTX) and siRNA's targeting antiapoptosis genes (e.g. BCL-2) possess the advantages to simultaneously overcome the efflux pump-mediated drug resistance and antiapoptosis-related drug resistance. However, tumor-penetrating drug delivery with this type of nanomedicines is extremely difficult due to their relatively big size compared to the single drug-loaded nanomedicines. Aiming at address this problem, US-responsive nanobubbles encapsulating both anti-cancer drug paclitaxel (PTX) and siRNA (PTX-NBs/siRNA) for HCC treatment were developed by hetero-assembly of polymeric micelles and liposomes in the present study. Utilizing an external low-frequency US force imposed to the tumor site, effective tumor-penetrating codelivery of siRNA and PTX was achieved via tail vein injection of PTX-NBs/siRNA into nude mice bearing human HepG2 xerografts. Consequently, the PTX treatment-inducible antiapoptosis in HepG2 cells was effectively suppressed by the codelivered siRNA targeting an antiapoptosis gene (BCL-2 siRNA) during chemotherapy. Owing to the synergistic anti-cancer effect of two therapeutic agents, tumor growth was completely inhibited using low-dose PTX in animal study. Our results highlight the great potential of this type of US-responsive hetero-assemblies carrying both anti-cancer drug and siRNA as an effective nanomedicinal system for HCC therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Steering Microbubbles in Physiologically Realistic Flows Using the Bjerknes Force

NASA Astrophysics Data System (ADS)

Clark, Alicia; Aliseda, Alberto

2017-11-01

Ultrasound contrast agents (UCAs) are lipid-coated microbubbles that are used to increase contrast in ultrasound imaging due to their ability to scatter sound. Additionally, UCAs can be used in conjunction with ultrasound in medical applications such as targeted drug delivery and thrombolysis. These applications utilize the Bjerknes force, an ultrasound-induced force caused by the phase difference between the incoming ultrasound pressure wave and the microbubble volume oscillations. The dynamics of microbubbles under ultrasound excitation have been studied thoroughly in stagnant fluid baths; however, understanding of the fundamental physics of microbubbles in physiologically realistic flows is lacking. An in vitroexperiment that reproduces the dynamics (Reynolds and Womersley numbers) of a medium-sized blood vessel was used to explore the behavior of microbubbles. Using Lagrangian tracking, the trajectory of each individual bubble was reconstructed using information obtained from high speed imaging. The balance of hydrodynamic forces (lift, drag, added mass, etc.) against the primary Bjerknes force was analyzed. The results show that an increase in ultrasound pulse repetition frequency leads to a linear increase in the Bjerknes force and the increase in the force is quadratic with the amplitude of the excitation.

pH-Sensitive stimulus-responsive nanocarriers for targeted delivery of therapeutic agents

PubMed Central

Karimi, Mahdi; Eslami, Masoud; Sahandi-Zangabad, Parham; Mirab, Fereshteh; Farajisafiloo, Negar; Shafaei, Zahra; Ghosh, Deepanjan; Bozorgomid, Mahnaz; Dashkhaneh, Fariba; Hamblin, Michael R.

2016-01-01

In recent years miscellaneous smart micro/nanosystems that respond to various exogenous/endogenous stimuli including temperature, magnetic/electric field, mechanical force, ultrasound/light irradiation, redox potentials, and biomolecule concentration have been developed for targeted delivery and release of encapsulated therapeutic agents such as drugs, genes, proteins, and metal ions specifically at their required site of action. Owing to physiological differences between malignant and normal cells, or between tumors and normal tissues, pH-sensitive nanosystems represent promising smart delivery vehicles for transport and delivery of anticancer agents. Furthermore, pH-sensitive systems possess applications in delivery of metal ions and biomolecules such as proteins, insulin, etc., as well as co-delivery of cargos, dual pH-sensitive nanocarriers, dual/multi stimuli-responsive nanosystems, and even in the search for new solutions for therapy of diseases such as Alzheimer’s. In order to design an optimized system, it is necessary to understand the various pH-responsive micro/nanoparticles and the different mechanisms of pH-sensitive drug release. This should be accompanied by an assessment of the theoretical and practical challenges in the design and use of these carriers. PMID:26762467

Photoacoustic Analysis of the Penetration Kinetics of Cordia verbenacea DC in Human Skin

NASA Astrophysics Data System (ADS)

Carvalho, S. S.; Barja, P. R.

2012-11-01

Phonophoresis consists of the utilization of ultrasound radiation associated to pharmacological agents in order to enhance transdermal penetration of applied drugs. It is a widely employed resource in physiotherapy practice, normally associated with anti-inflammatory drugs, such as Acheflan. This drug was developed in Brazil from the essential oil of Cordia verbenacea DC, a native plant of the Brazilian southern coast. In previous studies, the photoacoustic (PA) technique proved effective in the study of the penetration kinetics of topically applied products and in the evaluation of drug delivery after phonophoresis application. The present work aimed to evaluate the penetration kinetics of Acheflan in human skin, employing in vivo PA measurements after massage application or phonophoresis application. Ten volunteers (aged between 18 and 30 years) took part in the study. Time evolution of the PA signal was fitted to a Boltzmann curve, S-shaped. After statistical analysis, PA measurements have shown drug penetration for both application forms, but drug delivery was more evident after phonophoresis application, with a characteristic penetration time of less than 15 min for the stratum corneum.

Altered blood-brain barrier transport in neuro-inflammatory disorders.

PubMed

Schenk, Geert J; de Vries, Helga E

2016-06-01

During neurodegenerative and neuroinflammatory disorders of the central nervous system (CNS), such as Alzheimer's disease (AD) and multiple sclerosis (MS), the protective function of the blood-brain barrier (BBB) may be severely impaired. The general neuro-inflammatory response, ranging from activation of glial cells to immune cell infiltration that is frequently associated with such brain diseases may underlie the loss of the integrity and function of the BBB. Consequentially, the delivery and disposition of drugs to the brain will be altered and may influence the treatment efficiency of such diseases. Altered BBB transport of drugs into the CNS during diseases may be the result of changes in both specific transport and non-specific transport pathways. Potential alterations in transport routes like adsorptive mediated endocytosis and receptor-mediated endocytosis may affect drug delivery to the brain. As such, drugs that normally are unable to traverse the BBB may reach their target in the diseased brain due to increased permeability. In contrast, the delivery of (targeted) drugs could be hampered during inflammatory conditions due to disturbed transport mechanisms. Therefore, the inventory of the neuro-inflammatory status of the neurovasculature (or recovery thereof) is of utmost importance in choosing and designing an adequate drug targeting strategy under disease conditions. Within this review we will briefly discuss how the function of the BBB can be affected during disease and how this may influence the delivery of drugs into the diseased CNS. Copyright © 2016 Elsevier Ltd. All rights reserved.

A high-density lipoprotein-mediated drug delivery system.

PubMed

Mo, Zhong-Cheng; Ren, Kun; Liu, Xing; Tang, Zhen-Li; Yi, Guang-Hui

2016-11-15

High-density lipoprotein (HDL) is a comparatively dense and small lipoprotein that can carry lipids as a multifunctional aggregate in plasma. Several studies have shown that increasing the levels or improving the functionality of HDL is a promising target for treating a wide variety of diseases. Among lipoproteins, HDL particles possess unique physicochemical properties, including naturally synthesized physiological components, amphipathic apolipoproteins, lipid-loading and hydrophobic agent-incorporating characteristics, specific protein-protein interactions, heterogeneity, nanoparticles, and smaller size. Recently, the feasibility and superiority of using HDL particles as drug delivery vehicles have been of great interest. In this review, we summarize the structure, constituents, biogenesis, remodeling, and reconstitution of HDL drug delivery systems, focusing on their delivery capability, characteristics, applications, manufacturing, and drug-loading and drug-targeting characteristics. Finally, the future prospects are presented regarding the clinical application and challenges of using HDL as a pharmacodelivery carrier. Copyright © 2016 Elsevier B.V. All rights reserved.

Bioengineering Strategies for Designing Targeted Cancer Therapies

PubMed Central

Wen, Xuejun

2014-01-01

The goals of bioengineering strategies for targeted cancer therapies are (1) to deliver a high dose of an anticancer drug directly to a cancer tumor, (2) to enhance drug uptake by malignant cells, and (3) to minimize drug uptake by nonmalignant cells. Effective cancer-targeting therapies will require both passive- and active targeting strategies and a thorough understanding of physiologic barriers to targeted drug delivery. Designing a targeted therapy includes the selection and optimization of a nanoparticle delivery vehicle for passive accumulation in tumors, a targeting moiety for active receptor-mediated uptake, and stimuli-responsive polymers for control of drug release. The future direction of cancer targeting is a combinatorial approach, in which targeting therapies are designed to use multiple targeting strategies. The combinatorial approach will enable combination therapy for delivery of multiple drugs and dual ligand targeting to improve targeting specificity. Targeted cancer treatments in development and the new combinatorial approaches show promise for improving targeted anticancer drug delivery and improving treatment outcomes. PMID:23768509

Progression of ultrasound findings of fetal syphilis after maternal treatment.

PubMed

Rac, Martha W F; Bryant, Stefanie N; McIntire, Donald D; Cantey, Joseph B; Twickler, Diane M; Wendel, George D; Sheffield, Jeanne S

2014-10-01

The purpose of this study was to evaluate ultrasound findings of fetal syphilis and to describe their progression after maternal treatment. This was a retrospective cohort study from September 1981 to June 2011 of seropositive women after 18 weeks of gestation who had an ultrasound before treatment to evaluate for fetal syphilis. Only those women who received treatment after the initial ultrasound scan, but before delivery, were included. If the initial ultrasound scan was abnormal, serial sonography was performed until resolution of the abnormality or delivery. Patient demographics, ultrasound findings, stage of syphilis, delivery, and infant outcomes were recorded. Standard statistical analyses were performed. Kaplan-Meier estimates were constructed to estimate time to resolution. Two hundred thirty-five women met the inclusion criteria; 73 of them (30%) had evidence of fetal syphilis on initial ultrasound scan. Abnormalities included hepatomegaly (79%), placentomegaly (27%), polyhydramnios (12%), ascites (10%) and abnormal middle cerebral arterial Doppler assessment (33%). After treatment, middle cerebral arterial Doppler assessment abnormalities, ascites, and polyhydramnios resolved first, followed by placentomegaly and finally hepatomegaly. Infant outcomes were available for 173 deliveries; of these, 32 infants (18%) were diagnosed with congenital syphilis. Congenital syphilis was more common when antenatal ultrasound abnormalities were present (39% vs 12%; P < .001). Infant examination findings at delivery were similar between women with and without an abnormal pretreatment ultrasound scan. However, in those infants with congenital syphilis, hepatomegaly was the most frequent abnormality found, regardless of antenatal ultrasound findings. Sonographic signs of fetal syphilis confer a higher risk of congenital syphilis at delivery for all maternal stages. Hepatomegaly develops early and resolves last after antepartum treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Recent Advances in Stimuli-Responsive Release Function Drug Delivery Systems for Tumor Treatment.

PubMed

Ding, Chendi; Tong, Ling; Feng, Jing; Fu, Jiajun

2016-12-20

Benefiting from the development of nanotechnology, drug delivery systems (DDSs) with stimuli-responsive controlled release function show great potential in clinical anti-tumor applications. By using a DDS, the harsh side effects of traditional anti-cancer drug treatments and damage to normal tissues and organs can be avoided to the greatest extent. An ideal DDS must firstly meet bio-safety standards and secondarily the efficiency-related demands of a large drug payload and controlled release function. This review highlights recent research progress on DDSs with stimuli-responsive characteristics. The first section briefly reviews the nanoscale scaffolds of DDSs, including mesoporous nanoparticles, polymers, metal-organic frameworks (MOFs), quantum dots (QDs) and carbon nanotubes (CNTs). The second section presents the main types of stimuli-responsive mechanisms and classifies these into two categories: intrinsic (pH, redox state, biomolecules) and extrinsic (temperature, light irradiation, magnetic field and ultrasound) ones. Clinical applications of DDS, future challenges and perspectives are also mentioned.

The role of intracochlear drug delivery devices in the management of inner ear disease.

PubMed

Ayoob, Andrew M; Borenstein, Jeffrey T

2015-03-01

Diseases of the inner ear include those of the auditory and vestibular systems, and frequently result in disabling hearing loss or vertigo. Despite a rapidly expanding pipeline of potential cochlear therapeutics, the inner ear remains a challenging organ for targeted drug delivery, and new technologies are required to deliver these therapies in a safe and efficacious manner. In addition to traditional approaches for direct inner ear drug delivery, novel microfluidics-based systems are under development, promising improved control over pharmacokinetics over longer periods of delivery, ultimately with application towards hair cell regeneration in humans. Advances in the development of intracochlear drug delivery systems are reviewed, including passive systems, active microfluidic technologies and cochlear prosthesis-mediated delivery. This article provides a description of novel delivery systems and their potential future clinical applications in treating inner ear disease. Recent progresses in microfluidics and miniaturization technologies are enabling the development of wearable and ultimately implantable drug delivery microsystems. Progress in this field is being spurred by the convergence of advances in molecular biology, microfluidic flow control systems and models for drug transport in the inner ear. These advances will herald a new generation of devices, with near-term applications in preclinical models, and ultimately with human clinical use for a range of diseases of the inner ear.

