ADVANCED MOLECULAR DESIGN OF BIOPOLYMERS FOR TRANSMUCOSAL AND INTRACELLULAR DELIVERY OF CHEMOTHERAPEUTIC AGENTS AND BIOLOGICAL THERAPEUTICS

PubMed Central

Liechty, William B.; Caldorera-Moore, Mary; Phillips, Margaret A.; Schoener, Cody; Peppas, Nicholas A.

2011-01-01

Hydrogels have been instrumental in the development of polymeric systems for controlled release of therapeutic agents. These materials are attractive for transmucosal and intracellular drug delivery because of their facile synthesis, inherent biocompatibility, tunable physicochemical properties, and capacity to respond to various physiological stimuli. In this contribution, we outline a multifaceted hydrogel-based approach for expanding the range of therapeutics in oral formulations from classical small-molecule drugs to include proteins, chemotherapeutics, and nucleic acids. Through judicious materials selection and careful design of copolymer composition and molecular architecture, we can engineer systems capable of responding to distinct physiological cues, with tunable physicochemical properties that are optimized to load, protect, and deliver valuable macromolecular payloads to their intended site of action. These hydrogel carriers, including complexation hydrogels, tethered hydrogels, interpenetrating networks, nanoscale hydrogels, and hydrogels with decorated structures are investigated for their ability respond to changes in pH, to load and release insulin and fluorescein, and remain non-toxic to Caco-2 cells. Our results suggest these novel hydrogel networks have great potential for controlled delivery of proteins, chemotherapeutics, and nucleic acids. PMID:21699934

Recent Advances of Cocktail Chemotherapy by Combination Drug Delivery Systems

PubMed Central

Hu, Quanyin; Sun, Wujin; Wang, Chao; Gu, Zhen

2016-01-01

Combination chemotherapy is widely exploited for enhanced cancer treatment in clinic. However, the traditional cocktail administration of combination regimens often suffers from varying pharmacokinetics among different drugs. The emergence of nanotechnology offers an unparalleled opportunity for developing advanced combination drug delivery strategies with the ability to encapsulate various drugs simultaneously and unify the pharmacokinetics of each drug. This review surveys the most recent advances in combination delivery of multiple small molecule chemotherapeutics using nanocarriers. The mechanisms underlying combination chemotherapy, including the synergistic, additive and potentiation effects, are also discussed with typical examples. We further highlight the sequential and site-specific co-delivery strategies, which provide new guidelines for development of programmable combination drug delivery systems. Clinical outlook and challenges are also discussed in the end. PMID:26546751

Adsorption of doxorubicin on citrate-capped gold nanoparticles: insights into engineering potent chemotherapeutic delivery systems

NASA Astrophysics Data System (ADS)

Curry, Dennis; Cameron, Amanda; MacDonald, Bruce; Nganou, Collins; Scheller, Hope; Marsh, James; Beale, Stefanie; Lu, Mingsheng; Shan, Zhi; Kaliaperumal, Rajendran; Xu, Heping; Servos, Mark; Bennett, Craig; Macquarrie, Stephanie; Oakes, Ken D.; Mkandawire, Martin; Zhang, Xu

2015-11-01

Gold nanomaterials have received great interest for their use in cancer theranostic applications over the past two decades. Many gold nanoparticle-based drug delivery system designs rely on adsorbed ligands such as DNA or cleavable linkers to load therapeutic cargo. The heightened research interest was recently demonstrated in the simple design of nanoparticle-drug conjugates wherein drug molecules are directly adsorbed onto the as-synthesized nanoparticle surface. The potent chemotherapeutic, doxorubicin often serves as a model drug for gold nanoparticle-based delivery platforms; however, the specific interaction facilitating adsorption in this system remains understudied. Here, for the first time, we propose empirical and theoretical evidence suggestive of the main adsorption process where (1) hydrophobic forces drive doxorubicin towards the gold nanoparticle surface before (2) cation-π interactions and gold-carbonyl coordination between the drug molecule and the cations on AuNP surface facilitate DOX adsorption. In addition, biologically relevant compounds, such as serum albumin and glutathione, were shown to enhance desorption of loaded drug molecules from AuNP at physiologically relevant concentrations, providing insight into the drug release and in vivo stability of such drug conjugates.Gold nanomaterials have received great interest for their use in cancer theranostic applications over the past two decades. Many gold nanoparticle-based drug delivery system designs rely on adsorbed ligands such as DNA or cleavable linkers to load therapeutic cargo. The heightened research interest was recently demonstrated in the simple design of nanoparticle-drug conjugates wherein drug molecules are directly adsorbed onto the as-synthesized nanoparticle surface. The potent chemotherapeutic, doxorubicin often serves as a model drug for gold nanoparticle-based delivery platforms; however, the specific interaction facilitating adsorption in this system remains understudied

Nanocarrier mediated Delivery of siRNA/miRNA in Combination with Chemotherapeutic Agents for Cancer Therapy: Current Progress and Advances

PubMed Central

Gandhi, Nishant S.; Tekade, Rakesh K.; Chougule, Mahavir B.

2014-01-01

Chemotherapeutic agents have certain limitations when it comes to treating cancer, the most important being severe side effects along with multidrug resistance developed against them. Tumor cells exhibits drug resistance due to activation of various cellular level processes viz. activation of drug efflux pumps, anti-apoptotic defense mechanisms etc. Currently, RNA interference (RNAi) based therapeutic approaches are under vibrant scrutinization to seek cancer cure. Especially small interfering RNA (siRNA) and micro RNA (miRNA), are able to knock down the carcinogenic genes by targeting the mRNA expression, which underlies the uniqueness of this therapeutic approach. Recent research focus in the regime of cancer therapy involves the engagement of targeted delivery of siRNA/miRNA in combinations with other therapeutic agents (such as gene, DNA or chemotherapeutic drug) for targeting permeability glycoprotein (P-gp), Multidrug resistant protein 1(MRP-1), B-cell lymphoma (BCL-2) and other targets that are mainly responsible for resistance in cancer therapy. RNAi-chemotherapeutic drug combinations have also been found to be effective against different molecular targets as well and can increase the sensitization of cancer cells to therapy several folds. However, due to stability issues associated with siRNA/miRNA suitable protective carrier is needed and nanotechnology based approaches have been widely explored to overcome these drawbacks. Furthermore, it has been univocally advocated that the co-delivery of siRNA/miRNA with other chemodrugs significantly enhances their capability to overcome cancer resistance compared to naked counterparts. The objective of this article is to review recent nanocarrier based approaches adopted for the delivery of siRNA/miRNA combinations with other anticancer agents (siRNA/miRNA/pDNA/chemodrugs) to treat cancer. PMID:25204288

Nanocarrier mediated delivery of siRNA/miRNA in combination with chemotherapeutic agents for cancer therapy: current progress and advances.

PubMed

Gandhi, Nishant S; Tekade, Rakesh K; Chougule, Mahavir B

2014-11-28

Chemotherapeutic agents have certain limitations when it comes to treating cancer, the most important being severe side effects along with multidrug resistance developed against them. Tumor cells exhibit drug resistance due to activation of various cellular level processes viz. activation of drug efflux pumps, anti-apoptotic defense mechanisms, etc. Currently, RNA interference (RNAi) based therapeutic approaches are under vibrant scrutinization to seek cancer cure. Especially small interfering RNA (siRNA) and micro RNA (miRNA), are able to knock down the carcinogenic genes by targeting the mRNA expression, which underlies the uniqueness of this therapeutic approach. Recent research focus in the regime of cancer therapy involves the engagement of targeted delivery of siRNA/miRNA in combinations with other therapeutic agents (such as gene, DNA or chemotherapeutic drug) for targeting permeability glycoprotein (P-gp), multidrug resistant protein 1 (MRP-1), B-cell lymphoma (BCL-2) and other targets that are mainly responsible for resistance in cancer therapy. RNAi-chemotherapeutic drug combinations have also been found to be effective against different molecular targets as well and can increase the sensitization of cancer cells to therapy several folds. However, due to stability issues associated with siRNA/miRNA suitable protective carrier is needed and nanotechnology based approaches have been widely explored to overcome these drawbacks. Furthermore, it has been univocally advocated that the co-delivery of siRNA/miRNA with other chemodrugs significantly enhances their capability to overcome cancer resistance compared to naked counterparts. The objective of this article is to review recent nanocarrier based approaches adopted for the delivery of siRNA/miRNA combinations with other anticancer agents (siRNA/miRNA/pDNA/chemodrugs) to treat cancer. Copyright © 2014 Elsevier B.V. All rights reserved.

Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

PubMed

Alimoradi, Houman; Matikonda, Siddharth S; Gamble, Allan B; Giles, Gregory I; Greish, Khaled

2016-01-01

Hypoxia is a common characteristic of solid tumors. It is mainly determined by low levels of oxygen resulting from imperfect vascular networks supplying most tumors. In an attempt to improve the present chemotherapeutic treatment and reduce associated side effects, several prodrug strategies have been introduced to achieve hypoxia-specific delivery of cytotoxic anticancer agents. With the advances in nanotechnology, novel delivery systems activated by the consequent outcomes of hypoxia have been developed. However, developing hypoxia responsive drug delivery systems (which only depend on low oxygen levels) is currently naïve. This review discusses four main hypoxia responsive delivery systems: polymeric based drug delivery systems, oxygen delivery systems combined with radiotherapy and chemotherapy, anaerobic bacteria which are used for delivery of genes to express anticancer proteins such as tumor necrosis alpha (TNF-α) and hypoxia-inducible transcription factors 1 alpha (HIF1α) responsive gene delivery systems.

Biodegradable polymers for targeted delivery of anti-cancer drugs.

PubMed

Doppalapudi, Sindhu; Jain, Anjali; Domb, Abraham J; Khan, Wahid

2016-06-01

Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy. This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered. Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.

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

Inhaled Micro/Nanoparticulate Anticancer Drug Formulations: An Emerging Targeted Drug Delivery Strategy for Lung Cancers.