Role of Colloidal Drug Delivery Carriers in Taxane-mediated Chemotherapy: A Review.

PubMed

Kumar, Pramod; Raza, Kaisar; Kaushik, Lokesh; Malik, Ruchi; Arora, Shweta; Katare, Om Prakash

2016-01-01

Chemotherapy is one of the most frequently employed and reliable treatment options for the management of a variety of cancers. Taxanes (paclitaxel, docetaxel and cabazitaxel) are frequently prescribed to treat breast cancer, hormone refractory prostate cancer, non-small cell lung cancer and ovarian cancer. Most of the commercial products of taxanes are available as injectables, which are not patient compliant and are associated with frequent side effects like ototoxicity, baldness and neurotoxicity. Most of these concerns are ascribable to the presence of toxic solvents in these commercial formulations, which are used to solubilize these drug(s). However, there have been several attempts to develop toxic solvent free taxane formulations, especially employing novel drug delivery systems (NDDS). These systems have been reported to result in the advancement of anticancer activity, therapeutic index, stability, biocompatibility, tissue or organ targeting, encapsulation capacity, tissue permeability, oral bioavailability, reduced toxicity and reduced incidences of abnormal reactions, sustained and controlled release in comparison to the conventional solvent-based formulations. The review is an attempt to analyze the potential of NDDS-mediated taxane delivery for safer and effective cancer chemotherapy.

Microneedles As a Delivery System for Gene Therapy

PubMed Central

Chen, Wei; Li, Hui; Shi, De; Liu, Zhenguo; Yuan, Weien

2016-01-01

Gene delivery systems can be divided to two major types: vector-based (either viral vector or non-viral vector) and physical delivery technologies. Many physical carriers, such as electroporation, gene gun, ultrasound start to be proved to have the potential to enable gene therapy. A relatively new physical delivery technology for gene delivery consists of microneedles (MNs), which has been studied in many fields and for many molecule types and indications. Microneedles can penetrate the stratum corneum, which is the main barrier for drug delivery through the skin with ease of administration and without significant pain. Many different kinds of MNs, such as metal MNs, coated MNs, dissolving MNs have turned out to be promising in gene delivery. In this review, we discussed the potential as well as the challenges of utilizing MNs to deliver nucleic acids for gene therapy. We also proposed that a combination of MNs and other gene delivery approaches may lead to a better delivery system for gene therapy. PMID:27303298

Macrophages as Drug Delivery Carriers for Acoustic Phase-Change Droplets.

PubMed

Fan, Ching-Hsiang; Lee, Ya-Hsuan; Ho, Yi-Ju; Wang, Chung-Hsin; Kang, Shih-Tsung; Yeh, Chih-Kuang

2018-07-01

The major challenges in treating malignant tumors are transport of therapeutic agents to hypoxic regions and real-time assessment of successful drug release via medical imaging modalities. In this study, we propose the use of macrophages (RAW 264.7 cells) as carriers of drug-loaded phase-change droplets to penetrate ischemic or hypoxic regions within tumors. The droplets consist of perfluoropentane, lipid and the chemotherapeutic drug doxorubicin (DOX, DOX-droplets). The efficiency of DOX-droplet uptake, migration mobility and viability of DOX-droplet-loaded macrophages (DLMs) were measured using a transmembrane cell migration assay, the alamarBlue assay and flow cytometric analysis, respectively. Our results indicate the feasibility of utilizing macrophages as DOX-droplet carriers (DOX payload of DOX-droplets: 459.3 ± 35.8 µg/mL, efficiency of cell uptake DOX-droplets: 88.8 ± 3.5%). The migration mobility (total number of migrated microphages) of DLMs decreased to 32.3% compared with that of healthy macrophages, but the DLMs provided contrast-enhanced ultrasound imaging (1.7-fold enhancement) and anti-tumor effect (70.9% cell viability) after acoustic droplet vaporization, suggesting the potential theranostic applications of DLMs. Future work will assess the tumor penetration ability of DLMs, mechanical effect of droplet vaporization on in vivo anti-tumor therapy and the release of the carried drug by ultrasound-triggered vaporization. Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.

Combining drug-loaded nanobubbles and Extracorporeal Shock Waves for difficult-to-treat cancers.

PubMed

Cavalli, Roberta; Marano, Francesca; Argenziano, Monica; Varese, Alessandra; Frairia, Roberto; Catalano, Maria Graziella

2017-10-18

Despite the general great improvement in cancer therapy, to date, some aggressive tumors are still without an efficient therapy. Therefore, accurate delivery of anti-cancer drugs is a very important goal in order to obtain a successful therapy and reduce systemic side effects. Nanobubbles (NBs) are spherical core/shell vesicles filled by a gas with sizes in the nanometer order of magnitude. They have gained an increasing attention for drug delivery, because they can be versatile multifunctional carriers for the targeted release of gases, drugs and genes. Particularly, NBs can carry loaded drugs to the tumor site through the blood stream, taking advantage of the enhanced permeability and retention effect, due to the defective vascular architecture of the tumor (Fang et al. 2011). Unfortunately, vessel leakage, the absence of a functional lymphatic system and an increased extracellular matrix frictional resistance may limit drug delivery (Azzi et al. 2013, Carmeliet and Jain 2011). To overcome this problem, a better drug release to cancer tissues can be obtained by combining physical triggers (e.g. ultrasounds, US) with NBs (Gao et al. 2008, Collis et al. 2010, Cavalli et al. 2012, Cavalli et al. 2016, Argenziano et al. 2017). Indeed, US causes bubble cavitation resulting in cell sonoporation and allowing the extravasation of molecules (Collis et al. 2010). Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Characterisation of gene delivery using liposomal bubbles and ultrasound

NASA Astrophysics Data System (ADS)

Koshima, Risa; Suzuki, Ryo; Oda, Yusuke; Hirata, Keiichi; Nomura, Tetsuya; Negishi, Yoichi; Utoguchi, Naoki; Kudo, Nobuki; Maruyama, Kazuo

2011-09-01

The combination of nano/microbubbles and ultrasound is a novel technique for a non-viral gene deliver. We have previously developed novel ultrasound sensitive liposomes (Bubble liposomes) which contain the ultrasound imaging gas perfluoropropane. In this study, Bubble liposomes were compared with cationic lipid (CL)-DNA complexes as potential gene delivery carriers into tumors in vivo. The delivery of genes by bubble liposomes depended on the intensity of the applied ultrasound. The transfection efficiency plateaued at 0.7 W/cm2 ultrasound intensity. Bubble liposomes efficiently transferred genes into cultured cells even when the cells were exposed to ultrasound for only 1 s. In addition, bubble liposomes were able to introduce the luciferase gene more effectively than CL-DNA complexes into mouse ascites tumor cells. We conclude that the combination of Bubble liposomes and ultrasound is a good method for gene transfer in vivo.

Aptamer-Mediated Up-conversion Core/MOF Shell Nanocomposites for Targeted Drug Delivery and Cell Imaging

PubMed Central

Deng, Kerong; Hou, Zhiyao; Li, Xuejiao; Li, Chunxia; Zhang, Yuanxin; Deng, Xiaoran; Cheng, Ziyong; Lin, Jun

2015-01-01

Multifunctional nanocarriers for targeted bioimaging and drug delivery have attracted much attention in early diagnosis and therapy of cancer. In this work, we develop a novel aptamer-guided nanocarrier based on the mesoporous metal-organic framework (MOF) shell and up-conversion luminescent NaYF4:Yb3+/Er3+ nanoparticles (UCNPs) core for the first time to achieve these goals. These UCNPs, chosen as optical labels in biological assays and medical imaging, could emit strong green emission under 980 nm laser. The MOF structure based on iron (III) carboxylate materials [MIL-100 (Fe)] possesses high porosity and non-toxicity, which is of great value as nanocarriers for drug storage/delivery. As a unique nanoplatform, the hybrid inorganic-organic drug delivery vehicles show great promising for simultaneous targeted labeling and therapy of cancer cells. PMID:25597762

Delivering New Ultrasound System to International Space Station

NASA Technical Reports Server (NTRS)

Sugita, Yoshino

2011-01-01

Ultrasound has been used for medical purposes and experiments. The previous ultrasound, HDI 5000, was delivered to the ISS in 2001 and had expected its service life in February, 2012. Due to on-orbit ultrasound failure in February 2011, the delivery date of new ultrasound was moved to July 8, 2011, which is 7 months earlier than original delivery date. This report shows how the Ultrasound 2 team including myself worked to make new delivery date. Four-step approach, (1) understanding the project (literature search), (2) learning different documents, (3) performing certification tests and (4) participating crew trainings, were used to succeed my internship at NASA JSC. In addition, the participation in Summer Institution and other contributions are explained. i

Vancomycin-loaded nanobubbles: A new platform for controlled antibiotic delivery against methicillin-resistant Staphylococcus aureus infections.

PubMed

Argenziano, Monica; Banche, Giuliana; Luganini, Anna; Finesso, Nicole; Allizond, Valeria; Gulino, Giulia Rossana; Khadjavi, Amina; Spagnolo, Rita; Tullio, Vivian; Giribaldi, Giuliana; Guiot, Caterina; Cuffini, Anna Maria; Prato, Mauro; Cavalli, Roberta

2017-05-15

Vancomycin (Vm) currently represents the gold standard against methicillin-resistant Staphylococcus aureus (MRSA) infections. However, it is associated with low oral bioavailability, formulation stability issues, and severe side effects upon systemic administration. These drawbacks could be overcome by Vm topical administration if properly encapsulated in a nanocarrier. Intriguingly, nanobubbles (NBs) are responsive to physical external stimuli such as ultrasound (US), promoting drug delivery. In this work, perfluoropentane (PFP)-cored NBs were loaded with Vm by coupling to the outer dextran sulfate shell. Vm-loaded NBs (VmLNBs) displayed ∼300nm sizes, anionic surfaces and good drug encapsulation efficiency. In vitro, VmLNBs showed prolonged drug release kinetics, not accompanied by cytotoxicity on human keratinocytes. Interestingly, VmLNBs were generally more effective than Vm alone in MRSA killing, with VmLNB antibacterial activity being more sustained over time as a result of prolonged drug release profile. Besides, VmLNBs were not internalized by staphylococci, opposite to Vm solution. Further US association promoted drug delivery from VmLNBs through an in vitro model of porcine skin. Taken together, these results support the hypothesis that proper Vm encapsulation in US-responsive NBs might be a promising strategy for the topical treatment of MRSA wound infections. Copyright © 2017 Elsevier B.V. All rights reserved.

Development and optimization of doxorubicin loaded poly(lactic-co-glycolic acid) nanobubbles for drug delivery into HeLa cells.

PubMed

Deng, Liwei; Li, Li; Yang, Hong; Li, Li; Zhao, Fenglong; Wu, Chunhui; Liu, Yiyao

2014-04-01

Microbubbles (MBs, usually 2-8 microm) as ultrasound contrast agent and drug carrier are promising for ultrasonic imaging and drug delivery. However, MBs posed some limitations due to their large diameters. In the current study, we developed a nanoscale bubbles (nanobubbles, NBs) by encapsulating the doxorubicin (DOX) into poly(lactic-co-glycolic acid) (PLGA) shells (denoted as DOX-PLGA NBs) for drug delivery into cancer cells. The size, morphology, particle stability, drug encapsulation efficiency, and drug payload were determined. The results showed that the DOX-PLGA NBs were uniform (270 +/- 3 nm) and spherical with a smooth surface, and were well dispersed and stable in water. The encapsulation efficiency and payload of DOX increased with its initial loading concentrations. The release behavior of DOX from the DOX-PLGA NBs exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous release at both pH 7.4 and pH 4.4, and also presented in a pH-triggered releasing profile. The qualitative analysis of cellular internalization into HeLa cells by inverted fluorescence microscope showed that the cellular uptake of DOX-PLGA NBs was both concentration- and time-dependent. Moreover, the cell viability was also investigated using CCK-8 assay. It was found that DOX-PLGA NBs showed greater HeLa cell growth inhibition effect in vitro compared with free DOX. It was concluded that the DOX-PLGA NBs were biocompatible and appropriate for anti-cancer drug delivery, and were potentially promising as a new therapeutic system for cancer treatment.

Ultrasound-assisted powder-coating technique to improve content uniformity of low-dose solid dosage forms.