PubMed

Islam, Nazrul; Richard, Derek

2018-05-24

Local delivery of drug to the target organ via inhalation offers enormous benefits in the management of many diseases. Lung cancer is the most common of all cancers and it is the leading cause of death worldwide. Currently available treatment systems (intravenous or oral drug delivery) are not efficient in accumulating the delivered drug into the target tumor cells and are usually associated with various systemic and dose-related adverse effects. The pulmonary drug delivery technology would enable preferential accumulation of drug within the cancer cell and thus be superior to intravenous and oral delivery in reducing cancer cell proliferation and minimising the systemic adverse effects. Site-specific drug delivery via inhalation for the treatment of lung cancer is both feasible and efficient. The inhaled drug delivery system is non-invasive, produces high bioavailability at low dose and avoids first pass metabolism of the delivered drug. Various anticancer drugs including chemotherapeutics, proteins and genes have been investigated for inhalation in lung cancers with significant outcomes. Pulmonary delivery of drugs from dry powder inhaler (DPI) formulation is stable and has high patient compliance. Herein, we report the potential of pulmonary drug delivery from dry powder inhaler (DPI) formulations inhibiting lung cancer cell proliferation at very low dose with reduced unwanted adverse effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Design and Synthesis of Self-Assembled Polymeric Nanoparticles for Cancer Drug Delivery

NASA Astrophysics Data System (ADS)

Logie, Jennifer

Current chemotherapeutics are plagued by poor solubility and selectivity, requiring toxic excipients in formulations and causing a number of dose limiting side effects. Nanoparticle delivery has emerged as a strategy to more effectively deliver chemotherapeutics to the tumour site. Specifically, polymeric micelles enable the solubilization of hydrophobic small molecule drugs within the core and mitigate the necessity of excipients. Notwithstanding the significant progress made in polymeric micelle delivery, translation is limited by poor stability and low drug loading. In this work, a rational design approach is used to chemically modify poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate)-graft-poly(ethylene glycol) (P(LA-co-TMCC)-g-PEG) in order to overcome these limitations and effectively deliver drug to tumours. The PEG density of the polymer system was optimized to enhance the stability of our polymeric micelles. Higher PEG densities permitted the lyophilization of micelles and enhanced the serum stability of the system. To increase the drug loading of our system, we facilitated specific intermolecular interactions within the micelle core. For drugs that form colloidal aggregates, such as pentyl-PABC doxazolidine, polymers were used to stabilize the colloidal core against aggregation and protein adsorption. For more challenging molecules, where self-assembly cannot be controlled, such as docetaxel, we modified the polymeric backbone with a peptide from the binding site of the drug to achieve loadings five times higher than those achieved in conventional micelle systems. This novel docetaxel nanoparticle was assessed in vivo in an orthotopic mouse model of breast cancer, where it showed a wider therapeutic index than the conventional ethanolic polysorbate 80 formulation. The improved tolerability of this formulation enabled higher dosing regimens and led to heightened efficacy and survival in this mouse model. Combined, these studies validated P

Recent Progress in Functional Micellar Carriers with Intrinsic Therapeutic Activities for Anticancer Drug Delivery.

PubMed

Qu, Ying; Chu, BingYang; Shi, Kun; Peng, JinRong; Qian, ZhiYong

2017-12-01

Polymeric micelles have presented superior delivery properties for poorly water-soluble chemotherapeutic agents. However, it remains discouraging that there may be some additional short or long-term toxicities caused by the metabolites of high quantities of carriers. If carriers had simultaneous therapeutic effects with the drug, these issues would not be a concern. For this, carriers not only simply act as drug carriers, but also exert an intrinsic therapeutic effect as a therapeutic agent. The functional micellar carriers would be beneficial to maximize the anticancer effect, overcome the drug resistance and reduce the systemic toxicity. In this review, we aim to summarize the recent progress on the development of functional micellar carriers with intrinsic anticancer activities for the delivery of anticancer drugs. This review focuses on the design strategies, properties of carriers and the drug loading behavior. In addition, the combinational therapeutic effects between carriers and chemotherapeutic agents are also discussed.

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

Nano carriers that enable co-delivery of chemotherapy and RNAi agents for treatment of drug-resistant cancers.

PubMed

Tsouris, Vasilios; Joo, Min Kyung; Kim, Sun Hwa; Kwon, Ick Chan; Won, You-Yeon

2014-01-01

Tumor cells exhibit drug resistant phenotypes that decrease the efficacy of chemotherapeutic treatments. The drug resistance has a genetic basis that is caused by an abnormal gene expression. There are several types of drug resistance: efflux pumps reducing the cellular concentration of the drug, alterations in membrane lipids that reduce cellular uptake, increased or altered drug targets, metabolic alteration of the drug, inhibition of apoptosis, repair of the damaged DNA, and alteration of the cell cycle checkpoints (Gottesman et al., 2002; Holohan et al., 2013). siRNA is used to silence the drug resistant phenotype and prevent this drug resistance response. Of the listed types of drug resistance, pump-type resistance (e.g., high expression of ATP-binding cassette transporter proteins such as P-glycoproteins (Pgp; also known as multi-drug resistance protein 1 or MDR1, encoded by the ATP-Binding Cassette Sub-Family B Member 1 (ABCB1) gene)) and apoptosis inhibition (e.g., expression of anti-apoptotic proteins such as Bcl-2) are the most frequently targeted for gene silencing. The co-delivery of siRNA and chemotherapeutic drugs has a synergistic effect, but many of the current projects do not control the drug release from the nanocarrier. This means that the drug payload is released before the drug resistance proteins have degraded and the drug resistance phenotype has been silenced. Current research focuses on cross-linking the carrier's polymers to prevent premature drug release, but these carriers still rely on environmental cues to release the drug payload, and the drug may be released too early. In this review, we studied the release kinetics of siRNA and chemotherapeutic drugs from a broad range of carriers. We also give examples of carriers used to co-deliver siRNA and drugs to drug-resistant tumor cells, and we examine how modifications to the carrier affect the delivery. Lastly, we give our recommendations for the future directions of the co-delivery of si

Fe₃O₄ Nanoparticles in Targeted Drug/Gene Delivery Systems.

PubMed

Shen, Lazhen; Li, Bei; Qiao, Yongsheng

2018-02-23

Fe₃O₄ nanoparticles (NPs), the most traditional magnetic nanoparticles, have received a great deal of attention in the biomedical field, especially for targeted drug/gene delivery systems, due to their outstanding magnetism, biocompatibility, lower toxicity, biodegradability, and other features. Naked Fe₃O₄ NPs are easy to aggregate and oxidize, and thus are often made with various coatings to realize superior properties for targeted drug/gene delivery. In this review, we first list the three commonly utilized synthesis methods of Fe₃O₄ NPs, and their advantages and disadvantages. In the second part, we describe coating materials that exhibit noticeable features that allow functionalization of Fe₃O₄ NPs and summarize their methods of drug targeting/gene delivery. Then our efforts will be devoted to the research status and progress of several different functionalized Fe₃O₄ NP delivery systems loaded with chemotherapeutic agents, and we present targeted gene transitive carriers in detail. In the following section, we illuminate the most effective treatment systems of the combined drug and gene therapy. Finally, we propose opportunities and challenges of the clinical transformation of Fe₃O₄ NPs targeting drug/gene delivery systems.

Multifaceted Applications of Chitosan in Cancer Drug Delivery and Therapy.

PubMed

Babu, Anish; Ramesh, Rajagopal

2017-03-27

Chitosan is a versatile polysaccharide of biological origin. Due to the biocompatible and biodegradable nature of chitosan, it is intensively utilized in biomedical applications in scaffold engineering as an absorption enhancer, and for bioactive and controlled drug release. In cancer therapy, chitosan has multifaceted applications, such as assisting in gene delivery and chemotherapeutic delivery, and as an immunoadjuvant for vaccines. The present review highlights the recent applications of chitosan and chitosan derivatives in cancer therapy.

Multifunctional particles for melanoma-targeted drug delivery.

PubMed

Wadajkar, Aniket S; Bhavsar, Zarna; Ko, Cheng-Yu; Koppolu, Bhanuprasanth; Cui, Weina; Tang, Liping; Nguyen, Kytai T

2012-08-01

New magnetic-based core-shell particles (MBCSPs) were developed to target skin cancer cells while delivering chemotherapeutic drugs in a controlled fashion. MBCSPs consist of a thermo-responsive shell of poly(N-isopropylacrylamide-acrylamide-allylamine) and a core of poly(lactic-co-glycolic acid) (PLGA) embedded with magnetite nanoparticles. To target melanoma cancer cells, MBCSPs were conjugated with Gly-Arg-Gly-Asp-Ser (GRGDS) peptides that specifically bind to the α(5)β(3) receptors of melanoma cells. MBCSPs consist of unique multifunctional and controlled drug delivery characteristics. Specially, they can provide dual drug release mechanisms (a sustained release of drugs through degradation of PLGA core and a controlled release in response to changes in temperature via thermo-responsive polymer shell), and dual targeting mechanisms (magnetic localization and receptor-mediated targeting). Results from in vitro studies indicate that GRGDS-conjugated MBCSPs have an average diameter of 296 nm and exhibit no cytotoxicity towards human dermal fibroblasts up to 500 μg ml(-1). Further, a sustained release of curcumin from the core and a temperature-dependent release of doxorubicin from the shell of MBCSPs were observed. The particles also produced a dark contrast signal in magnetic resonance imaging. Finally, the particles were accumulated at the tumor site in a B16F10 melanoma orthotopic mouse model, especially in the presence of a magnet. Results indicate great potential of MBCSPs as a platform technology to target, treat and monitor melanoma for targeted drug delivery to reduce side effects of chemotherapeutic reagents. Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Therapeutic applications of hydrogels in oral drug delivery

PubMed Central

Sharpe, Lindsey A; Daily, Adam M; Horava, Sarena D; Peppas, Nicholas A

2015-01-01

Introduction Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications. Areas covered This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed. Expert opinion Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest. PMID:24848309

Multifaceted Applications of Chitosan in Cancer Drug Delivery and Therapy

PubMed Central

Babu, Anish; Ramesh, Rajagopal

2017-01-01

Chitosan is a versatile polysaccharide of biological origin. Due to the biocompatible and biodegradable nature of chitosan, it is intensively utilized in biomedical applications in scaffold engineering as an absorption enhancer, and for bioactive and controlled drug release. In cancer therapy, chitosan has multifaceted applications, such as assisting in gene delivery and chemotherapeutic delivery, and as an immunoadjuvant for vaccines. The present review highlights the recent applications of chitosan and chitosan derivatives in cancer therapy. PMID:28346381

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.