PubMed

Genina, Natalja; Räikkönen, Heikki; Antikainen, Osmo; Heinämäki, Jyrki; Yliruusi, Jouko

2010-09-01

An ultrasound-assisted powder-coating technique was used to produce a homogeneous powder formulation of a low-dose active pharmaceutical ingredient (API). The powdered particles of microcrystalline cellulose (MCC; Avicel® PH-200) were coated with a 4% m/V aqueous solution of riboflavin sodium phosphate, producing a uniform drug layer on the particle surfaces. It was possible to regulate the amount of API in the treated powder. The thickness of the API layer on the surface of the MCC particles increased near linearly as the number of coating cycles increased, allowing a precise control of the drug content. The tablets (n = 950) prepared from the coated powder showed significantly improved weight and content uniformity in comparison with the reference tablets compressed from a physical binary powder mixture. This was due to the coated formulation remaining uniform during the entire tabletting process, whereas the physical mixture of the powders was subject to segregation. In conclusion, the ultrasound-assisted technique presented here is an effective tool for homogeneous drug coating of powders of irregular particle shape and broad particle size distribution, improving content uniformity of low-dose API in tablets, and consequently, ensuring the safe delivery of a potent active substance to patients.

Lipid-polymer hybrid nanoparticle-mediated therapeutics delivery: advances and challenges.

PubMed

Bose, Rajendran J C; Ravikumar, Rramaswamy; Karuppagounder, Vengadeshprabu; Bennet, Devasier; Rangasamy, Sabarinathan; Thandavarayan, Rajarajan A

2017-08-01

With rapid advances in nanomedicine, lipid-polymer hybrid nanoparticles (LPHNPs) have emerged as promising nanocarriers for several biomedical applications, including therapeutics delivery and biomedical imaging. Significant research has been dedicated to biomimetic or targeting functionalization, as well as controlled and image-guided drug-release capabilities. Despite this research, the clinical translation of LPHNP-mediated therapeutics delivery has progressed incrementally. In this review, we discuss the recent advances in and challenges to the development and application of LPHNPs, present examples to demonstrate the advantages of LPHNPs in therapeutics delivery and imaging applications, and discuss the translational obstacles to LPHNP technology. Copyright © 2017. Published by Elsevier Ltd.

Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts.

PubMed

Shen, Yuanyuan; Pi, Zhaoke; Yan, Fei; Yeh, Chih-Kuang; Zeng, Xiaojun; Diao, Xianfen; Hu, Yaxin; Chen, Siping; Chen, Xin; Zheng, Hairong

2017-01-01

Paclitaxel liposomes (PTX-LIPO) are a clinically promising antineoplastic drug formulation for the treatment of various extracranial cancers, excluding glioblastoma. A main reason for this is the presence of the blood-brain barrier (BBB) or blood-tumor barrier (BTB), preventing liposomal drugs from crossing at a therapeutically meaningful level. Focused ultrasound (FUS) in conjunction with microbubbles (MBs) has been suggested in many studies to be an effective approach to increase the BBB or BTB permeability. In this study, we investigated the feasibility of enhancing the delivery of PTX-LIPO in intracranial glioblastoma-bearing nude mice using pulsed low-intensity FUS exposure in the presence of MBs. Our results showed that the delivery efficiency of PTX-LIPO could be effectively improved in terms of the penetration of both the BBB in vitro and BTB in vivo by pulsed FUS sonication with a 10 ms pulse length and 1 Hz pulse repetition frequency at 0.64 MPa peak-rarefactional pressure in the presence of MBs. Quantitative analysis showed that a 2-fold higher drug concentration had accumulated in the glioblastoma 3 h after FUS treatment, with 7.20±1.18 µg PTX per g glioma tissue. Longitudinal magnetic resonance imaging analysis illustrated that the intracranial glioblastoma progression in nude mice treated with PTX-LIPO delivered via FUS with MBs was suppressed consistently for 4 weeks compared to the untreated group. The medium survival time of these tumor-bearing nude mice was significantly prolonged by 20.8%, compared to the untreated nude mice. Immunohistochemical analysis further confirmed the antiproliferation effect and cell apoptosis induction. Our study demonstrated that noninvasive low-intensity FUS with MBs can be used as an effective approach to deliver PTX-LIPO in order to improve their chemotherapy efficacy toward glioblastoma.

Magnetic resonance guided high-intensity focused ultrasound ablation of musculoskeletal tumors

PubMed Central

Avedian, Raffi S.; Gold, Garry; Ghanouni, Pejman; Pauly, Kim Butts

2015-01-01

This article reviews the fundamental principles and clinical experimental uses of magnetic resonance guided high-intensity focused ultrasound (MRgHIFU) ablation of musculoskeletal tumors. MRgHIFU is a noninvasive treatment modality that takes advantage of the ability of magnetic resonance to measure tissue temperature and uses this technology to guide high-intensity focused ultrasound waves to a specific focus within the human body that results in heat generation and complete thermal necrosis of the targeted tissue. Adjacent normal tissues are spared because of the accurate delivery of thermal energy, as well as, local blood perfusion that provides a cooling effect. MRgHIFU is approved by the Food and Drug Administration for the treatment of uterine fibroids and is used on an experimental basis to treat breast, prostate, liver, bone, and brain tumors. PMID:26120376

A New Carbon Nanotube-Based Breast Cancer Drug Delivery System: Preparation and In Vitro Analysis Using Paclitaxel.

PubMed

Shao, Wei; Paul, Arghya; Rodes, Laetitia; Prakash, Satya

2015-04-01

Paclitaxel (PTX) is one of the most important drugs for breast cancer; however, the drug effects are limited by its systematic toxicity and poor water solubility. Nanoparticles have been applied for delivery of cancer drugs to overcome their limitations. Toward this goal, a novel single-walled carbon nanotube (SWNT)-based drug delivery system was developed by conjugation of human serum albumin (HSA) nanoparticles for loading of antitumor agent PTX. The nanosized macromolecular SWNT-drug carrier (SWNT-HSA) was characterized by TEM, UV-Vis-NIR spectrometry, and TGA. The SWNT-based drug carrier displayed high intracellular delivery efficiency (cell uptake rate of 80%) in breast cancer MCF-7 cells, as examined by fluorescence-labeled drug carriers, suggesting the needle-shaped SWNT-HSA drug carrier was able to transport drugs across cell membrane despite its macromolecular structure. The drug loading on SWNT-based drug carrier was through high binding affinity of PTX to HSA proteins. The PTX formulated with SWNT-HSA showed greater growth inhibition activity in MCF-7 breast cancer cells than PTX formulated with HSA nanoparticle only (cell viability of 63 vs 70% in 48 h and 53 vs 62% in 72 h). The increased drug efficacy could be driven by SWNT-mediated cell internalization. These data suggest that the developed SWNT-based antitumor agent is functional and effective. However, more studies for in vivo drug delivery efficacy and other properties are needed before this delivery system can be fully realized.

Harnessing the capacity of cell-penetrating peptides for drug delivery to the central nervous system.

PubMed

Kang, Ting; Gao, Xiaoling; Chen, Jun

2014-01-01

The existence of blood-brain barrier (BBB) represents the most formidable challenge for drug delivery to the central nervous system (CNS). Modern breakthrough in biology offers multiple choices for overcoming this barrier but yields modest outcomes for clinical application due to various problems such as safety concerns, insufficient delivery efficiency and poor penetration. Cell penetrating peptides (CPPs) possessing powerful transmembrane capacity have been shown to be effective transport vectors for bioactive molecules and an attractive alternative to traditional active targeting approaches. However, the non-specificity of CPPs has hindered them from targeting a desired site of action. Promisingly, design of novel CPP-mediated nanoparticulate delivery systems with specific targeting property may extricate CPPs from the dilemma. In this review, both the traditional and novel applications of CPPs-based strategies for CNS drug delivery will be discussed.

Therapeutic Role and Drug Delivery Potential of Neuroinflammation as a Target in Neurodegenerative Disorders.

PubMed

Singh, Abhijeet; Chokriwal, Ankit; Sharma, Madan Mohan; Jain, Devendra; Saxena, Juhi; Stephen, Bjorn John

2017-08-16

Neuroinflammation, the condition associated with the hyperactivity of immune cells within the CNS (central nervous system), has recently been linked to a host range of neurodegenerative disorders. Targeting neuroinflammation could be of prime importance as recent research highlights the beneficial aspects associated with modulating the inflammatory mediators associated with the CNS. One of the main obstructions in neuroinflammatory treatments is the hindrance posed by the blood-brain barrier for the delivery of drugs. Hence, research has focused on novel modes of transport for drugs to cross the barrier through drug delivery and nanotechnology approaches. In this Review, we highlight the therapeutic advancement made in the field of neurodegenerative disorders by focusing on the effect neuroinflammation treatment has on these conditions.

Microneedles for enhanced transdermal and intraocular drug delivery.

PubMed

Moffatt, Kurtis; Wang, Yujing; Raj Singh, Thakur Raghu; Donnelly, Ryan F

2017-10-01

Microneedle mediated delivery based research has garnered great interest in recent years. In the past, the initial focus was delivery of macromolecules of biological origin, however the field has now broadened its scope to include transdermal delivery of conventional low molecular weight drug molecules. Great success has been demonstrated utilising this approach, particularly in the field of vaccine delivery. Current technological advances have permitted an enhancement in design formulation, allowing delivery of therapeutic doses of small molecule drugs and biomolecules, aided by larger patch sizes and scalable manufacture. In addition, it has been recently shown that microneedles are beneficial in localisation of drug delivery systems within targeted ocular tissues. Microneedles have the capacity to modify the means in which therapeutics and formulations are delivered to the eye. However, further research is still required due to potential drawbacks and challenges. Indeed, no true microneedle-based transdermal or ocular drug delivery system has yet been marketed. Some concerns have been raised regarding regulatory issues and manufacturing processes of such systems, and those in the field are now actively working to address them. Microneedle-based transdermal and ocular drug delivery systems have the potential to greatly impact not only patient benefits, but also industry, and through diligence, innovation and collaboration, their true potential will begin to be realised within the next 3-5 years. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nanomedicines for Back of the Eye Drug Delivery, Gene Delivery, and Imaging

PubMed Central

Kompella, Uday B.; Amrite, Aniruddha C.; Ravi, Rashmi Pacha; Durazo, Shelley A.

2013-01-01

Treatment and management of diseases of the posterior segment of the eye such as diabetic retinopathy, retinoblastoma, retinitis pigmentosa, and choroidal neovascularization is a challenging task due to the anatomy and physiology of ocular barriers. For instance, traditional routes of drug delivery for therapeutic treatment are hindered by poor intraocular penetration and/or rapid ocular elimination. One possible approach to improve ocular therapy is to employ nanotechnology. Nanomedicines, products of nanotechnology, having at least one dimension in the nanoscale include nanoparticles, micelles, nanotubes, and dendrimers, with and without targeting ligands, are making a significant impact in the fields of ocular drug delivery, gene delivery, and imaging, the focus of this review. Key applications of nanotechnology discussed in this review include a) bioadhesive nanomedicines; b) functionalized nanomedicines that enhance target recognition and/or cell entry; c) nanomedicines capable of controlled release of the payload; d) nanomedicines capable of enhancing gene transfection and duration of transfection; f) nanomedicines responsive to stimuli including light, heat, ultrasound, electrical signals, pH, and oxidative stress; g) diversely sized and colored nanoparticles for imaging, and h) nanowires for retinal prostheses. Additionally, nanofabricated delivery systems including implants, films, microparticles, and nanoparticles are described. Although the above nanomedicines may be administered by various routes including topical, intravitreal, intravenous, transscleral, suprachoroidal, and subretinal routes, each nanomedicine should be tailored for the disease, drug, and site of administration. In addition to the nature of materials used in nanomedicine design, depending on the site of nanomedicine administration, clearance and toxicity are expected to differ. PMID:23603534

Advancements in the delivery of epigenetic drugs

PubMed Central

Cramer, Samantha A.; Adjei, Isaac M.; Labhasetwar, Vinod

2015-01-01

Introduction Advancements in epigenetic treatments are not only coming from new drugs but from modifications or encapsulation of the existing drugs into different formulations leading to greater stability and enhanced delivery to the target site. The epigenome is highly regulated and complex; therefore it is important that off-target effects of epigenetic drugs be minimized. The step from in vitro to in vivo treatment of these drugs often requires development of a method of effective delivery for clinical translation. Areas covered This review covers epigenetic mechanisms such as DNA methylation, chromatin remodeling and small RNA mediated gene regulation. There is a section in the review with examples of diseases where epigenetic alterations lead to impaired pathways, with an emphasis on cancer. Epigenetic drugs, their targets and clinical status are presented. Advantages of using a delivery method for epigenetic drugs as well as examples of current advancements and challenges are also discussed. Expert opinion Epigenetic drugs have the potential to be very effective therapy against a number of diseases, especially cancers and neurological disorders. As with many chemotherapeutics, undesired side effects need to be minimized. Finding a suitable delivery method means reducing side effects and achieving a higher therapeutic index. Each drug may require a unique delivery method exploiting the drug's chemistry or other physical characteristic requiring interdisciplinary participation and would benefit from a better understanding of the mechanisms of action. PMID:25739728

Biodegradable polymer based theranostic agents for photoacoustic imaging and cancer therapy

NASA Astrophysics Data System (ADS)

Wang, Yan J.; Strohm, Eric M.; Kolios, Michael C.

2016-03-01

In this study, multifunctional theranostic agents for photoacoustic (PA), ultrasound (US), fluorescent imaging, and for therapeutic drug delivery were developed and tested. These agents consisted of a shell made from a biodegradable Poly(lactide-co-glycolic acid) (PLGA) polymer, loaded with perfluorohexane (PFH) liquid and gold nanoparticles (GNPs) in the core, and lipophilic carbocyanines fluorescent dye DiD and therapeutic drug Paclitaxel (PAC) in the shell. Their multifunctional capacity was investigated in an in vitro study. The PLGA/PFH/DiD-GNPs particles were synthesized by a double emulsion technique. The average PLGA particle diameter was 560 nm, with 50 nm diameter silica-coated gold nano-spheres in the shell. MCF7 human breast cancer cells were incubated with PLGA/PFH/DiDGNPs for 24 hours. Fluorescent and PA images were recorded using a fluorescent/PA microscope using a 1000 MHz transducer and a 532 nm pulsed laser. For the particle vaporization and drug delivery test, MCF7 cells were incubated with the PLGA/PFH-GNPs-PAC or PLGA/PFH-GNPs particles for 6, 12 and 24 hours. The effects of particle vaporization and drug delivery inside the cells were examined by irradiating the cells with a laser fluence of 100 mJ/cm2, and cell viability quantified using the MTT assay. The PA images of MCF7 cells containing PLGA/PFH/DiD-GNPs were spatially coincident with the fluorescent images, and confirmed particle uptake. After exposure to the PLGA/PFHGNP- PAC for 6, 12 and 24 hours, the cell survival rate was 43%, 38%, and 36% respectively compared with the control group, confirming drug delivery and release inside the cells. Upon vaporization, cell viability decreased to 20%. The particles show potential as imaging agents and drug delivery vehicles.

Intracellular Delivery System for Antibody–Peptide Drug Conjugates

PubMed Central

Berguig, Geoffrey Y; Convertine, Anthony J; Frayo, Shani; Kern, Hanna B; Procko, Erik; Roy, Debashish; Srinivasan, Selvi; Margineantu, Daciana H; Booth, Garrett; Palanca-Wessels, Maria Corinna; Baker, David; Hockenbery, David; Press, Oliver W; Stayton, Patrick S

2015-01-01

Antibodies armed with biologic drugs could greatly expand the therapeutic potential of antibody–drug conjugates for cancer therapy, broadening their application to disease targets currently limited by intracellular delivery barriers. Additional selectivity and new therapeutic approaches could be realized with intracellular protein drugs that more specifically target dysregulated pathways in hematologic cancers and other malignancies. A multifunctional polymeric delivery system for enhanced cytosolic delivery of protein drugs has been developed that incorporates endosomal-releasing activity, antibody targeting, and a biocompatible long-chain ethylene glycol component for optimized safety, pharmacokinetics, and tumor biodistribution. The pH-responsive polymeric micelle carrier, with an internalizing anti-CD22 monoclonal targeting antibody, effectively delivered a proapoptotic Bcl-2 interacting mediator (BIM) peptide drug that suppressed tumor growth for the duration of treatment and prolonged survival in a xenograft mouse model of human B-cell lymphoma. Antitumor drug activity was correlated with a mechanistic induction of the Bcl-2 pathway biomarker cleaved caspase-3 and a marked decrease in the Ki-67 proliferation biomarker. Broadening the intracellular target space by more effective delivery of protein/peptide drugs could expand the repertoire of antibody–drug conjugates to currently undruggable disease-specific targets and permit tailored drug strategies to stratified subpopulations and personalized medicines. PMID:25669432

Prevention of Oxidized Low Density Lipoprotein-Induced Endothelial Cell Injury by DA-PLGA-PEG-cRGD Nanoparticles Combined with Ultrasound

PubMed Central

Li, Zhaojun; Huang, Hui; Huang, Lili; Du, Lianfang; Sun, Ying; Duan, Yourong

2017-01-01

In general, atherosclerosis is considered to be a form of chronic inflammation. Dexamethasone has anti-inflammatory effects in atherosclerosis, but it was not considered for long-term administration on account of a poor pharmacokinetic profile and adverse side effects. Nanoparticles in which drugs can be dissolved, encapsulated, entrapped or chemically attached to the particle surface have abilities to incorporate dexamethasone and to be used as controlled or targeted drug delivery system. Long circulatory polymeric nanoparticles present as an assisting approach for controlled and targeted release of the encapsulated drug at the atherosclerotic site. Polymeric nanoparticles combined with ultrasound (US) are widely applied in cancer treatment due to their time applications, low cost, simplicity, and safety. However, there are few studies on atherosclerosis treatment using polymeric nanoparticles combined with US. In this study, targeted dexamethasone acetate (DA)-loaded poly (lactide-glycolide)-polyethylene glycol-cRGD (PLGA-PEG-cRGD) nanoparticles (DA-PLGA-PEG-cRGD NPs) were prepared by the emulsion-evaporation method using cRGD modified PLGA-PEG polymeric materials (PLGA-PEG-cRGD) prepared as the carrier. The average particle size of DA-PLGA-PEG-cRGD NPs was 221.6 ± 0.9 nm. Morphology of the nanoparticles was spherical and uniformly dispersed. In addition, the DA released profiles suggested that ultrasound could promote drug release from the nanocarriers and accelerate the rate of release. In vitro, the cellular uptake process of fluorescein isothiocyanate (FITC)@DA-PLGA-PEG-cRGD NPs combined with US into the damaged human umbilical vein endothelial cells (HUVECs) indicated that US promoted rapid intracellular uptake of FITC@DA- PLGA-PEG-cRGD NPs. The cell viability of DA-PLGA-PEG-cRGD NPs combined with US reached 91.9% ± 0.2%, which demonstrated that DA-PLGA-PEG-cRGD NPs combined with US had a positive therapeutic effect on damaged HUVECs. Overall, DA-PLGA-PEG-cRGD NPs in combination with US may provide a promising drug delivery system to enhance the therapeutic effects of these chemotherapeutics at the cellular level. PMID:28406431

Prevention of Oxidized Low Density Lipoprotein-Induced Endothelial Cell Injury by DA-PLGA-PEG-cRGD Nanoparticles Combined with Ultrasound.

PubMed

Li, Zhaojun; Huang, Hui; Huang, Lili; Du, Lianfang; Sun, Ying; Duan, Yourong

2017-04-13

In general, atherosclerosis is considered to be a form of chronic inflammation. Dexamethasone has anti-inflammatory effects in atherosclerosis, but it was not considered for long-term administration on account of a poor pharmacokinetic profile and adverse side effects. Nanoparticles in which drugs can be dissolved, encapsulated, entrapped or chemically attached to the particle surface have abilities to incorporate dexamethasone and to be used as controlled or targeted drug delivery system. Long circulatory polymeric nanoparticles present as an assisting approach for controlled and targeted release of the encapsulated drug at the atherosclerotic site. Polymeric nanoparticles combined with ultrasound (US) are widely applied in cancer treatment due to their time applications, low cost, simplicity, and safety. However, there are few studies on atherosclerosis treatment using polymeric nanoparticles combined with US. In this study, targeted dexamethasone acetate (DA)-loaded poly (lactide-glycolide)-polyethylene glycol-cRGD (PLGA-PEG-cRGD) nanoparticles (DA-PLGA-PEG-cRGD NPs) were prepared by the emulsion-evaporation method using cRGD modified PLGA-PEG polymeric materials (PLGA-PEG-cRGD) prepared as the carrier. The average particle size of DA-PLGA-PEG-cRGD NPs was 221.6 ± 0.9 nm. Morphology of the nanoparticles was spherical and uniformly dispersed. In addition, the DA released profiles suggested that ultrasound could promote drug release from the nanocarriers and accelerate the rate of release. In vitro, the cellular uptake process of fluorescein isothiocyanate (FITC)@DA-PLGA-PEG-cRGD NPs combined with US into the damaged human umbilical vein endothelial cells (HUVECs) indicated that US promoted rapid intracellular uptake of FITC@DA- PLGA-PEG-cRGD NPs. The cell viability of DA-PLGA-PEG-cRGD NPs combined with US reached 91.9% ± 0.2%, which demonstrated that DA-PLGA-PEG-cRGD NPs combined with US had a positive therapeutic effect on damaged HUVECs. Overall, DA-PLGA-PEG-cRGD NPs in combination with US may provide a promising drug delivery system to enhance the therapeutic effects of these chemotherapeutics at the cellular level.

Noninvasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound

PubMed Central

Miller, G. Wilson; Song, Ji; Louttit, Cameron; Klibanov, Alexander L; Shih, Ting-Yu; Swaminathan, Ganesh; Tamargo, Rafael J.; Woodworth, Graeme F.; Hanes, Justin; Price, Richard J.

2014-01-01

The blood-brain barrier (BBB) presents a significant obstacle for the treatment of many central nervous system (CNS) disorders, including invasive brain tumors, Alzheimer’s, Parkinson’s and stroke. Therapeutics must be capable of bypassing the BBB and also penetrate the brain parenchyma to achieve a desired effect within the brain. In this study, we test the unique combination of a noninvasive approach to BBB permeabilization with a therapeutically relevant polymeric nanoparticle platform capable of rapidly penetrating within the brain microenvironment. MR-guided focused ultrasound (FUS) with intravascular microbubbles (MBs) is able to locally and reversibly disrupt the BBB with submillimeter spatial accuracy. Densely poly(ethylene-co-glycol) (PEG) coated, brain-penetrating nanoparticles (BPNs) are long-circulating and diffuse 10-fold slower in normal rat brain tissue compared to diffusion in water. Following intravenous administration of model and biodegradable BPN in normal healthy rats, we demonstrate safe, pressure-dependent delivery of 60 nm BPNs to the brain parenchyma in regions where the BBB is disrupted by FUS and MBs. Delivery of BPNs with MR-guided FUS has the potential to improve efficacy of treatments for many CNS diseases, while reducing systemic side effects by providing sustained, well-dispersed drug delivery into select regions of the brain. PMID:24979210

Microcapsules: Reverse Sonoporation and Long-lasting, Safe Contrast

NASA Astrophysics Data System (ADS)

Wrenn, Steven; Dicker, Stephen; Small, Eleanor; Maghnouj, Abdelouahid; Hahn, Stephan A.; Mleczko, Michał; Hensel, Karin; Schmitz, Georg

We present a novel vehicle designed to serve the dual roles of enhanced ultrasound contrast and ultrasound-triggered drug delivery. The vehicle is comprised of a microcapsule that is filled with water in whose aqueous core a population of freely floating, phospholipid-coated microbubbles is suspended. At ultrasound intensities below the inertial cavitation threshold of the microbubbles, the microbubbles provide enhanced ultrasound contrast. The measured contrast is comparable in strength with SonoVue®. Encapsulation of microbubbles within microcapsules putatively eliminates - or at least significantly slows - dissolution of gas in the bulk aqueous medium, thereby avoiding disappearance of microbubbles that would otherwise occur due to pressure-induced gas diffusion across the surfactant monolayer coating the microbubble-water interface. Results suggest that our vehicle might provide longer lasting contrast in a clinical setting. We demonstrate that encapsulation of the microbubbles within microcapsules causes at least a doubling of the ultrasound intensity necessary to induce inertial cavitation. Moreover, no cell death was observed when cells were insonified in the presence of microbubble-containing microcapsules, whereas appreciable cell death occurs with unencapsulated microbubbles. These results point toward a potential safety benefit during ultrasound contrast imaging by using encapsulated microbubbles. Studies are underway to investigate the feasibility of ultrasound-triggered release of drug from the microcapsules, owing to inertial- or stable-cavitation, or both. Whereas leakage from polymeric microcapsule shells, such as poly(lactic acid), seemingly requires shell rupture and is exceedingly difficult to achieve, leakage across a lipid bilayer microcapsule shells appears feasible. Leakage across a bilayer shell has the additional benefit that the leakage mechanism can be tuned via phase behavior (liquid-ordered versus liquid-disordered) and cavitation mechanism (stable versus inertial).

Ultrasound contrast agent fabricated from microbubbles containing instant adhesives, and its ultrasound imaging ability

NASA Astrophysics Data System (ADS)

Makuta, T.; Tamakawa, Y.