Imaging Intratumoral Convection: Pressure Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors

PubMed Central

Gade, Terence P.F.; Buchanan, Ian M.; Motley, Matthew W.; Mazaheri, Yousef; Spees, William M.; Koutcher, Jason A.

2014-01-01

Purpose Low molecular weight (LMW) chemotherapeutics are believed to reach tumors through diffusion across capillary beds as well as membrane transporters. Unexpectedly, the delivery of these agents appears to be augmented by reductions in tumor interstitial fluid pressure (TIFP), an effect typically associated with high molecular weight molecules which reach tumors principally through convection. We investigated the hypothesis that improved intratumoral convection can alter tumor metabolism and enhance the delivery of a LMW chemotherapeutic agent to solid tumors. Experimental Design For this purpose we applied 31P/19F MR spectroscopy and spectroscopic imaging to examine the influence of type I collagenase on tumor bioenergetics and the delivery of 5-fluorouracil (5FU) to HT29 human colorectal tumors grown subcutaneously in mice. Results Collagenase effected a 34% reduction in TIFP with an attendant disintegration of intratumoral collagen. Neither mice administered collagenase nor controls receiving PBS demonstrated changes in 31PMRS-measured tumor bioenergetics; however, a time-dependent increase in the content of extracellular inorganic phosphate (Pie) was observed in tumors of collagenase-treated animals. 31PMRSI demonstrated that this increase underscored a more homogeneous distribution of Pie in tumors of experimental mice. 19FMRS showed that these changes were associated with a 50% increase in 5FU uptake in tumors of experimental versus control animals; however, this increase resulted in an increase in 5FU catabolites rather than fluoronucleotide intermediates that are required for subsequent cytotoxicity. Conclusions These data indicate that the modulation of convective flow within tumors can improve the delivery of (LMW) chemotherapeutics and demonstrate the potential role for non-invasive imaging of this process in vivo. PMID:19118052

Polymer based drug delivery systems for mycobacterial infections.

PubMed

Pandey, Rajesh; Khuller, G K

2004-07-01

In the last decade, polymer based technologies have found wide biomedical applications. Polymers, whether synthetic (e.g. polylactide-co-glycolide or PLG) or natural (e.g. alginate, chitosan etc.), have the property of encapsulating a diverse range of molecules of biological interest and bear distinct therapeutic advantages such as controlled release of drugs, protection against the premature degradation of drugs and reduction in drug toxicity. These are important considerations in the long-duration treatment of chronic infectious diseases such as tuberculosis in which patient non-compliance is the major obstacle to successful chemotherapy. Antitubercular drugs, singly or in combination, have been encapsulated in polymers to provide controlled drug release and the system also offers the flexibility of selecting various routes of administration such as oral, subcutaneous and aerosol. The present review highlights the approaches towards the preparation of polymeric antitubercular drug delivery systems, emphasizing how the route of administration may influence drug bioavailability as well as the chemotherapeutic efficacy. In addition, the pros and cons of the various delivery systems are also discussed.

Targeted drug delivery using genetically engineered diatom biosilica.

PubMed

Delalat, Bahman; Sheppard, Vonda C; Rasi Ghaemi, Soraya; Rao, Shasha; Prestidge, Clive A; McPhee, Gordon; Rogers, Mary-Louise; Donoghue, Jacqueline F; Pillay, Vinochani; Johns, Terrance G; Kröger, Nils; Voelcker, Nicolas H

2015-11-10

The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites.

Engineered Peptides for Applications in Cancer-Targeted Drug Delivery and Tumor Detection.

PubMed

Soudy, R; Byeon, N; Raghuwanshi, Y; Ahmed, S; Lavasanifar, A; Kaur, K

2017-01-01

Cancer-targeting peptides as ligands for targeted delivery of anticancer drugs or drug carriers have the potential to significantly enhance the selectivity and the therapeutic benefit of current chemotherapeutic agents. Identification of tumor-specific biomarkers like integrins, aminopeptidase N, and epidermal growth factor receptor as well as the popularity of phage display techniques along with synthetic combinatorial methods used for peptide design and structure optimization have fueled the advancement and application of peptide ligands for targeted drug delivery and tumor detection in cancer treatment, detection and guided therapy. Although considerable preclinical data have shown remarkable success in the use of tumor targeting peptides, peptides generally suffer from poor pharmacokinetics, enzymatic instability, and weak receptor affinity, and they need further structural modification before successful translation to clinics is possible. The current review gives an overview of the different engineering strategies that have been developed for peptide structure optimization to confer selectivity and stability. We also provide an update on the methods used for peptide ligand identification, and peptide- receptor interactions. Additionally, some applications for the use of peptides in targeted delivery of chemotherapeutics and diagnostics over the past 5 years are summarized. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Nanotechnology-Based Drug Delivery Systems for Melanoma Antitumoral Therapy: A Review

PubMed Central

Rigon, Roberta Balansin; Oyafuso, Márcia Helena; Fujimura, Andressa Terumi; do Prado, Alice Haddad; Gremião, Maria Palmira Daflon

2015-01-01

Melanoma (MEL) is a less common type of skin cancer, but it is more aggressive with a high mortality rate. The World Cancer Research Fund International (GLOBOCAN 2012) estimates that there were 230,000 new cases of MEL in the world in 2012. Conventional MEL treatment includes surgery and chemotherapy, but many of the chemotherapeutic agents used present undesirable properties. Drug delivery systems are an alternative strategy by which to carry antineoplastic agents. Encapsulated drugs are advantageous due to such properties as high stability, better bioavailability, controlled drug release, a long blood circulation time, selective organ or tissue distribution, a lower total required dose, and minimal toxic side effects. This review of scientific research supports applying a nanotechnology-based drug delivery system for MEL therapy. PMID:26078967

Nanotechnology-Based Drug Delivery Systems for Melanoma Antitumoral Therapy: A Review.

PubMed

Rigon, Roberta Balansin; Oyafuso, Márcia Helena; Fujimura, Andressa Terumi; Gonçalez, Maíra Lima; do Prado, Alice Haddad; Gremião, Maria Palmira Daflon; Chorilli, Marlus

2015-01-01

Melanoma (MEL) is a less common type of skin cancer, but it is more aggressive with a high mortality rate. The World Cancer Research Fund International (GLOBOCAN 2012) estimates that there were 230,000 new cases of MEL in the world in 2012. Conventional MEL treatment includes surgery and chemotherapy, but many of the chemotherapeutic agents used present undesirable properties. Drug delivery systems are an alternative strategy by which to carry antineoplastic agents. Encapsulated drugs are advantageous due to such properties as high stability, better bioavailability, controlled drug release, a long blood circulation time, selective organ or tissue distribution, a lower total required dose, and minimal toxic side effects. This review of scientific research supports applying a nanotechnology-based drug delivery system for MEL therapy.

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

). 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.

Polymeric micelles with ionic cores containing biodegradable cross-links for delivery of chemotherapeutic agents.

PubMed

Kim, Jong Oh; Sahay, Gaurav; Kabanov, Alexander V; Bronich, Tatiana K

2010-04-12

Novel functional polymeric nanocarriers with ionic cores containing biodegradable cross-links were developed for delivery of chemotherapeutic agents. Block ionomer complexes (BIC) of poly(ethylene oxide)-b-poly(methacylic acid) (PEO-b-PMA) and divalent metal cations (Ca(2+)) were utilized as templates. Disulfide bonds were introduced into the ionic cores by using cystamine as a biodegradable cross-linker. The resulting cross-linked micelles with disulfide bonds represented soft, hydrogel-like nanospheres and demonstrated a time-dependent degradation in the conditions mimicking the intracellular reducing environment. The ionic character of the cores allowed to achieve a very high level of doxorubicin (DOX) loading (50% w/w) into the cross-linked micelles. DOX-loaded degradable cross-linked micelles exhibited more potent cytotoxicity against human A2780 ovarian carcinoma cells as compared to micellar formulations without disulfide linkages. These novel biodegradable cross-linked micelles are expected to be attractive candidates for delivery of anticancer drugs.

Nanoscale coordination polymers for anticancer drug delivery

NASA Astrophysics Data System (ADS)

Phillips, Rachel Huxford

This dissertation reports the synthesis and characterization of nanoscale coordination polymers (NCPs) for anticancer drug delivery. Nanoparticles have been explored in order to address the limitations of small molecule chemotherapeutics. NCPs have been investigated as drug delivery vehicles as they can exhibit the same beneficial properties as the bulk metal-organic frameworks as well as interesting characteristics that are unique to nanomaterials. Gd-MTX (MTX = methotrexate) NCPs with a MTX loading of 71.6 wt% were synthesized and stabilized by encapsulation within a lipid bilayer containing anisamide (AA), a small molecule that targets sigma receptors which are overexpressed in many cancer tissues. Functionalization with AA allows for targeted delivery and controlled release to cancer cells, as shown by enhanced efficacy against leukemia cells. The NCPs were doped with Ru(bpy)32+ (bpy = 2,2'-bipyridine), and this formulation was utilized as an optical imaging agent by confocal microscopy. NCPs containing the chemotherapeutic pemetrexed (PMX) were synthesized using different binding metals. Zr-based materials could not be stabilized by encapsulation with a lipid bilayer, and Gd-based materials showed that PMX had degraded during synthesis. However, Hf-based NCPs containing 19.7 wt% PMX were stabilized by a lipid coating and showed in vitro efficacy against non-small cell lung cancer (NSCLC) cell lines. Enhanced efficacy was observed for formulations containing AA. Additionally, NCP formulations containing the cisplatin prodrug disuccinatocisplatin were prepared; one of these formulations could be stabilized by encapsulation within a lipid layer. Coating with a lipid layer doped with AA rendered this formulation an active targeting agent. The resulting formulation proved more potent than free cisplatin in NSCLC cell lines. Improved NCP uptake was demonstrated by confocal microscopy and competitive binding assays. Finally, a Pt(IV) oxaliplatin prodrug was