2012-04-01

Non-invasive surgery techniques and drug delivery system with acoustic characteristics of ultrasound contrast agent have been studied intensively in recent years. Ultrasound contrast agent collapses easily under the blood circulating and the ultrasound irradiating because it is just a stabilized bubble without solid-shell by surface adsorption of surfactant or lipid. For improving the imaging stability, we proposed the fabrication method of the hollow microcapsule with polymer shell, which can be fabricated just blowing vapor of commonly-used instant adhesive (Cyanoacrylate monomer) into water as microbubbles. Therefore, the cyanoacrylate vapor contained inside microbubble initiates polymerization on the gasliquid interface soon after microbubbles are generated in water. Consequently, hollow microspheres coated by cyanoacrylate thin film are generated. In this report, we revealed that diameter distributions of microbubbles and microcapsules were approximately same and most of them were less than 10 μm, that is, smaller than blood capillary. In addition, we also revealed that hollow microcapsules enhanced the acoustic signal especially in the harmonic contrast imaging and were broken or agglomerated under the ultrasound field. As for the yield of hollow microcapsules, we revealed that sodium dodecyl sulfate addition to water phase instead of deoxycolic acid made the fabrication yield increased.

Development and evaluation of a novel VEGFR2-targeted nanoscale ultrasound contrast agents

NASA Astrophysics Data System (ADS)

Yu, Houqiang; Li, Chunfang; He, Xiaoling; Zhou, Qibing; Ding, Mingyue

2016-04-01

Recent literatures have reported that the targeted nanoscale ultrasound contrast agents are becoming more and more important in medical application, like ultrasound imaging, detection of perfusion, drug delivery and molecular imaging and so on. In this study, we fabricated an uniform nanoscale bubbles (257 nm with the polydispersity index of 0.458) by incorporation of antibody targeted to vascular endothelial growth factor receptor 2 (VEGFR2) into the nanobubbles membrane by using avidin-biotin interaction. Some fundamental characterizations such as nanobubble suspension, surface morphology, particle size distribution and zeta potential were investigated. The concentration and time-intensity curves (TICs) were obtained with a self-made ultrasound experimental setup in vitro evaluation. In addition, in order to evaluate the contrast enhancement ability and the potential tumor-targeted ability in vivo, normal Wistar rats and nude female BALB/c mice were intravascular administration of the nanobubbles via tail vein injection, respectively. Significant contrast enhancement of ultrasound imaging within liver and tumor were visualized. These experiments demonstrated that the targeted nanobubbles is efficient in ultrasound molecular imaging by enhancement of the contrast effect and have potential capacity for targeted tumor diagnosis and therapy in the future.

Real-time imaging and kinetics measurements of focused ultrasound-induced extravasation in skeletal muscle using SPECT/CT.

PubMed

Sanches, Pedro Gomes; Rossin, Raffaella; Böhmer, Marcel; Tiemann, Klaus; Grüll, Holger

2013-06-28

Drugs need to overcome several biological barriers such as the endothelium and cellular membranes in order to reach their target. Promising new therapeutics, many of which are charged and macromolecular, are not able to passively extravasate, let alone cross cell membranes, and stay mainly in the blood pool upon intravenous injection until clearance. Using focused ultrasound (fUS) in combination with circulating microbubbles (MBs) leads to temporary localized tissue permeabilization allowing extravasation of (macro) molecules from the vascular system. Thus, fUS is a promising approach for localized drug delivery. However, little is known about the permeabilization kinetics in skeletal muscle. In this study, we used single photon emission computed tomography (SPECT) to characterize the kinetics of extravasation of ¹¹¹In-labeled bovine serum albumin (BSA), a model macromolecular drug, in muscle treated with fUS and MBs. The same fUS protocol was applied to 6 groups of mice with different times, ∆t, between fUS application and BSA injection (∆t=-10, 2.5, 10, 30, 60, 90 min) followed by SPECT imaging. For ∆t ≤30min we observed an exponential accumulation of activity in an area of the treated muscle which extended to a volume larger than the fUS pattern with highest accumulation for short waiting times ∆t. The extent of extravasation decreased exponentially with increasing ∆t, with a calculated half-life of ca. 21 min, defining the time window of extravasation. The same treatment without MBs did not induce extravasation of BSA thus supporting MBs and drug co-injection strategies. These results provide essential information for the development of fUS based strategies for localized drug delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

Photoacoustic micro-imaging of focused ultrasound induced blood-brain-barrier opening in a rat model

NASA Astrophysics Data System (ADS)

Wang, Po-Hsun; Hsu, Po-Hung; Liu, Hao-Li; Wang, Churng-Ren Chris; Li, Meng-Lin

2010-02-01

Blood brain barrier (BBB) prevents most of the drug from transmitting into the brain tissue and decreases the treatment performance for brain disease. One of the methods to overcome the difficulty of drug delivery is to locally increase the permeability of BBB with high-intensity focused ultrasound. In this study, we have investigated the feasibility of photoacoustic microscopy of focused-ultrasound induced BBB opening in a rat model in vivo with gold nanorods (AuNRs) as a contrast agent. This study takes advantage of the strong near-infrared absorption of AuNRs and their extravasation tendency from BBB opening foci due to their nano-scale size. Before the experiments, craniotomy was performed on rats to provide a path for focused ultrasound beam. Localized BBB opening at the depth of about 3 mm from left cortex of rat brains was achieved by delivering 1.5 MHz focused ultrasound energy into brain tissue in the presence of microbubbles. PEGylated AuNRs with a peak optical absorption at ~800 nm were then intravenously administered. Pre-scan prior to BBB disruption and AuNR injection was taken to mark the signal background. After injection, the distribution of AuNRs in rat brains was monitored up to 2 hours. Experimental results show that imaging AuNRs reveals BBB disruption area in left brains while there are no changes observed in the right brains. From our results, photoacoustic imaging plus AuNRs shows the promise as a novel monitoring strategy in identifying the location and variation of focused-ultrasound BBB-opening in a rat model.

Chlorotoxin-conjugated graphene oxide for targeted delivery of an anticancer drug

PubMed Central

Wang, Hao; Gu, Wei; Xiao, Ning; Ye, Ling; Xu, Qunyuan

2014-01-01

Current chemotherapy for glioma is rarely satisfactory due to low therapeutic efficiency and systemic side effects. We have developed a glioma-targeted drug delivery system based on graphene oxide. Targeted peptide chlorotoxin-conjugated graphene oxide (CTX-GO) sheets were successfully synthesized and characterized. Doxorubicin was loaded onto CTX-GO (CTX-GO/DOX) with high efficiency (570 mg doxorubicin per gram CTX-GO) via noncovalent interactions. Doxorubicin release was pH-dependent and showed sustained-release properties. Cytotoxicity experiments demonstrated that CTX-GO/DOX mediated the highest rate of death of glioma cells compared with free doxorubicin or graphene oxide loaded with doxorubicin only. Further, conjugation with chlorotoxin enhanced accumulation of doxorubicin within glioma cells. These findings indicate that CTX-GO is a promising platform for drug delivery and provide a rationale for developing a glioma-specific drug delivery system. PMID:24672236

Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery

PubMed Central

Kesharwani, Prashant; Iyer, Arun K.

2015-01-01

Advances in the application of nanotechnology in medicine have given rise to multifunctional smart nanocarriers that can be engineered with tunable physicochemical characteristics to deliver one or more therapeutic agent(s) safely and selectively to cancer cells, including intracellular organelle-specific targeting. Dendrimers having properties resembling biomolecules, with well-defined 3D nanopolymeric architectures, are emerging as a highly attractive class of drug and gene delivery vector. The presence of numerous peripheral functional groups on hyperbranched dendrimers affords efficient conjugation of targeting ligands and biomarkers that can recognize and bind to receptors overexpressed on cancer cells for tumor-cell-specific delivery. The present review compiles the recent advances in dendrimer-mediated drug and gene delivery to tumors by passive and active targeting principles with illustrative examples. PMID:25555748

Peptide-chaperone-directed transdermal protein delivery requires energy.

PubMed

Ruan, Renquan; Jin, Peipei; Zhang, Li; Wang, Changli; Chen, Chuanjun; Ding, Weiping; Wen, Longping

2014-11-03

The biologically inspired transdermal enhanced peptide TD1 has been discovered to specifically facilitate transdermal delivery of biological macromolecules. However, the biological behavior of TD1 has not been fully defined. In this study, we find that energy is required for the TD1-mediated transdermal protein delivery through rat and human skins. Our results show that the permeation activity of TD1-hEGF, a fusion protein composed of human epidermal growth factor (hEGF) and the TD1 sequence connected with a glycine-serine linker (GGGGS), can be inhibited by the energy inhibitor, rotenone or oligomycin. In addition, adenosine triphosphate (ATP), the essential energetic molecule in organic systems, can effectively facilitate the TD1 directed permeation of the protein-based drug into the skin in a dose-dependent fashion. Our results here demonstrate a novel energy-dependent permeation process during the TD1-mediated transdermal protein delivery that could be valuable for the future development of promising new transdermal drugs.

Protease-mediated drug delivery

NASA Astrophysics Data System (ADS)

Dickson, Eva F.; Goyan, Rebecca L.; Kennedy, James C.; Mackay, M.; Mendes, M. A. K.; Pottier, Roy H.

2003-12-01

Drugs used in disease treatment can cause damage to both malignant and normal tissue. This toxicity limits the maximum therapeutic dose. Drug targeting is of high interest to increase the therapeutic efficacy of the drug without increasing systemic toxicity. Certain tissue abnormalities, disease processes, cancers, and infections are characterized by high levels of activity of specific extracellular and/or intracellular proteases. Abnormally high activity levels of specific proteases are present at sites of physical or chemical trauma, blood clots, malignant tumors, rheumatoid arthritis, inflammatory bowel disease, gingival disease, glomerulonerphritis, and acute pancreatitis. Abnormal protease activity is suspected in development of liver thrombosis, pulmonary emphysema, atherosclerosis, and muscular dystrophy. Inactiviating disease-associated proteases by the administration of appropriate protease inhibitors has had limited success. Instead, one could use such proteases to target drugs to treat the condition. Protease mediated drug delivery offers such a possibility. Solubilizing groups are attached to insoluble drugs via a polypeptide chain which is specifically cleavable by certian proteases. When the solubilized drug enounters the protease, the solubilizing moieties are cleaved, and the drug precipitates at the disease location. Thus, a smaller systemic dosage could result in a therapeutic drug concentration at the treatment site with less systemic toxicity.

Direct Macromolecular Drug Delivery to Cerebral Ischemia Area using Neutrophil-Mediated Nanoparticles

PubMed Central

Zhang, Chun; Ling, Cheng-li; Pang, Liang; Wang, Qi; Liu, Jing-xin; Wang, Bing-shan; Liang, Jian-ming; Guo, Yi-zhen; Qin, Jing; Wang, Jian-xin

2017-01-01

Delivery of macromolecular drugs to the brain is impeded by the blood brain barrier. The recruitment of leukocytes to lesions in the brain, a typical feature of neuroinflammation response which occurs in cerebral ischemia, offers a unique opportunity to deliver drugs to inflammation sites in the brain. In the present study, cross-linked dendrigraft poly-L-lysine (DGL) nanoparticles containing cis-aconitic anhydride-modified catalase and modified with PGP, an endogenous tripeptide that acts as a ligand with high affinity to neutrophils, were developed to form the cl PGP-PEG-DGL/CAT-Aco system. Significant binding efficiency to neutrophils, efficient protection of catalase enzymatic activity from degradation and effective transport to receiver cells were revealed in the delivery system. Delivery of catalase to ischemic subregions and cerebral neurocytes in MCAO mice was significantly enhanced, which obviously reducing infarct volume in MCAO mice. Thus, the therapeutic outcome of cerebral ischemia was greatly improved. The underlying mechanism was found to be related to the inhibition of ROS-mediated apoptosis. Considering that neuroinflammation occurs in many neurological disorders, the strategy developed here is not only promising for treatment of cerebral ischemia but also an effective approach for various CNS diseases related to inflammation. PMID:28900508

In situ cross-linkable high molecular weight hyaluronan-bisphosphonate conjugate for localized delivery and cell-specific targeting: a hydrogel linked prodrug approach.