Logical enzyme triggered (LET) layer-by-layer nanocapsules for drug delivery system

NASA Astrophysics Data System (ADS)

Kelley, Marie-Michelle

Breast cancer is the second leading cause of morbidity and mortality among women in the United States. Early detection and treatment methods have resulted in 100% 5-year survival rates for stage 0-I breast cancer. Unfortunately, the 5-year survival rate of metastatic breast cancer (stage IV) is reduced fivefold. The most challenging issues of metastatic breast cancer treatment are the ability to selectively target the adenoma and adenocarcinoma cells both in their location of origin and as they metastasize following initial treatment. Multilayer/Layer-by-Layer (LbL) nanocapsules have garnered vast interest as anticancer drug delivery systems due to their ability to be easily modified, their capacity to encapsulate a wide range of chemicals and proteins, and their improved pharmacokinetics. Multilayer nanocapsule formation requires the layering of opposing charged polyelectrolytic polymers over a removable core nanoparticle. Our goal is to have a programmable nanocapsules degrade only after receiving and validating specific breast cancer biomarkers. The overall objective is to fabricate a novel programmable LbL nanocapsule with a specific logical system that will enhance functions pertinent to drug delivery systems. Our central hypothesis is that LbL technology coupled with extracellular matrix (ECM) protein substrates will result in a logical enzyme triggered LbL nanocapsule drug delivery system. This platform represents a novel approach toward a logically regulated nano-encapsulated cancer therapy that can selectively follow and deliver chemotherapeutics to cancer cells. The rationale for this project is to overcome a crucial limitation of existing drug delivery systems where chemotherapeutic can be erroneously delivered to non-carcinogenic cells.

Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery.

PubMed

Petrella, Francesco; Rimoldi, Isabella; Rizzo, Stefania; Spaggiari, Lorenzo

2017-11-23

Mesenchymal stromal cells are a population of undifferentiated multipotent adult cells possessing extensive self-renewal properties and the potential to differentiate into a variety of mesenchymal lineage cells. They express broad anti-inflammatory and immunomodulatory activity on the immune system and after transplantation can interact with the surrounding microenvironment, promoting tissue healing and regeneration. For this reason, mesenchymal stromal cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Another clinical application of mesenchymal stromal cells is the targeted delivery of chemotherapeutic agents to neoplastic cells, maximizing the cytotoxic activity against cancer cells and minimizing collateral damage to non-neoplastic tissues. Mesenchymal stem cells are home to the stroma of several primary and metastatic neoplasms and hence can be used as vectors for targeted delivery of antineoplastic drugs to the tumour microenvironment, thereby reducing systemic toxicity and maximizing antitumour effects. Paclitaxel and gemcitabine are the chemotherapeutic drugs best loaded by mesenchymal stromal cells and delivered to neoplastic cells, whereas other agents, like pemetrexed, are not internalized by mesenchymal stromal cells and therefore are not suitable for advanced antineoplastic therapy. This review focuses on the state of the art of advanced antineoplastic cell therapy and its future perspectives, emphasizing in vitro and in vivo preclinical results and future clinical applications.

Self-assembled Nanomaterials for Chemotherapeutic Applications

NASA Astrophysics Data System (ADS)

Shieh, Aileen

The self-assembly of short designed peptides into functional nanostructures is becoming a growing interest in a wide range of fields from optoelectronic devices to nanobiotechnology. In the medical field, self-assembled peptides have especially attracted attention with several of its attractive features for applications in drug delivery, tissue regeneration, biological engineering as well as cosmetic industry and also the antibiotics field. We here describe the self-assembly of peptide conjugated with organic chromophore to successfully deliver sequence independent micro RNAs into human non-small cell lung cancer cell lines. The nanofiber used as the delivery vehicle is completely non-toxic and biodegradable, and exhibit enhanced permeability effect for targeting malignant tumors. The transfection efficiency with nanofiber as the delivery vehicle is comparable to that of the commercially available RNAiMAX lipofectamine while the toxicity is significantly lower. We also conjugated the peptide sequence with camptothecin (CPT) and observed the self-assembly of nanotubes for chemotherapeutic applications. The peptide scaffold is non-toxic and biodegradable, and drug loading of CPT is high, which minimizes the issue of systemic toxicity caused by extensive burden from the elimination of drug carriers. In addition, the peptide assembly drastically increases the solubility and stability of CPT under physiological conditions in vitro, while active CPT is gradually released from the peptide chain under the slight acidic tumor cell environment. Cytotoxicity results on human colorectal cancer cells and non-small cell lung cancer cell lines display promising anti-cancer properties compared to the parental CPT drug, which cannot be used clinically due to its poor solubility and lack of stability in physiological conditions. Moreover, the peptide sequence conjugated with 5-fluorouracil formed a hydrogel with promising topical chemotherapeutic applications that also display

Advances in Bone-targeted Drug Delivery Systems for Neoadjuvant Chemotherapy for Osteosarcoma.

PubMed

Li, Cheng-Jun; Liu, Xiao-Zhou; Zhang, Lei; Chen, Long-Bang; Shi, Xin; Wu, Su-Jia; Zhao, Jian-Ning

2016-05-01

Targeted therapy for osteosarcoma includes organ, cell and molecular biological targeting; of these, organ targeting is the most mature. Bone-targeted drug delivery systems are used to concentrate chemotherapeutic drugs in bone tissues, thus potentially resolving the problem of reaching the desired foci and minimizing the toxicity and adverse effects of neoadjuvant chemotherapy. Some progress has been made in bone-targeted drug delivery systems for treatment of osteosarcoma; however, most are still at an experimental stage and there is a long transitional period to clinical application. Therefore, determining how to combine new, polymolecular and multi-pathway targets is an important research aspect of designing new bone-targeted drug delivery systems in future studies. The purpose of this article was to review the status of research on targeted therapy for osteosarcoma and to summarize the progress made thus far in developing bone-targeted drug delivery systems for neoadjuvant chemotherapy for osteosarcoma with the aim of providing new ideas for highly effective therapeutic protocols with low toxicity for patients with osteosarcoma. © 2016 Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.

Folic acid-conjugated amphiphilic alternating copolymer as a new active tumor targeting drug delivery platform.

PubMed

Li, Xia; Szewczuk, Myron R; Malardier-Jugroot, Cecile

2016-01-01

Targeted drug delivery using polymeric nanostructures is an emerging cancer research area, engineered for safer, more efficient, and effective use of chemotherapeutic drugs. A pH-responsive, active targeting delivery system was designed using folic acid functionalized amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA). The polymeric template is pH responsive, forming amphiphilic nanostructures at pH 7, allowing the encapsulation of hydrophobic drugs on its interior. Moreover, the structure is stable only at neutral pH and collapses in the acidic tumor microenvironment, releasing drugs on-site from its core. The delivery vehicle is investigated using human pancreatic PANC-1 cancer cells and RAW-Blue™ mouse macrophage reporter cell line, both of which have overly expression of folic acid receptors. To trace the cellular uptake by both cell lines, curcumin was selected as a dye and drug mimic owing to its fluorescence nature and hydrophobic properties. Fluorescent microscopy of FA-DABA-SMA loaded with curcumin revealed a significant internalization of the dye by human pancreatic PANC-1 cancer cells compared to those with unfunctionalized polymers (SMA). Moreover, the FA-DABA-SMA polymers exhibit rodlike association specific to the cells. Both empty SMA and FA-DABA-SMA show little toxicity to PANC-1 cells as characterized by WST-1 cell proliferation assay. These results clearly indicate that FA-DABA-SMA polymers show potential as an active tumor targeting drug delivery system with the ability to internalize hydrophobic chemotherapeutics after they specifically attach to cancer cells.

Hierarchically Self-Assembled Supramolecular Host-Guest Delivery System for Drug Resistant Cancer Therapy.

PubMed

Cheng, Hongwei; Fan, Xiaoshan; Wang, Xiaoyuan; Ye, Enyi; Loh, Xian Jun; Li, Zibiao; Wu, Yun-Long

2018-06-11

In this report, a new star-like copolymer β-CD- g-(PNIPAAm- b-POEGA) x , consisting of a β-CD core, grafted with temperature-responsive poly( N-isopropylacrylamide) (PNIPAAm) and biocompatible poly(oligo(ethylene glycol) acrylate) (POEGA) in a block copolymer of the arms, was used to deliver chemotherapeutics to drug resistant cancer cells and tumors. The first step of the self-assembly process involves the encapsulation of chemotherapeutics through host-guest inclusion complexation between the β-cyclodextrin cavity and the anticancer drug. Next, the chain interaction of the PNIPAAm segment at elevated temperature drives the drug-loaded β-CD- g-(PNIPAAm- b-POEGA) x /PTX inclusion complex to hierarchically self-assemble into nanosized supramolecular assemblies at 37 °C, whereas the presence of poly(ethylene glycol) (PEG) chains in the distal end of the star-like copolymer arms impart enhanced stability to the self-assembled structure. More interestingly, this supramolecular host-guest nanocomplex promoted the enhanced cellular uptake of chemotherapeutics in MDR-1 up-regulated drug resistant cancer cells and exhibited high therapeutic efficacy for suppressing drug resistant tumor growth in an in vivo mouse model, due to the increased stability, improvement in aqueous solubility, enhanced cellular uptake, and partial membrane pump impairment by taking the advantage of PEGylation and supramolecular complex between this star-like copolymer and chemotherapeutics. This work signifies that temperature-sensitive PEGylated supramolecular nanocarriers with good biocompatibility are effective in combating MDR-1 mediated drug resistance in both in vitro and in vivo models, which is of significant importance for the advanced drug delivery platform designed to combat drug resistant cancer.

Fe3O4 Nanoparticles in Targeted Drug/Gene Delivery Systems

PubMed Central

Shen, Lazhen; Li, Bei; Qiao, Yongsheng

2018-01-01

Fe3O4 nanoparticles (NPs), the most traditional magnetic nanoparticles, have received a great deal of attention in the biomedical field, especially for targeted drug/gene delivery systems, due to their outstanding magnetism, biocompatibility, lower toxicity, biodegradability, and other features. Naked Fe3O4 NPs are easy to aggregate and oxidize, and thus are often made with various coatings to realize superior properties for targeted drug/gene delivery. In this review, we first list the three commonly utilized synthesis methods of Fe3O4 NPs, and their advantages and disadvantages. In the second part, we describe coating materials that exhibit noticeable features that allow functionalization of Fe3O4 NPs and summarize their methods of drug targeting/gene delivery. Then our efforts will be devoted to the research status and progress of several different functionalized Fe3O4 NP delivery systems loaded with chemotherapeutic agents, and we present targeted gene transitive carriers in detail. In the following section, we illuminate the most effective treatment systems of the combined drug and gene therapy. Finally, we propose opportunities and challenges of the clinical transformation of Fe3O4 NPs targeting drug/gene delivery systems. PMID:29473914

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.

Drug Delivery Innovations for Enhancing the Anticancer Potential of Vitamin E Isoforms and Their Derivatives

PubMed Central

Neophytou, Christiana M.; Constantinou, Andreas I.

2015-01-01

Vitamin E isoforms have been extensively studied for their anticancer properties. Novel drug delivery systems (DDS) that include liposomes, nanoparticles, and micelles are actively being developed to improve Vitamin E delivery. Furthermore, several drug delivery systems that incorporate Vitamin E isoforms have been synthesized in order to increase the bioavailability of chemotherapeutic agents or to provide a synergistic effect. D-alpha-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) is a synthetic derivative of natural alpha-tocopherol which is gaining increasing interest in the development of drug delivery systems and has also shown promising anticancer effect as a single agent. This review provides a summary of the properties and anticancer effects of the most potent Vitamin E isoforms and an overview of the various formulations developed to improve their efficacy, with an emphasis on the use of TPGS in drug delivery approaches. PMID:26137487

Silica-based mesoporous nanoparticles for controlled drug delivery

PubMed Central

Kwon, Sooyeon; Singh, Rajendra K; Perez, Roman A; Abou Neel, Ensanya A

2013-01-01

Drug molecules with lack of specificity and solubility lead patients to take high doses of the drug to achieve sufficient therapeutic effects. This is a leading cause of adverse drug reactions, particularly for drugs with narrow therapeutic window or cytotoxic chemotherapeutics. To address these problems, there are various functional biocompatible drug carriers available in the market, which can deliver therapeutic agents to the target site in a controlled manner. Among the carriers developed thus far, mesoporous materials emerged as a promising candidate that can deliver a variety of drug molecules in a controllable and sustainable manner. In particular, mesoporous silica nanoparticles are widely used as a delivery reagent because silica possesses favourable chemical properties, thermal stability and biocompatibility. Currently, sol-gel-derived mesoporous silica nanoparticles in soft conditions are of main interest due to simplicity in production and modification and the capacity to maintain function of bioactive agents. The unique mesoporous structure of silica facilitates effective loading of drugs and their subsequent controlled release. The properties of mesopores, including pore size and porosity as well as the surface properties, can be altered depending on additives used to fabricate mesoporous silica nanoparticles. Active surface enables functionalisation to modify surface properties and link therapeutic molecules. The tuneable mesopore structure and modifiable surface of mesoporous silica nanoparticle allow incorporation of various classes of drug molecules and controlled delivery to the target sites. This review aims to present the state of knowledge of currently available drug delivery system and identify properties of an ideal drug carrier for specific application, focusing on mesoporous silica nanoparticles. PMID:24020012

Multifunctional nanomedicine platform for concurrent delivery of chemotherapeutic drugs and mild hyperthermia to ovarian cancer cells.

PubMed

Taratula, Olena; Dani, Raj Kumar; Schumann, Canan; Xu, Hong; Wang, Andrew; Song, Han; Dhagat, Pallavi; Taratula, Oleh

2013-12-15

A multifunctional tumor-targeting delivery system was developed and evaluated for an efficient treatment of drug-resistant ovarian cancer by combinatorial therapeutic modality based on chemotherapy and mild hyperthermia. The engineered iron oxide nanoparticle (IONPs)-based nanocarrier served as an efficient delivery vehicle for doxorubicin and provided the ability to heat cancer cells remotely upon exposure to an alternating magnetic field (AMF). The nanocarrier was additionally modified with polyethylene glycol and LHRH peptide to improve its biocompatibility and ability to target tumor cells. The synthesized delivery system has an average size of 97.1 nm and a zeta potential close to zero, both parameters favorable for increased stability in biological media and decreased elimination by the immune system. The nanocarrier demonstrated faster drug release in acidic conditions that mimic the tumor environment. It was also observed that the LHRH targeted delivery system could effectively enter drug resistant ovarian cancer cells, and the fate of doxorubicin was tracked with fluorescence microscope. Mild hyperthermia (40°C) generated by IONPs under exposure to AMF synergistically increased the cytotoxicity of doxorubicin delivered by the developed nanocarrier to cancer cells. Thus, the developed IONPs-based delivery system has high potential in the effective treatment of ovarian cancer by combinatorial approach. Copyright © 2013 Elsevier B.V. All rights reserved.

The application of prodrug-based nano-drug delivery strategy in cancer combination therapy.

PubMed

Ge, Yanxiu; Ma, Yakun; Li, Lingbing

2016-10-01

Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review, we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the combination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent literature are discussed to demonstrate the feasibilities of relevant technology. Copyright © 2016 Elsevier B.V. All rights reserved.

Strategy for chemotherapeutic delivery using a nanosized porous metal-organic framework with a central composite design

PubMed Central

Li, Yingpeng; Li, Xiuyan; Guan, Qingxia; Zhang, Chunjing; Xu, Ting; Dong, Yujing; Bai, Xinyu; Zhang, Weiping

2017-01-01

Background Enhancing drug delivery is an ongoing endeavor in pharmaceutics, especially when the efficacy of chemotherapy for cancer is concerned. In this study, we prepared and evaluated nanosized HKUST-1 (nanoHKUST-1), nanosized metal-organic drug delivery framework, loaded with 5-fluorouracil (5-FU) for potential use in cancer treatment. Materials and methods NanoHKUST-1 was prepared by reacting copper (II) acetate [Cu(OAc)2] and benzene-1,3,5-tricarboxylic acid (H3BTC) with benzoic acid (C6H5COOH) at room temperature (23.7°C±2.4°C). A central composite design was used to optimize 5-FU-loaded nanoHKUST-1. Contact time, ethanol concentration, and 5-FU:material ratios were the independent variables, and the entrapment efficiency of 5-FU was the response parameter measured. Powder X-ray diffraction, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nitrogen adsorption were used to determine the morphology of nanoHKUST-1. In addition, 5-FU release studies were conducted, and the in vitro cytotoxicity was evaluated. Results Entrapment efficiency and drug loading were 9.96% and 40.22%, respectively, while the small-angle X-ray diffraction patterns confirmed a regular porous structure. The SEM and TEM images of the nanoHKUST-1 confirmed the presence of round particles (diameter: approximately 100 nm) and regular polygon arrays of mesoporous channels of approximately 2–5 nm. The half-maximal lethal concentration (LC50) of the 5-FU-loaded nanoHKUST-1 was approximately 10 µg/mL. Conclusion The results indicated that nanoHKUST-1 is a potential vector worth developing as a cancer chemotherapeutic drug delivery system. PMID:28260892

Strategy for chemotherapeutic delivery using a nanosized porous metal-organic framework with a central composite design.

PubMed

Li, Yingpeng; Li, Xiuyan; Guan, Qingxia; Zhang, Chunjing; Xu, Ting; Dong, Yujing; Bai, Xinyu; Zhang, Weiping

2017-01-01

Enhancing drug delivery is an ongoing endeavor in pharmaceutics, especially when the efficacy of chemotherapy for cancer is concerned. In this study, we prepared and evaluated nanosized HKUST-1 (nanoHKUST-1), nanosized metal-organic drug delivery framework, loaded with 5-fluorouracil (5-FU) for potential use in cancer treatment. NanoHKUST-1 was prepared by reacting copper (II) acetate [Cu(OAc) 2 ] and benzene-1,3,5-tricarboxylic acid (H 3 BTC) with benzoic acid (C 6 H 5 COOH) at room temperature (23.7°C±2.4°C). A central composite design was used to optimize 5-FU-loaded nanoHKUST-1. Contact time, ethanol concentration, and 5-FU:material ratios were the independent variables, and the entrapment efficiency of 5-FU was the response parameter measured. Powder X-ray diffraction, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nitrogen adsorption were used to determine the morphology of nanoHKUST-1. In addition, 5-FU release studies were conducted, and the in vitro cytotoxicity was evaluated. Entrapment efficiency and drug loading were 9.96% and 40.22%, respectively, while the small-angle X-ray diffraction patterns confirmed a regular porous structure. The SEM and TEM images of the nanoHKUST-1 confirmed the presence of round particles (diameter: approximately 100 nm) and regular polygon arrays of mesoporous channels of approximately 2-5 nm. The half-maximal lethal concentration (LC 50 ) of the 5-FU-loaded nanoHKUST-1 was approximately 10 µg/mL. The results indicated that nanoHKUST-1 is a potential vector worth developing as a cancer chemotherapeutic drug delivery system.

PLGA Nanoparticles and Their Versatile Role in Anticancer Drug Delivery.

PubMed

Khan, Iliyas; Gothwal, Avinash; Sharma, Ashok Kumar; Kesharwani, Prashant; Gupta, Lokesh; Iyer, Arun K; Gupta, Umesh

2016-01-01

Nanotechnological advancement has become a key standard for the diagnosis and treatment of several complex disorders such as cancer by utilizing the enhanced permeability and retention effect and tumor-specific targeting. Synthesis and designing the formulation of active agents in terms of their efficient delivery is of prime importance for healthcare. The use of nanocarriers has resolved the undesirable characteristics of anticancer drugs such as low solubility and poor permeability in cells. Several types of nanoparticles (NPs) have been designed with the use of various polymers along or devoid of surface engineering for targeting tumor cells. All NPs include polymers in their framework and, of these, polylactide-co-glycolide (PLGA) is biodegradable and Food and Drug Administration approved for human use. PLGA has been used extensively in the development of NPs for anticancer drug delivery. The extensive use of PLGA NPs is promising for cancer therapy, with higher efficiency and less adverse effects. The present review focused on recent developments regarding PLGA NPs, the methods used for their preparation, their characterization, and their utility in the delivery of chemotherapeutic agents.