PubMed

Varghese, Oommen P; Sun, Weilun; Hilborn, Jöns; Ossipov, Dmitri A

2009-07-01

We present here a novel synthesis route to functionalize high molecular weight hyaluronan (HMW-HA) with a hydrazide group and a bioactive ligand, namely bisphosphonate (BP). For this purpose, a new symmetrical self-immolative biscarbazate linker has been devised. The hydrazide group was used to form hydrazone cross-linked hydrogel upon treating with previously described aldehyde modified hyaluronan. The 1:1 weight ratio of these two polymers gave hydrogel in less than 30 s. In this communication we present the first in vitro results showing that even though HA can target CD44 positive cancer cells (HCT-116), receptor mediated endocytosis could only occur by cleavage of high molecular weight HA with an ubiquitous enzyme, hyaluronidase (Hase). The cancer cells are known to overexpress CD44 receptors and also increase the hyaluronidase activity in vivo. Thus the pro-drug design, based on drug conjugation to HMW-HA, represents a new drug delivery platform where the drug potency is triggered by Hase mediated degradation of the HA-drug conjugate. We have successfully demonstrated that the cross-linkable HA-BP conjugate first undergoes Hase-mediated scission to the fragments of suitable sizes so as to be internalized by CD44 positive cells. The specificity of this targeting was proven by comparing the results with less CD44 positive HEK-293T cells. The localized delivery of such drugs at the surgical resection site opens up avenues to control tumor recurrence after removal of the tumor. In the form of hydrogel it would prevent systemic exposure of the drug and would allow its controlled release.

Current trends in the use of liposomes for tumor targeting

PubMed Central

Deshpande, Pranali P; Biswas, Swati; Torchilin, Vladimir P

2013-01-01

The use of liposomes for drug delivery began early in the history of pharmaceutical nanocarriers. These nanosized, lipid bilayered vesicles have become popular as drug delivery systems owing to their efficiency, biocompatibility, nonimmunogenicity, enhanced solubility of chemotherapeutic agents and their ability to encapsulate a wide array of drugs. Passive and ligand-mediated active targeting promote tumor specificity with diminished adverse off-target effects. The current field of liposomes focuses on both clinical and diagnostic applications. Recent efforts have concentrated on the development of multifunctional liposomes that target cells and cellular organelles with a single delivery system. This review discusses the recent advances in liposome research in tumor targeting. PMID:23914966

The application of polysaccharide-based nanogels in peptides/proteins and anticancer drugs delivery.

PubMed

Zhang, Lin; Pan, Jifei; Dong, Shibo; Li, Zhaoming

2017-09-01

Finding adequate carriers for proteins/peptides and anticancer drugs delivery has become an urgent need, owing to the growing number of therapeutic macromolecules and the increasing amount of cancer incidence. Polysaccharide-based nanogels have attracted interest as carriers for proteins/peptides and anticancer drugs because of their characteristic properties like biodegradability, biocompatibility, stimuli-responsive behaviour, softness and swelling to help achieve a controlled, triggered response at the target site. In addition, the groups of the polysaccharide backbone are able to be modified to develop functional nanogels. Some polysaccharides have the intrinsic ability to recognise specific cell types, allowing the design of targeted drug delivery systems through receptor-mediated endocytosis. This review is aimed at describing and exploring the potential of polysaccharides that are used in nanogels which can help to deliver proteins/peptides and anticancer drugs.

Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier

PubMed Central

Strazielle, Nathalie; Ghersi-Egea, Jean-François

2016-01-01

The blood-brain interfaces restrict the cerebral bioavailability of pharmacological compounds. Various drug delivery strategies have been developed to improve drug penetration into the brain. Most strategies target the microvascular endothelium forming the blood-brain barrier proper. Targeting the blood-cerebrospinal fluid (CSF) barrier formed by the epithelium of the choroid plexuses in addition to the blood-brain barrier may offer added-value for the treatment of central nervous system diseases. For instance, targeting the CSF spaces, adjacent tissue, or the choroid plexuses themselves is of interest for the treatment of neuroinflammatory and infectious diseases, cerebral amyloid angiopathy, selected brain tumors, hydrocephalus or neurohumoral dysregulation. Selected CSF-borne materials seem to reach deep cerebral structures by mechanisms that need to be understood in the context of chronic CSF delivery. Drug delivery through both barriers can reduce CSF sink action towards parenchymal drugs. Finally, targeting the choroid plexus-CSF system can be especially relevant in the context of neonatal and pediatric diseases of the central nervous system. Transcytosis appears the most promising mechanism to target in order to improve drug delivery through brain barriers. The choroid plexus epithelium displays strong vesicular trafficking and secretory activities that deserve to be explored in the context of cerebral drug delivery. Folate transport and exosome release into the CSF, plasma protein transport, and various receptor-mediated endocytosis pathways may prove useful mechanisms to exploit for efficient drug delivery into the CSF. This calls for a clear evaluation of transcytosis mechanisms at the blood-CSF barrier, and a thorough evaluation of CSF drug delivery rates. PMID:27464721

Ultrasound-mediated microbubble enhancement of radiation therapy studied using three-dimensional high-frequency power Doppler ultrasound.

PubMed

Kwok, Sheldon J J; El Kaffas, Ahmed; Lai, Priscilla; Al Mahrouki, Azza; Lee, Justin; Iradji, Sara; Tran, William Tyler; Giles, Anoja; Czarnota, Gregory J

2013-11-01

Tumor responses to high-dose (>8 Gy) radiation therapy are tightly connected to endothelial cell death. In the study described here, we investigated whether ultrasound-activated microbubbles can locally enhance tumor response to radiation treatments of 2 and 8 Gy by mechanically perturbing the endothelial lining of tumors. We evaluated vascular changes resulting from combined microbubble and radiation treatments using high-frequency 3-D power Doppler ultrasound in a breast cancer xenograft model. We compared treatment effects and monitored vasculature damage 3 hours, 24 hours and 7 days after treatment delivery. Mice treated with 2 Gy radiation and ultrasound-activated microbubbles exhibited a decrease in vascular index to 48 ± 10% at 24 hours, whereas vascular indices of mice treated with 2 Gy radiation alone or microbubbles alone were relatively unchanged at 95 ± 14% and 78 ± 14%, respectively. These results suggest that ultrasound-activated microbubbles enhance the effects of 2 Gy radiation through a synergistic mechanism, resulting in alterations of tumor blood flow. This novel therapy may potentiate lower radiation doses to preferentially target endothelial cells, thus reducing effects on neighboring normal tissue and increasing the efficacy of cancer treatments. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

MRI-Guided Focused Ultrasound Surgery

PubMed Central

Jolesz, Ferenc A.

2014-01-01

MRI-guided focused ultrasound (MRgFUS) surgery is a noninvasive thermal ablation method that uses magnetic resonance imaging (MRI) for target definition, treatment planning, and closed-loop control of energy deposition. Integrating FUS and MRI as a therapy delivery system allows us to localize, target, and monitor in real time, and thus to ablate targeted tissue without damaging normal structures. This precision makes MRgFUS an attractive alternative to surgical resection or radiation therapy of benign and malignant tumors. Already approved for the treatment of uterine fibroids, MRgFUS is in ongoing clinical trials for the treatment of breast, liver, prostate, and brain cancer and for the palliation of pain in bone metastasis. In addition to thermal ablation, FUS, with or without the use of microbubbles, can temporarily change vascular or cell membrane permeability and release or activate various compounds for targeted drug delivery or gene therapy. A disruptive technology, MRgFUS provides new therapeutic approaches and may cause major changes in patient management and several medical disciplines. PMID:19630579

Protein stability in pulmonary drug delivery via nebulization.

PubMed

Hertel, Sebastian P; Winter, Gerhard; Friess, Wolfgang

2015-10-01

Protein inhalation is a delivery route which offers high potential for direct local lung application of proteins. Liquid formulations are usually available in early stages of biopharmaceutical development and nebulizers are the device of choice for atomization avoiding additional process steps like drying and enabling fast progression to clinical trials. While some proteins were proven to remain stable throughout aerosolization e.g. DNase, many biopharmaceuticals are more susceptible towards the stresses encountered during nebulization. The main reason for protein instability is unfolding and aggregation at the air-liquid interface, a problem which is of particular challenge in the case of ultrasound and jet nebulizers due to recirculation of much of the generated droplets. Surfactants are an important formulation component to protect the sensitive biomolecules. A second important challenge is warming of ultrasound and vibrating mesh devices, which can be overcome by overfilling, precooled solutions or cooling of the reservoir. Ultimately, formulation development has to go hand in hand with device evaluation. Copyright © 2014 Elsevier B.V. All rights reserved.

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

PubMed Central

Hosoya, Hitomi; Dobroff, Andrey S.; Driessen, Wouter H. P.; Cristini, Vittorio; Brinker, Lina M.; Staquicini, Fernanda I.; Cardó-Vila, Marina; D’Angelo, Sara; Ferrara, Fortunato; Proneth, Bettina; Lin, Yu-Shen; Dunphy, Darren R.; Dogra, Prashant; Melancon, Marites P.; Stafford, R. Jason; Miyazono, Kohei; Gelovani, Juri G.; Kataoka, Kazunori; Brinker, C. Jeffrey; Sidman, Richard L.; Arap, Wadih; Pasqualini, Renata

2016-01-01

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications. PMID:26839407

Curb Challenges of the “Trojan Horse” Approach: Smart Strategies in Achieving Effective yet Safe Cell-penetrating Peptide-based Drug Delivery

PubMed Central

Huang, Yongzhuo; Jiang, Yifan; Wang, Huiyuan; Wang, Jianxin; Shin, Meong Cheol; Byun, Youngro; He, Huining; Liang, Yanqin; Yang, Victor C.

2013-01-01

Cell-penetrating peptide (CPP)-mediated intracellular drug delivery system, often specifically termed as “the Trojan horse approach”, has become the “holy grail” in achieving effective delivery of macromolecular compounds such as proteins, DNA, siRNAs, and drug carriers. It is characterized by the unique cell- (or receptor-), temperature-, and payload-independent mechanisms, therefore offering potent means to improve poor cellular uptake of a variety of macromolecular drugs. Nevertheless, this “Trojan horse” approach also acts like a double-edged sword, causing serious safety and toxicity concerns to normal tissues or organs for in vivo application, due to lack of target selectivity of the powerful cell penetrating activity. To overcome this problem of potent yet non-selective penetration vs. targeting delivery, a number of “smart” strategies have been developed in recent years, including controllable CPP-based drug delivery systems based on various stimuli-responsive mechanisms. This review article provides a fundamental understanding of these smart systems, as well as a discussion of their real-time in vivo applicability. PMID:23369828

Current Multistage Drug Delivery Systems Based on the Tumor Microenvironment

PubMed Central

Chen, Binlong; Dai, Wenbing; He, Bing; Zhang, Hua; Wang, Xueqing; Wang, Yiguang; Zhang, Qiang

2017-01-01

The development of traditional tumor-targeted drug delivery systems based on EPR effect and receptor-mediated endocytosis is very challenging probably because of the biological complexity of tumors as well as the limitations in the design of the functional nano-sized delivery systems. Recently, multistage drug delivery systems (Ms-DDS) triggered by various specific tumor microenvironment stimuli have emerged for tumor therapy and imaging. In response to the differences in the physiological blood circulation, tumor microenvironment, and intracellular environment, Ms-DDS can change their physicochemical properties (such as size, hydrophobicity, or zeta potential) to achieve deeper tumor penetration, enhanced cellular uptake, timely drug release, as well as effective endosomal escape. Based on these mechanisms, Ms-DDS could deliver maximum quantity of drugs to the therapeutic targets including tumor tissues, cells, and subcellular organelles and eventually exhibit the highest therapeutic efficacy. In this review, we expatiate on various responsive modes triggered by the tumor microenvironment stimuli, introduce recent advances in multistage nanoparticle systems, especially the multi-stimuli responsive delivery systems, and discuss their functions, effects, and prospects. PMID:28255348

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release.

PubMed

Hosoya, Hitomi; Dobroff, Andrey S; Driessen, Wouter H P; Cristini, Vittorio; Brinker, Lina M; Staquicini, Fernanda I; Cardó-Vila, Marina; D'Angelo, Sara; Ferrara, Fortunato; Proneth, Bettina; Lin, Yu-Shen; Dunphy, Darren R; Dogra, Prashant; Melancon, Marites P; Stafford, R Jason; Miyazono, Kohei; Gelovani, Juri G; Kataoka, Kazunori; Brinker, C Jeffrey; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

2016-02-16

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.

Current Multistage Drug Delivery Systems Based on the Tumor Microenvironment.

PubMed

Chen, Binlong; Dai, Wenbing; He, Bing; Zhang, Hua; Wang, Xueqing; Wang, Yiguang; Zhang, Qiang

2017-01-01

The development of traditional tumor-targeted drug delivery systems based on EPR effect and receptor-mediated endocytosis is very challenging probably because of the biological complexity of tumors as well as the limitations in the design of the functional nano-sized delivery systems. Recently, multistage drug delivery systems (Ms-DDS) triggered by various specific tumor microenvironment stimuli have emerged for tumor therapy and imaging. In response to the differences in the physiological blood circulation, tumor microenvironment, and intracellular environment, Ms-DDS can change their physicochemical properties (such as size, hydrophobicity, or zeta potential) to achieve deeper tumor penetration, enhanced cellular uptake, timely drug release, as well as effective endosomal escape. Based on these mechanisms, Ms-DDS could deliver maximum quantity of drugs to the therapeutic targets including tumor tissues, cells, and subcellular organelles and eventually exhibit the highest therapeutic efficacy. In this review, we expatiate on various responsive modes triggered by the tumor microenvironment stimuli, introduce recent advances in multistage nanoparticle systems, especially the multi-stimuli responsive delivery systems, and discuss their functions, effects, and prospects.