Potential applications for halloysite nanotubes based drug delivery systems

NASA Astrophysics Data System (ADS)

Sun, Lin

Drug delivery refers to approaches, formulations, technologies, and systems for transporting a drug in the body. The purpose is to enhance the drug efficacy and to reduce side reactions, which can significantly improve treatment outcomes. Halloysite is a naturally occurred alumino-silicate clay with a tubular structure. It is a biocompatible material with a big surface area which can be used for attachment of targeted molecules. Besides, loaded molecules can present a sustained release manner in solution. These properties make halloysite nanotubes (HNTs) a good option for drug delivery. In this study, a drug delivery system was built based on halloysite via three different fabrication methods: physical adsorption, vacuum loading and layer-by-layer coating. Methotrexate was used as the model drug. Factors that may affect performance in both drug loading and release were tested. Results showed that methotrexate could be incorporated within the HNTs system and released in a sustained manner. Layer-by-layer coating showed a better potential than the other two methods in both MTX loading and release. Besides, lower pH could greatly improve MTX loading and release while the increased number of polyelectrolytes bilayers had a limited impact. Osteosarcoma is the most common primary bone malignancy in children and adolescents. Postoperative recurrence and metastasis has become one of the leading causes for patient death after surgical remove of the tumor mass. A strategy could be a sustained release of chemotherapeutics directly at the primary tumor sites where recurrence would mostly occur. Then, this HNTs based system was tested with osteosarcoma cells in vitro to show the potential of delivering chemotherapeutics in the treatment of osteosarcoma. Methotrexate was incorporated within HNTs with a layer-bylayer coating technique, and drug coated HNTs were filled into nylon-6 which is a common material for surgical sutures in industry. Results showed that (1) methotrexate

Tumor-targeting delivery of herb-based drugs with cell-penetrating/tumor-targeting peptide-modified nanocarriers

PubMed Central

Kebebe, Dereje; Liu, Yuanyuan; Wu, Yumei; Vilakhamxay, Maikhone; Liu, Zhidong; Li, Jiawei

2018-01-01

Cancer has become one of the leading causes of mortality globally. The major challenges of conventional cancer therapy are the failure of most chemotherapeutic agents to accumulate selectively in tumor cells and their severe systemic side effects. In the past three decades, a number of drug delivery approaches have been discovered to overwhelm the obstacles. Among these, nanocarriers have gained much attention for their excellent and efficient drug delivery systems to improve specific tissue/organ/cell targeting. In order to enhance targeting efficiency further and reduce limitations of nanocarriers, nanoparticle surfaces are functionalized with different ligands. Several kinds of ligand-modified nanomedicines have been reported. Cell-penetrating peptides (CPPs) are promising ligands, attracting the attention of researchers due to their efficiency to transport bioactive molecules intracellularly. However, their lack of specificity and in vivo degradation led to the development of newer types of CPP. Currently, activable CPP and tumor-targeting peptide (TTP)-modified nanocarriers have shown dramatically superior cellular specific uptake, cytotoxicity, and tumor growth inhibition. In this review, we discuss recent advances in tumor-targeting strategies using CPPs and their limitations in tumor delivery systems. Special emphasis is given to activable CPPs and TTPs. Finally, we address the application of CPPs and/or TTPs in the delivery of plant-derived chemotherapeutic agents. PMID:29563797

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

Liposomal temozolomide drug delivery using convection enhanced delivery.

PubMed

Nordling-David, Mirjam M; Yaffe, Roni; Guez, David; Meirow, Hadar; Last, David; Grad, Etty; Salomon, Sharona; Sharabi, Shirley; Levi-Kalisman, Yael; Golomb, Gershon; Mardor, Yael

2017-09-10

Even though some progress in diagnosis and treatment has been made over the years, there is still no definitive treatment available for Glioblastoma multiforme (GBM). Convection-enhanced delivery (CED), a continuous infusion-mediated pressure gradient via intracranial catheters, studied in clinical trials, enables in situ drug concentrations several orders of magnitude greater than those achieved by systemic administration. We hypothesized that the currently limited efficacy of CED could be enhanced by a liposomal formulation, thus achieving enhanced drug localization to the tumor site with minimal toxicity. We hereby describe a novel approach for treating GBM by CED of liposomes containing the known chemotherapeutic agent, temozolomide (TMZ). A new technique for encapsulating TMZ in hydrophilic (PEGylated) liposomes, characterized by nano-size (121nm), low polydispersity index (<0.13) and with near-neutral charge (-ʒ,0.2mV), has been developed. Co-infusion of PEGylated Gd-DTPA liposomes and TMZ-liposomes by CED in GBM bearing rats, resulted in enhanced tumor detection with longer residence time than free Gd-DTPA. Treatment of GBM-bearing rats with either TMZ solution or TMZ-liposomes resulted in greater tumor inhibition and significantly higher survival. However, the longer survival and smaller tumor volumes exhibited by TMZ liposomal treatment in comparison to TMZ in solution were insignificant (p<0.053); and only significantly lower edema volumes were observed. Thus, there are no clear-cut advantages to use a liposomal delivery system of TMZ via CED over a drug solution. Copyright © 2017 Elsevier B.V. All rights reserved.

Method for protecting bone marrow against chemotherapeutic drugs and radiation therapy using transforming growth factor beta 1

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

Keller, J.R.; Ruscetti, F.W.; Wiltrout, R.

1989-06-29

Presented is a method for protecting hematopoietic stem cells from the myelotoxicity of chemotherapeutic drugs or radiation therapy, which comprises administering to a subject a therapeutically effective amount of transforming growth factor beta 1 for protecting bone marrow from the myelotoxicity of chemotherapeutic drugs or radiation therapy.

Magnetic mesoporous silica nanoparticles for potential delivery of chemotherapeutic drugs and hyperthermia.

PubMed

Tao, Cuilian; Zhu, Yufang

2014-11-07

Magnetic mesoporous silica (MMS) nanoparticles with controllable magnetization have been synthesized by encapsulating Fe3O4 nanoparticles in a mesoporous silica matrix. The structure, magnetic heating capacity and drug delivery ability of MMS nanoparticles were evaluated. The results showed that MMS nanoparticles had an average particle size of 150 nm and showed low cytotoxicity and efficient cell uptake ability. MMS nanoparticles exhibited a sustained drug release in the medium of pH 5.0, but a very slow release in the medium of pH 7.4. On the other hand, MMS nanoparticles could controllably generate heat to reach the hyperthermia temperature within a short time upon exposure to an alternating magnetic field due to the superparamagnetic behavior and controllable magnetization. Therefore, MMS nanoparticles could provide a promising multifunctional platform for the combination of chemotherapy and hyperthermia for cancer therapy.

Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come

PubMed Central

Yingchoncharoen, Phatsapong; Kalinowski, Danuta S.

2016-01-01

Cancer is a leading cause of death in many countries around the world. However, the efficacy of current standard treatments for a variety of cancers is suboptimal. First, most cancer treatments lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts. Second, many anticancer agents are highly toxic, and thus, limit their use in treatment. Third, a number of cytotoxic chemotherapeutics are highly hydrophobic, which limits their utility in cancer therapy. Finally, many chemotherapeutic agents exhibit short half-lives that curtail their efficacy. As a result of these deficiencies, many current treatments lead to side effects, noncompliance, and patient inconvenience due to difficulties in administration. However, the application of nanotechnology has led to the development of effective nanosized drug delivery systems known commonly as nanoparticles. Among these delivery systems, lipid-based nanoparticles, particularly liposomes, have shown to be quite effective at exhibiting the ability to: 1) improve the selectivity of cancer chemotherapeutic agents; 2) lower the cytotoxicity of anticancer drugs to normal tissues, and thus, reduce their toxic side effects; 3) increase the solubility of hydrophobic drugs; and 4) offer a prolonged and controlled release of agents. This review will discuss the current state of lipid-based nanoparticle research, including the development of liposomes for cancer therapy, different strategies for tumor targeting, liposomal formulation of various anticancer drugs that are commercially available, recent progress in liposome technology for the treatment of cancer, and the next generation of lipid-based nanoparticles. PMID:27363439

Well-defined single polymer nanoparticles for the antibody-targeted delivery of chemotherapeutic agents.

PubMed

Lane, D D; Chiu, D Y; Su, F Y; Srinivasan, S; Kern, H B; Press, O W; Stayton, P S; Convertine, A J

2015-02-28

Aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a series of linear copolymers of N,N-dimethylacrylamide (DMA) and 2-hydroxyethylacrylamide (HEAm) with narrow Đ values over a molecular weight range spanning three orders of magnitude (10 3 to 10 6 Da). Trithiocarbonate-based RAFT chain transfer agents (CTAs) were grafted onto these scaffolds using carbodiimide chemistry catalyzed with DMAP. The resultant graft chain transfer agent (gCTA) was subsequently employed to synthesize polymeric brushes with a number of important vinyl monomer classes including acrylamido, methacrylamido, and methacrylate. Brush polymerization kinetics were evaluated for the aqueous RAFT polymerization of DMA from a 10 arm gCTA. Polymeric brushes containing hydroxyl functionality were further functionalized in order to prepare 2nd generation gCTAs which were subsequently employed to prepare polymers with a brushed-brush architecture with molecular weights in excess of 10 6 Da. These resultant single particle nanoparticles (SNPs) were employed as drug delivery vehicles for the anthracycline-based drug doxorubicin via copolymerization of DMA with a protected carbazate monomer (bocSMA). Cell-specific targeting functionality was also introduced via copolymerization with a biotin-functional monomer (bioHEMA). Drug release of the hydrazone linked doxorubicin was evaluated as function of pH and serum and chemotherapeutic activity was evaluated in SKOV3 ovarian cancer cells.

Manufacture and Drug Delivery Applications of Silk Nanoparticles.

PubMed

Wongpinyochit, Thidarat; Johnston, Blair F; Seib, F Philipp

2016-10-08

Silk is a promising biopolymer for biomedical and pharmaceutical applications due to its outstanding mechanical properties, biocompatibility and biodegradability, as well its ability to protect and subsequently release its payload in response to a trigger. While silk can be formulated into various material formats, silk nanoparticles are emerging as promising drug delivery systems. Therefore, this article covers the procedures for reverse engineering silk cocoons to yield a regenerated silk solution that can be used to generate stable silk nanoparticles. These nanoparticles are subsequently characterized, drug loaded and explored as a potential anticancer drug delivery system. Briefly, silk cocoons are reverse engineered first by degumming the cocoons, followed by silk dissolution and clean up, to yield an aqueous silk solution. Next, the regenerated silk solution is subjected to nanoprecipitation to yield silk nanoparticles - a simple but powerful method that generates uniform nanoparticles. The silk nanoparticles are characterized according to their size, zeta potential, morphology and stability in aqueous media, as well as their ability to entrap a chemotherapeutic payload and kill human breast cancer cells. Overall, the described methodology yields uniform silk nanoparticles that can be readily explored for a myriad of applications, including their use as a potential nanomedicine.

A targeted nanoplatform co-delivering chemotherapeutic and antiangiogenic drugs as a tool to reverse multidrug resistance in breast cancer.

PubMed

Tian, Fengchun; Dahmani, Fatima Zohra; Qiao, Jianan; Ni, Jiang; Xiong, Hui; Liu, Tengfei; Zhou, Jianping; Yao, Jing

2018-06-03

Several obstacles are currently impeding the successful treatment of breast cancer, namely impaired drug accumulation into the tumor site, toxicity to normal cells and narrow therapeutic index of chemotherapy, multidrug resistance (MDR) and the metastatic spread of cancer cells through the blood and lymphatic vessels. In this regard, we designed a novel multifunctional nano-sized drug delivery system based on LyP-1 peptide-modified low-molecular-weight heparin-quercetin conjugate (PLQ). This nanosystem was developed for targeted co-delivery of multiple anticancer drugs to p32-overexpressing tumor cells and peritumoral lymphatic vessels, using LyP-1 peptide as active targeting ligand, with the aim to achieve a targeted combinatorial chemo/angiostatic therapy and MDR reversal. The cellular uptake of PLQ nanoparticles by p32-overexpressing breast cancer cells was significantly higher than nonfunctionalized nanoparticles. Besides, the anti-angiogenic activity of PLQ nanoparticles was proven by the effective inhibition of the bFGF-induced neovascularization in subcutaneous Matrigel plugs. More importantly, PLQ/GA nanoparticles with better targeting ability toward p32-positive tumors, displayed a high antitumor outcome by inhibition of tumor cells proliferation and angiogenesis. Immunohistochemistry and western blot assay showed that PLQ/GA nanoparticles significantly disrupted the lymphatic formation of tumor, and inhibited the P-glycoprotein (P-gp) expression in MCF-7 tumor cells, respectively. In conclusion, PLQ/GA nanoparticles provide a synergistic strategy for effective targeted co-delivery of chemotherapeutic and antiangiogenic agents and reversing MDR and metastasis in breast cancer. Herein, we successfully developed a novel amphiphilic nanomaterial, LyP-1-LMWH-Qu (PLQ) conjugate, consisting of a tumor-targeting moiety LyP-1, a hydrophobic quercetin (a multidrug resistance [MDR]-reversing drug) inner core, and a hydrophilic low-molecular-weight heparin (an

In vitro evaluation of paclitaxel loaded amorphous chitin nanoparticles for colon cancer drug delivery.

PubMed

Smitha, K T; Anitha, A; Furuike, T; Tamura, H; Nair, Shantikumar V; Jayakumar, R

2013-04-01

Chitin and its derivatives have been widely used in drug delivery applications due to its biocompatible, biodegradable and non-toxic nature. In this study, we have developed amorphous chitin nanoparticles (150±50 nm) and evaluated its potential as a drug delivery system. Paclitaxel (PTX), a major chemotherapeutic agent was loaded into amorphous chitin nanoparticles (AC NPs) through ionic cross-linking reaction using TPP. The prepared PTX loaded AC NPs had an average diameter of 200±50 nm. Physico-chemical characterization of the prepared nanoparticles was carried out. These nanoparticles were proven to be hemocompatible and in vitro drug release studies showed a sustained release of PTX. Cellular internalization of the NPs was confirmed by fluorescent microscopy as well as by flow cytometry. Anticancer activity studies proved the toxicity of PTX-AC NPs toward colon cancer cells. These preliminary results indicate the potential of PTX-AC NPs in colon cancer drug delivery. Copyright © 2012 Elsevier B.V. All rights reserved.

Nanodiamonds as novel nanomaterials for biomedical applications: drug delivery and imaging systems

PubMed Central

Kaur, Randeep; Badea, Ildiko

2013-01-01

Detonation nanodiamonds (NDs) are emerging as delivery vehicles for small chemical drugs and macromolecular biotechnology products due to their primary particle size of 4 to 5 nm, stable inert core, reactive surface, and ability to form hydrogels. Nanoprobe technology capitalizes on the intrinsic fluorescence, high refractive index, and unique Raman signal of the NDs, rendering them attractive for in vitro and in vivo imaging applications. This review provides a brief introduction of the various types of NDs and describes the development of procedures that have led to stable single-digit-sized ND dispersions, a crucial feature for drug delivery systems and nanoprobes. Various approaches used for functionalizing the surface of NDs are highlighted, along with a discussion of their biocompatibility status. The utilization of NDs to provide sustained release and improve the dispersion of hydrophobic molecules, of which chemotherapeutic drugs are the most investigated, is described. The prospects of improving the intracellular delivery of nucleic acids by using NDs as a platform are exemplified. The photoluminescent and optical scattering properties of NDs, together with their applications in cellular labeling, are also reviewed. Considering the progress that has been made in understanding the properties of NDs, they can be envisioned as highly efficient drug delivery and imaging biomaterials for use in animals and humans. PMID:23326195

Nanodiamonds as novel nanomaterials for biomedical applications: drug delivery and imaging systems.

PubMed

Kaur, Randeep; Badea, Ildiko

2013-01-01

Detonation nanodiamonds (NDs) are emerging as delivery vehicles for small chemical drugs and macromolecular biotechnology products due to their primary particle size of 4 to 5 nm, stable inert core, reactive surface, and ability to form hydrogels. Nanoprobe technology capitalizes on the intrinsic fluorescence, high refractive index, and unique Raman signal of the NDs, rendering them attractive for in vitro and in vivo imaging applications. This review provides a brief introduction of the various types of NDs and describes the development of procedures that have led to stable single-digit-sized ND dispersions, a crucial feature for drug delivery systems and nanoprobes. Various approaches used for functionalizing the surface of NDs are highlighted, along with a discussion of their biocompatibility status. The utilization of NDs to provide sustained release and improve the dispersion of hydrophobic molecules, of which chemotherapeutic drugs are the most investigated, is described. The prospects of improving the intracellular delivery of nucleic acids by using NDs as a platform are exemplified. The photoluminescent and optical scattering properties of NDs, together with their applications in cellular labeling, are also reviewed. Considering the progress that has been made in understanding the properties of NDs, they can be envisioned as highly efficient drug delivery and imaging biomaterials for use in animals and humans.

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.

Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come.

PubMed

Yingchoncharoen, Phatsapong; Kalinowski, Danuta S; Richardson, Des R

2016-07-01

Cancer is a leading cause of death in many countries around the world. However, the efficacy of current standard treatments for a variety of cancers is suboptimal. First, most cancer treatments lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts. Second, many anticancer agents are highly toxic, and thus, limit their use in treatment. Third, a number of cytotoxic chemotherapeutics are highly hydrophobic, which limits their utility in cancer therapy. Finally, many chemotherapeutic agents exhibit short half-lives that curtail their efficacy. As a result of these deficiencies, many current treatments lead to side effects, noncompliance, and patient inconvenience due to difficulties in administration. However, the application of nanotechnology has led to the development of effective nanosized drug delivery systems known commonly as nanoparticles. Among these delivery systems, lipid-based nanoparticles, particularly liposomes, have shown to be quite effective at exhibiting the ability to: 1) improve the selectivity of cancer chemotherapeutic agents; 2) lower the cytotoxicity of anticancer drugs to normal tissues, and thus, reduce their toxic side effects; 3) increase the solubility of hydrophobic drugs; and 4) offer a prolonged and controlled release of agents. This review will discuss the current state of lipid-based nanoparticle research, including the development of liposomes for cancer therapy, different strategies for tumor targeting, liposomal formulation of various anticancer drugs that are commercially available, recent progress in liposome technology for the treatment of cancer, and the next generation of lipid-based nanoparticles. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Sericin/Dextran Injectable Hydrogel as an Optically Trackable Drug Delivery System for Malignant Melanoma Treatment.

PubMed

Liu, Jia; Qi, Chao; Tao, Kaixiong; Zhang, Jinxiang; Zhang, Jian; Xu, Luming; Jiang, Xulin; Zhang, Yunti; Huang, Lei; Li, Qilin; Xie, Hongjian; Gao, Jinbo; Shuai, Xiaoming; Wang, Guobin; Wang, Zheng; Wang, Lin

2016-03-01

Severe side effects of cancer chemotherapy prompt developing better drug delivery systems. Injectable hydrogels are an effective site-target system. For most of injectable hydrogels, once delivered in vivo, some properties including drug release and degradation, which are critical to chemotherapeutic effects and safety, are challenging to monitor. Developing a drug delivery system for effective cancer therapy with in vivo real-time noninvasive trackability is highly desired. Although fluorescence dyes are used for imaging hydrogels, the cytotoxicity limits their applications. By using sericin, a natural photoluminescent protein from silk, we successfully synthesized a hydrazone cross-linked sericin/dextran injectable hydrogel. This hydrogel is biodegradable and biocompatible. It achieves efficient drug loading and controlled release of both macromolecular and small molecular drugs. Notably, sericin's photoluminescence from this hydrogel is directly and stably correlated with its degradation, enabling long-term in vivo imaging and real-time monitoring of the remaining drug. The hydrogel loaded with Doxorubicin significantly suppresses tumor growth. Together, the work demonstrates the efficacy of this drug delivery system, and the in vivo effectiveness of this sericin-based optical monitoring strategy, providing a potential approach for improving hydrogel design toward optimal efficiency and safety of chemotherapies, which may be widely applicable to other drug delivery systems.