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

DOE PAGES

Hosoya, Hitomi; Dobroff, Andrey S.; Driessen, Wouter H. P.; ...

2016-02-02

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared,more » thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. We conclude that these results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.« less

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hosoya, Hitomi; Dobroff, Andrey S.; Driessen, Wouter H. P.

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared,more » thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. We conclude that these results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.« less

Comparing the efficacy of photodynamic and sonodynamic therapy in non-melanoma and melanoma skin cancer.

PubMed

McEwan, Conor; Nesbitt, Heather; Nicholas, Dean; Kavanagh, Oisin N; McKenna, Kevin; Loan, Philip; Jack, Iain G; McHale, Anthony P; Callan, John F

2016-07-01

Sonodynamic therapy (SDT) involves the activation of a non-toxic sensitiser drug using low-intensity ultrasound to produce cytotoxic reactive oxygen species (ROS). Given the low tissue attenuation of ultrasound, SDT provides a significant benefit over the more established photodynamic therapy (PDT) as it enables activation of sensitisers at a greater depth within human tissue. In this manuscript, we compare the efficacy of aminolevulinic acid (ALA) mediated PDT and SDT in a squamous cell carcinoma (A431) cell line as well as the ability of these treatments to reduce the size of A431 ectopic tumours in mice. Similarly, the relative cytotoxic ability of Rose Bengal mediated PDT and SDT was investigated in a B16-melanoma cell line and also in a B16 ectopic tumour model. The results reveal no statistically significant difference in efficacy between ALA mediated PDT or SDT in the non-melanoma model while Rose Bengal mediated SDT was significantly more efficacious than PDT in the melanoma model. This difference in efficacy was, at least in part, attributed to the dark pigmentation of the melanoma cells that effectively filtered the excitation light preventing it from activating the sensitiser while the use of ultrasound circumvented this problem. These results suggest SDT may provide a better outcome than PDT when treating highly pigmented cancerous skin lesions. Copyright © 2016. Published by Elsevier Ltd.

Glycyrrhetinic Acid-Mediated Polymeric Drug Delivery Targeting the Acidic Microenvironment of Hepatocellular Carcinoma.

PubMed

Zhang, Jinming; Zhang, Min; Ji, Juan; Fang, Xiefan; Pan, Xin; Wang, Yitao; Wu, Chuanbin; Chen, Meiwan

2015-10-01

The major hurdle of current drug carrier against hepatocellular carcinoma (HCC) is the lack of specific and selective drug delivery to HCC. In this study, a novel glycyrrhetinic acid (GA) and poly(L-Histidine) (PHIS) mediated polymeric drug delivery system was developed to target HCC that have GA binding receptors and release its encapsulated anticancer drug in the acidic microenvironment of HCC. Firstly, GA and PHIS were conjugated to form poly (ethylene glycol)-poly(lactic-co-glycolic acid) (GA-PEG-PHIS-PLGA, GA-PPP) micelles by grafting reaction between active terminal groups. Secondly, andrographolide (AGP) was encapsulated to GA-PPP to make AGP/GA-PPP using the solvent evaporation method. The pH-responsive property of AGP/GA-PPP micelles was validated by monitoring its stability and drug release behavior in different pH conditions. Furthermore, selective hepatocellular uptake of GA-PPP micelles in vitro, liver specific drug accumulation in vivo, as well as the enhanced antitumor effects of AGP/GA-PPP micelles confirmed the HCC targeting property of our novel drug delivery system. Average size of AGP/GA-PPP micelles increased significantly and the encapsulated AGP released faster in vitro at pH 5.0, while micelles keeping stable in pH 7.4. AGP/GA-PPP micelles were uptaken more efficiently by human Hep3B liver cells than that by human MDA-MB-231 breast cancer cells. GA-PPP micelles accumulated specifically in the liver and possessed long retention time in vivo. AGP/GA-PPP micelles significantly inhibited tumor growth and provided better therapeutic outcomes compared to free AGP and AGP/PEG-PLGA(AGP/PP) micelles without GA and PHIS decoration. This novel GA-PPP polymeric carrier is promising for targeted treatment of HCC.

Delivery of Hydrogen Sulfide by Ultrasound Targeted Microbubble Destruction Attenuates Myocardial Ischemia-reperfusion Injury

PubMed Central

Chen, Gangbin; Yang, Li; Zhong, Lintao; Kutty, Shelby; Wang, Yuegang; Cui, Kai; Xiu, Jiancheng; Cao, Shiping; Huang, Qiaobing; Liao, Wangjun; Liao, Yulin; Wu, Juefei; Zhang, Wenzhu; Bin, Jianping

2016-01-01

Hydrogen sulfide (H2S) is an attractive agent for myocardial ischemia-reperfusion injury, however, systemic delivery of H2S may cause unwanted side effects. Ultrasound targeted microbubble destruction has become a promising tool for organ specific delivery of bioactive substance. We hypothesized that delivery of H2S by ultrasound targeted microbubble destruction attenuates myocardial ischemia-reperfusion injury and could avoid unwanted side effects. We prepared microbubbles carrying hydrogen sulfide (hs-MB) with different H2S/C3F8 ratios (4/0, 3/1, 2/2, 1/3, 0/4) and determined the optimal ratio. Release of H2S triggered by ultrasound was investigated. The cardioprotective effect of ultrasound targeted hs-MB destruction was investigated in a rodent model of myocardial ischemia-reperfusion injury. The H2S/C3F8 ratio of 2/2 was found to be an optimal ratio to prepare stable hs-MB with higher H2S loading capability. Ultrasound targeted hs-MB destruction triggered H2S release and increased the concentration of H2S in the myocardium and lung. Ultrasound targeted hs-MB destruction limited myocardial infarct size, preserved left ventricular function and had no influence on haemodynamics and respiratory. This cardioprotective effect was associated with alleviation of apoptosis and oxidative stress. Delivery of H2S to the myocardium by ultrasound targeted hs-MB destruction attenuates myocardial ischemia-reperfusion injury and may avoid unwanted side effects. PMID:27469291

Enzyme-activated intracellular drug delivery with tubule clay nanoformulation

DOE PAGES

Dzamukova, Maria R.; Naumenko, Ekaterina A.; Lvov, Yuri M.; ...

2015-05-15

Fabrication of stimuli-triggered drug delivery vehicle is is an important milestone in treating cancer. Here we demonstrate the selective anticancer drug delivery into human cells with biocompatible 50-nm diameter halloysite nanotube carriers. Physically-adsorbed dextrin end stoppers secure the intercellular release of brilliant green. Drug-loaded nanotubes penetrate through the cellular membranes and their uptake efficiency depends on the cells growth rate. Intercellular glycosyl hydrolases-mediated decomposition of the dextrin tube-end stoppers triggers the release of the lumen-loaded brilliant green, which allowed for preferable elimination of human lung carcinoma cells (А549) as compared with hepatoma cells (Hep3b). In conclusion, the enzyme-activated intracellular deliverymore » of brilliant green using dextrin-coated halloysite nanotubes is a promising platform for anticancer treatment.« less

Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems.

PubMed

Karimi, Mahdi; Ghasemi, Amir; Sahandi Zangabad, Parham; Rahighi, Reza; Moosavi Basri, S Masoud; Mirshekari, H; Amiri, M; Shafaei Pishabad, Z; Aslani, A; Bozorgomid, M; Ghosh, D; Beyzavi, A; Vaseghi, A; Aref, A R; Haghani, L; Bahrami, S; Hamblin, Michael R

2016-03-07

New achievements in the realm of nanoscience and innovative techniques of nanomedicine have moved micro/nanoparticles (MNPs) to the point of becoming actually useful for practical applications in the near future. Various differences between the extracellular and intracellular environments of cancerous and normal cells and the particular characteristics of tumors such as physicochemical properties, neovasculature, elasticity, surface electrical charge, and pH have motivated the design and fabrication of inventive "smart" MNPs for stimulus-responsive controlled drug release. These novel MNPs can be tailored to be responsive to pH variations, redox potential, enzymatic activation, thermal gradients, magnetic fields, light, and ultrasound (US), or can even be responsive to dual or multi-combinations of different stimuli. This unparalleled capability has increased their importance as site-specific controlled drug delivery systems (DDSs) and has encouraged their rapid development in recent years. An in-depth understanding of the underlying mechanisms of these DDS approaches is expected to further contribute to this groundbreaking field of nanomedicine. Smart nanocarriers in the form of MNPs that can be triggered by internal or external stimulus are summarized and discussed in the present review, including pH-sensitive peptides and polymers, redox-responsive micelles and nanogels, thermo- or magnetic-responsive nanoparticles (NPs), mechanical- or electrical-responsive MNPs, light or ultrasound-sensitive particles, and multi-responsive MNPs including dual stimuli-sensitive nanosheets of graphene. This review highlights the recent advances of smart MNPs categorized according to their activation stimulus (physical, chemical, or biological) and looks forward to future pharmaceutical applications.

Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance.

PubMed

Khdair, Ayman; Chen, Di; Patil, Yogesh; Ma, Linan; Dou, Q Ping; Shekhar, Malathy P V; Panyam, Jayanth

2010-01-25

Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors. Copyright 2009 Elsevier B.V. All rights reserved.

Microbubble-assisted p53, RB, and p130 gene transfer in combination with radiation therapy in prostate cancer.

PubMed

Nande, Rounak; Greco, Adelaide; Gossman, Michael S; Lopez, Jeffrey P; Claudio, Luigi; Salvatore, Marco; Brunetti, Arturo; Denvir, James; Howard, Candace M; Claudio, Pier Paolo

2013-06-01

Combining radiation therapy and direct intratumoral (IT) injection of adenoviral vectors has been explored as a means to enhance the therapeutic potential of gene transfer. A major challenge for gene transfer is systemic delivery of nucleic acids directly into an affected tissue. Ultrasound (US) contrast agents (microbubbles) are viable candidates to enhance targeted delivery of systemically administered genes. Here we show that p53, pRB, and p130 gene transfer mediated by US cavitation of microbubbles at the tumor site resulted in targeted gene transduction and increased reduction in tumor growth compared to DU-145 prostate cancer cell xenografts treated intratumorally with adenovirus (Ad) or radiation alone. Microbubble-assisted/US-mediated Ad.p53 and Ad.RB treated tumors showed significant reduction in tumor volume compared to Ad.p130 treated tumors (p<0.05). Additionally, US mediated microbubble delivery of p53 and RB combined with external beam radiation resulted in the most profound tumor reduction in DU-145 xenografted nude mice (p<0.05) compared to radiation alone. These findings highlight the potential therapeutic applications of this novel image-guided gene transfer technology in combination with external beam radiation for prostate cancer patients with therapy resistant disease.

Current and Future Clinical Applications of High-Intensity Focused Ultrasound (HIFU) for Pancreatic Cancer.

PubMed

Jang, Hyun Joo; Lee, Jae-Young; Lee, Don-Haeng; Kim, Won-Hong; Hwang, Joo Ha

2010-09-01

High-intensity focused ultrasound (HIFU) is a novel therapeutic modality that permits noninvasive treatment of various benign and malignant solid tumors, including prostatic cancer, uterine fibroids, hepatic tumors, renal tumors, breast cancers, and pancreatic cancers. Several preclinical and clinical studies have investigated the safety and efficacy of HIFU for treating solid tumors, including pancreatic cancer. The results of nonrandomized studies of HIFU therapy in patients with pancreatic cancer have suggested that HIFU treatment can effectively alleviate cancer-related pain without any significant complications. This noninvasive method of delivering ultrasound energy into the body has recently been evolving from a method for purely thermal ablation to harnessing the mechanical effects of HIFU to induce a systemic immune response and to enhance targeted drug delivery. This review provides a brief overview of HIFU, describes current clinical applications of HIFU for pancreatic cancer, and discusses future applications and challenges.

Current and Future Clinical Applications of High-Intensity Focused Ultrasound (HIFU) for Pancreatic Cancer

PubMed Central

Jang, Hyun Joo; Lee, Jae-Young; Lee, Don-Haeng; Kim, Won-Hong

2010-01-01

High-intensity focused ultrasound (HIFU) is a novel therapeutic modality that permits noninvasive treatment of various benign and malignant solid tumors, including prostatic cancer, uterine fibroids, hepatic tumors, renal tumors, breast cancers, and pancreatic cancers. Several preclinical and clinical studies have investigated the safety and efficacy of HIFU for treating solid tumors, including pancreatic cancer. The results of nonrandomized studies of HIFU therapy in patients with pancreatic cancer have suggested that HIFU treatment can effectively alleviate cancer-related pain without any significant complications. This noninvasive method of delivering ultrasound energy into the body has recently been evolving from a method for purely thermal ablation to harnessing the mechanical effects of HIFU to induce a systemic immune response and to enhance targeted drug delivery. This review provides a brief overview of HIFU, describes current clinical applications of HIFU for pancreatic cancer, and discusses future applications and challenges. PMID:21103296

Conformal drug delivery and instantaneous monitoring based on an inverse synthesis method at a diagnostic ultrasound platform

NASA Astrophysics Data System (ADS)

Xu, Shanshan; Zong, Yujin; Liu, Xiaodong; Lu, Mingzhu; Wan, Mingxi

2017-03-01

In this paper, based on a programmable diagnostic ultrasound scanner, a combined approach was proposed, in which a variable-sized focal region wherein the acoustic pressure is above the ultrasound contrast agents (UCA) fragmentation threshold is synthesized by reasonably matching the excitation voltage and the transmit aperture of the linear array at 5MHz, the UCAs' temporal and spatial distribution before and after the microbubbles fragmentation is monitored using the plane-wave transmission and reception at 400Hz and, simultaneously, the broadband noise emission during the microbubbles fragmentation is extracted using the backscattering of focused release bursts (destruction pulse) themselves on the linear array. Then, acquired radio frequency (RF) data are processed to draw parameters which can be correlated with the indicator of broadband noise emission level, namely inertial cavitation dose (ICD) and microbubble fragmentation efficiency, namely decay rate of microbubbles.

Learning Ultrasound-Guided Needle Insertion Skills through an Edutainment Game

NASA Astrophysics Data System (ADS)

Chan, Wing-Yin; Ni, Dong; Pang, Wai-Man; Qin, Jing; Chui, Yim-Pan; Yu, Simon Chun-Ho; Heng, Pheng-Ann

Ultrasound-guided needle insertion is essential in many of minimally invasive surgeries or procedures, such as biopsy, drug delivery, spinal anaesthesia, etc. Accurate and safe needle insertion is a difficult task due to the high requirement of hand-eye coordination skills. Many proposed virtual reality (VR) based training systems put their emphasis on realistic simulation instead of pedagogical efficiency. The lack of schematic training scenario leads to boredom of repetitive operations. To solve this, we present our novel training system with the integration of game elements in order to retain the trainees' enthusiasm. Task-oriented scenarios, time attack scenarios and performance evaluation are introduced. Besides, some state-of-art technologies are also presented, including ultrasound simulation, needle haptic rendering as well as a mass-spring-based needle-tissue interaction simulation. These works are shown to be effective to keep the trainees up with learning.

Modeling Encapsulated Microbubble Dynamics at High Pressure Amplitudes

NASA Astrophysics Data System (ADS)

Heyse, Jan F.; Bose, Sanjeeb; Iaccarino, Gianluca

2017-11-01

Encapsulated microbubbles are commonly used in ultrasound contrast imaging and are of growing interest in therapeutic applications where local cavitation creates temporary perforations in cell membranes allowing for enhanced drug delivery. Clinically used microbubbles are encapsulated by a shell commonly consisting of protein, polymer, or phospholipid; the response of these bubbles to externally imposed ultrasound waves is sensitive to the compressibility of the encapsulating shell. Existing models approximate the shell compressibility via an effective surface tension (Marmottant et al. 2005). We present simulations of microbubbles subjected to high amplitude ultrasound waves (on the order of 106 Pa) and compare the results with the experimental measurements of Helfield et al. (2016). Analysis of critical points (corresponding to maximum and minimum expansion) in the governing Rayleigh-Plesset equation is used to make estimates of the parameters used to characterize the effective surface tension of the encapsulating shell. Stanford Graduate Fellowship.

Multi-Modal Strategies for Overcoming Tumor Drug Resistance: Hypoxia, Warburg’s Effect, Stem Cells, and Multifunctional Nanotechnology

PubMed Central

Milane, Lara; Ganesh, Shanthi; Shah, Shruti; Duan, Zhen-feng; Amiji, Mansoor

2011-01-01

Inefficiency in systemic drug delivery and tumor residence as well microenvironmental selection pressures contribute to the development of multidrug resistance (MDR) in cancer. Characteristics of MDR include abnormal vasculature, regions of hypoxia, up-regulation of ABC-transporters, aerobic glycolysis, and an elevated apoptotic threshold. Nano-sized delivery vehicles are ideal for treating MDR cancer as they can improve the therapeutic index of drugs and they can be engineered to achieve multifunctional parameters. The multifunctional ability of nanocarriers makes them more adept at treating heterogeneous tumor mass than traditional chemotherapy. Nanocarriers also have preferential tumor accumulation via the EPR effect; this accumulation can be further enhanced by actively targeting the biological profile of MDR cells. Perhaps the most significant benefit of using nanocarrier drug delivery to treat MDR cancer is that nanocarrier delivery diverts the effects of ABC-transporter mediated drug efflux; which is the primary mechanism of MDR. This review discusses the capabilities, applications, and examples of multifunctional nanocarriers for the treatment of MDR. This review emphasizes multifunctional nanocarriers that enhance drug delivery efficiency, the application of RNAi, modulation of the tumor apoptotic threshold, and physical approaches to overcome MDR. PMID:21497176

Stimuli-responsive chitosan-based nanocarriers for cancer therapy

PubMed Central

Fathi, Marziyeh; Sahandi Zangabad, Parham; Majidi, Sima; Barar, Jaleh; Erfan-Niya, Hamid

2017-01-01

Introduction: Stimuli-responsive nanocarriers offer unique advantages over the traditional drug delivery systems (DDSs) in terms of targeted drug delivery and on-demand release of cargo drug molecules. Of these, chitosan (CS)-based DDSs offer several advantages such as high compatibility with biological settings. Methods: In this study, we surveyed the literature in terms of the stimuli-responsive nanocarriers and discussed the most recent advancements in terms of CS-based nanosystems and their applications in cancer therapy and diagnosis. Results: These advanced DDSs are able to release the entrapped drugs in response to a specific endogenous stimulus (e.g., pH, glutathione concentration or certain enzymes) or exogenous stimulus (e.g., temperature, light, ultrasound, and magnetic field) at the desired time and target site. Dual-responsive nanocarriers by the combination of different stimuli have also been developed as efficient and improved DDSs. Among the stimuli-responsive nanocarriers, CS-based DDSs offer several advantages, including biocompatibility and biodegradability, antibacterial activity, ease of modification and functionalization, and non-immunogenicity. They are as one of the most ideal smart multifunction DDSs. Conclusion: The CS-based stimuli-responsive multifunctional nanosystems (NSs) offer unique potential for the targeted delivery of anticancer agents and provide great potential for on-demand and controlled-release of anticancer agents in response to diverse external/internal stimuli. PMID:29435435

Stimuli-responsive chitosan-based nanocarriers for cancer therapy.

PubMed

Fathi, Marziyeh; Sahandi Zangabad, Parham; Majidi, Sima; Barar, Jaleh; Erfan-Niya, Hamid; Omidi, Yadollah

2017-01-01

Introduction: Stimuli-responsive nanocarriers offer unique advantages over the traditional drug delivery systems (DDSs) in terms of targeted drug delivery and on-demand release of cargo drug molecules. Of these, chitosan (CS)-based DDSs offer several advantages such as high compatibility with biological settings. Methods: In this study, we surveyed the literature in terms of the stimuli-responsive nanocarriers and discussed the most recent advancements in terms of CS-based nanosystems and their applications in cancer therapy and diagnosis. Results: These advanced DDSs are able to release the entrapped drugs in response to a specific endogenous stimulus (e.g., pH, glutathione concentration or certain enzymes) or exogenous stimulus (e.g., temperature, light, ultrasound, and magnetic field) at the desired time and target site. Dual-responsive nanocarriers by the combination of different stimuli have also been developed as efficient and improved DDSs. Among the stimuli-responsive nanocarriers, CS-based DDSs offer several advantages, including biocompatibility and biodegradability, antibacterial activity, ease of modification and functionalization, and non-immunogenicity. They are as one of the most ideal smart multifunction DDSs. Conclusion: The CS-based stimuli-responsive multifunctional nanosystems (NSs) offer unique potential for the targeted delivery of anticancer agents and provide great potential for on-demand and controlled-release of anticancer agents in response to diverse external/internal stimuli.

Boron nitride nanotube as a delivery system for platinum drugs: Drug encapsulation and diffusion coefficient prediction.

PubMed

Khatti, Zahra; Hashemianzadeh, Seyed Majid

2016-06-10

Molecular dynamics (MD) simulation has been applied to investigate a drug delivery system based on boron nitride nanotubes, particularly the delivery of platinum-based anticancer drugs. For this propose, the behavior of carboplatin drugs inserted in boron nitride nanotubes (BNNT) as a carrier was studied. The diffusion rate of water molecules and carboplatin was investigated inside functionalized and pristine boron nitride nanotubes. The penetration rate of water and drug in functionalized BNNT was higher than that in pristine BNNT due to favorable water-mediated hydrogen bonding in hydroxyl edge-functionalized BNNT. Additionally, the encapsulation of multiple carboplatin drugs inside functionalized boron nitride nanotubes with one to five drug molecules confined inside the nanotube cavity was examined. At high drug loading, the hydrogen bond formation between adjacent drugs and the non-bonded van der Waals interaction between carboplatin and functionalized BNNT inner surface were found to be influential in drug displacement within the functionalized BNNT cavity for higher drug-loading capacity. Copyright © 2016 Elsevier B.V. All rights reserved.

Polymeric Cups for Cavitation-mediated Delivery of Oncolytic Vaccinia Virus

PubMed Central

Myers, Rachel; Coviello, Christian; Erbs, Philippe; Foloppe, Johann; Rowe, Cliff; Kwan, James; Crake, Calum; Finn, Seán; Jackson, Edward; Balloul, Jean-Marc; Story, Colin; Coussios, Constantin; Carlisle, Robert

2016-01-01

Oncolytic viruses (OV) could become the most powerful and selective cancer therapies. However, the limited transport of OV into and throughout tumors following intravenous injection means their clinical administration is often restricted to direct intratumoral dosing. Application of physical stimuli, such as focused ultrasound, offers a means of achieving enhanced mass transport. In particular, shockwaves and microstreaming resulting from the instigation of an ultrasound-induced event known as inertial cavitation can propel OV hundreds of microns. We have recently developed a polymeric cup formulation which, when delivered intravenously, provides the nuclei for instigation of sustained inertial cavitation events within tumors. Here we report that exposure of tumors to focused ultrasound after intravenous coinjection of cups and oncolytic vaccinia virus , leads to substantial and significant increases in activity. When cavitation was instigated within SKOV-3 or HepG2 xenografts, reporter gene expression from vaccinia virus was enhanced 1,000-fold (P < 0.0001) or 10,000-fold (P < 0.001), respectively. Similar increases in the number of vaccinia virus genomes recovered from tumors were also observed. In survival studies, the application of cup mediated cavitation to a vaccinia virus expressing a prodrug converting enzyme provided significant (P < 0.05) retardation of tumor growth. This technology could improve the clinical utility of all biological therapeutics including OV. PMID:27375160

Nanocarrier-mediated drugs targeting cancer stem cells: an emerging delivery approach.

PubMed

Malhi, Sarandeep; Gu, Xiaochen

2015-07-01

Cancer stem cells (CSCs) play an important role in the development of drug resistance, metastasis and recurrence. Current conventional therapies do not commonly target CSCs. Nanocarrier-based delivery systems targeting cancer cells have entered a new era of treatment, where specific targeting to CSCs may offer superior outcomes to efficient cancer therapies. This review discusses the involvement of CSCs in tumor progression and relevant mechanisms associated with CSCs resistance to conventional chemo- and radio-therapies. It highlights CSCs-targeted strategies that are either under evaluation or could be explored in the near future, with a focus on various nanocarrier-based delivery systems of drugs and nucleic acids to CSCs. Novel nanocarriers targeting CSCs are presented in a cancer-specific way to provide a current perspective on anti-CSCs therapeutics. The field of CSCs-targeted therapeutics is still emerging with a few small molecules and macromolecules currently proving efficacy in clinical trials. However considering the complexities of CSCs and existing delivery difficulties in conventional anticancer therapies, CSC-specific delivery systems would face tremendous technical and clinical challenges. Nanocarrier-based approaches have demonstrated significant potential in specific drug delivery and targeting; their success in CSCs-targeted drug delivery would not only significantly enhance anticancer treatment but also address current difficulties associated with cancer resistance, metastasis and recurrence.