The delivery of poly(lactic acid)-poly(ethylene glycol) nanoparticles loaded with non-toxic drug to overcome drug resistance for the treatment of neuroblastoma

NASA Astrophysics Data System (ADS)

Dhulekar, Jhilmil

Neuroblastoma is a rare cancer of the sympathetic nervous system. A neuroblastoma tumor develops in the nerve tissue and is diagnosed in infants and children. Approximately 10.2 per million children under the age of 15 are affected in the United States and is slightly more common in boys. Neuroblastoma constitutes 6% of all childhood cancers and has a long-term survival rate of only 15%. There are approximately 700 new cases of neuroblastoma each year in the United States. With such a low rate of survival, the development of more effective treatment methods is necessary. A number of therapies are available for the treatment of these tumors; however, clinicians and their patients face the challenges of systemic side effects and drug resistance of the tumor cells. The application of nanoparticles has the potential to provide a safer and more effective method of delivery drugs to tumors. The advantage of using nanoparticles for drug delivery is the ability to specifically or passively target tumors while reducing the harmful side effects of chemotherapeutics. Drug delivery via nanoparticles can also allow for lower dosage requirements with controlled release of the drugs, which can further reduce systemic toxicity. The aim of this research was to develop a polymeric nanoparticle drug delivery system for the treatment of high-risk neuroblastoma. Nanoparticles composed of a poly(lactic acid)-poly(ethylene glycol) block copolymer were formulated to deliver a non-toxic drug in combination with Temozolomide, a commonly used chemotherapeutic drug for the treatment of neuroblastoma. The non-toxic drug acts as an inhibitor to the DNA-repair protein present in neuroblastoma cells that is responsible for inducing drug resistance in the cells, which would potentially allow for enhanced temozolomide activity. A variety of studies were completed to prove the nanoparticles' low toxicity, loading abilities, and uptake into cells. Additionally, studies were performed to determine the

Drug delivery systems for ovarian cancer treatment: a systematic review and meta-analysis of animal studies

PubMed Central

Raavé, René; de Vries, Rob B.M.; Massuger, Leon F.; van Kuppevelt, Toin H.

2015-01-01

Current ovarian cancer treatment involves chemotherapy that has serious limitations, such as rapid clearance, unfavorable biodistribution and severe side effects. To overcome these limitations, drug delivery systems (DDS) have been developed to encapsulate chemotherapeutics for delivery to tumor cells. However, no systematic assessment of the efficacy of chemotherapy by DDS compared to free chemotherapy (not in a DDS) has been performed for animal studies. Here, we assess the efficacy of chemotherapy in DDS on survival and tumor growth inhibition in animal studies. We searched PubMed and EMBASE (via OvidSP) to systematically identify studies evaluating chemotherapeutics encapsulated in DDS for ovarian cancer treatment in animal studies. Studies were assessed for quality and risk of bias. Study characteristics were collected and outcome data (survival/hazard ratio or tumor growth inhibition) were extracted and used for meta-analyses. Meta-analysis was performed to identify and explore which characteristics of DDS influenced treatment efficacy. A total of 44 studies were included after thorough literature screening (2,735 studies found after initial search). The risk of bias was difficult to assess, mainly because of incomplete reporting. A total of 17 studies (377 animals) and 16 studies (259 animals) could be included in the meta-analysis for survival and tumor growth inhibition, respectively. In the majority of the included studies chemotherapeutics entrapped in a DDS significantly improved efficacy over free chemotherapeutics regarding both survival and tumor growth inhibition. Subgroup analyses, however, revealed that cisplatin entrapped in a DDS did not result in additional tumor growth inhibition compared to free cisplatin, although it did result in improved survival. Micelles did not show a significant tumor growth inhibition compared to free chemotherapeutics, which indicates that micelles may not be a suitable DDS for ovarian cancer treatment. Other

Ultra-small lipid-polymer hybrid nanoparticles for tumor-penetrating drug delivery

NASA Astrophysics Data System (ADS)

Dehaini, Diana; Fang, Ronnie H.; Luk, Brian T.; Pang, Zhiqing; Hu, Che-Ming J.; Kroll, Ashley V.; Yu, Chun Lai; Gao, Weiwei; Zhang, Liangfang

2016-07-01

Lipid-polymer hybrid nanoparticles, consisting of a polymeric core coated by a layer of lipids, are a class of highly scalable, biodegradable nanocarriers that have shown great promise in drug delivery applications. Here, we demonstrate the facile synthesis of ultra-small, sub-25 nm lipid-polymer hybrid nanoparticles using an adapted nanoprecipitation approach and explore their utility for targeted delivery of a model chemotherapeutic. The fabrication process is first optimized to produce a monodisperse population of particles that are stable under physiological conditions. It is shown that these ultra-small hybrid nanoparticles can be functionalized with a targeting ligand on the surface and loaded with drug inside the polymeric matrix. Further, the in vivo fate of the nanoparticles after intravenous injection is characterized by examining the blood circulation and biodistribution. In a final proof-of-concept study, targeted ultra-small hybrid nanoparticles loaded with the cancer drug docetaxel are used to treat a mouse tumor model and demonstrate improved efficacy compared to a clinically available formulation of the drug. The ability to synthesize a significantly smaller version of the established lipid-polymer hybrid platform can ultimately enhance its applicability across a wider range of applications.

Polymer-lipid hybrid systems: merging the benefits of polymeric and lipid-based nanocarriers to improve oral drug delivery.

PubMed

Rao, Shasha; Prestidge, Clive A

2016-01-01

A number of biobarriers limit efficient oral drug absorption; both polymer-based and lipid-based nanocarriers have demonstrated properties and delivery mechanisms to overcome these biobarriers in preclinical settings. Moreover, in order to address the multifaceted oral drug delivery challenges, polymer-lipid hybrid systems are now being designed to merge the beneficial features of both polymeric and lipid-based nanocarriers. Recent advances in the development of polymer-lipid hybrids with a specific focus on their viability in oral delivery are reviewed. Three classes of polymer-lipid hybrids have been identified, i.e. lipid-core polymer-shell systems, polymer-core lipid-shell systems, and matrix-type polymer-lipid hybrids. We focus on their application to overcome the various biological barriers to oral drug absorption, as exemplified by selected preclinical studies. Numerous studies have demonstrated the superiority of polymer-lipid hybrid systems to their non-hybrid counterparts in providing improved drug encapsulation, modulated drug release, and improved cellular uptake. These features have encouraged their applications in the delivery of chemotherapeutics, proteins, peptides, and vaccines. With further research expected to optimize the manufacturing and scaling up processes and in-depth pre-clinical pharmacological and toxicological assessments, these multifaceted drug delivery systems will have significant clinical impact on the oral delivery of pharmaceuticals and biopharmaceuticals.

A 3D-printed local drug delivery patch for pancreatic cancer growth suppression.

PubMed

Yi, Hee-Gyeong; Choi, Yeong-Jin; Kang, Kyung Shin; Hong, Jung Min; Pati, Ruby Gupta; Park, Moon Nyeo; Shim, In Kyong; Lee, Chan Mi; Kim, Song Cheol; Cho, Dong-Woo

2016-09-28

Since recurrence and metastasis of pancreatic cancer has a worse prognosis, chemotherapy has been typically performed to attack the remained malignant cells after resection. However, it is difficult to achieve the therapeutic concentration at the tumor site with systemic chemotherapy. Numerous local drug delivery systems have been studied to overcome the shortcomings of systemic delivery. However, because most systems involve dissolution of the drug within the carrier, the concentration of the drug is limited to the saturation solubility, and consequently cannot reach the sufficient drug dose. Therefore, we hypothesized that 3D printing of a biodegradable patch incorporated with a high drug concentration would provide a versatile shape to be administered at the exact tumor site as well as an appropriate therapeutic drug concentration with a controlled release. Here, we introduce the 3D-printed patches composed of a blend of poly(lactide-co-glycolide), polycaprolactone, and 5-fluorouracil for delivering the anti-cancer drug in a prolonged controlled manner and therapeutic dose. 3D printing technology can manipulate the geometry of the patch and the drug release kinetics. The patches were flexible, and released the drug over four weeks, and thereby suppressed growth of the subcutaneous pancreatic cancer xenografts in mice with minimized side effects. Our approach reveals that 3D printing of bioabsorbable implants containing anti-cancer drugs could be a powerful method for an effective local delivery of chemotherapeutic agents to treatment of cancers. Copyright © 2016 Elsevier B.V. All rights reserved.

Glutathionylation of UCP2 sensitizes drug resistant leukemia cells to chemotherapeutics.

PubMed

Pfefferle, Aline; Mailloux, Ryan J; Adjeitey, Cyril Nii-Klu; Harper, Mary-Ellen

2013-01-01

Uncoupling protein-2 (UCP2) is used by cells to control reactive oxygen species (ROS) production by mitochondria. This ability depends on the glutathionylation state of UCP2. UCP2 is often overexpressed in drug resistant cancer cells and therein controls cell ROS levels and limits drug toxicity. With our recent observation that glutathionylation deactivates proton leak through UCP2, we decided to test if diamide, a glutathionylation catalyst, can sensitize drug resistant cells to chemotherapeutic agents. Using drug sensitive HL-60 cells and the drug resistant HL-60 subline, Mx2, we show that chemical induction of glutathionylation selectively deactivates proton leak through UCP2 in Mx2 cells. Chemical glutathionylation of UCP2 disables chemoresistance in the Mx2 cells. Exposure to 200μM diamide led to a significant increase in Mx2 cell death that was augmented when cells were exposed to either menadione or the anthracycline doxorubicin. Diamide also sensitized Mx2 cells to a number of other chemotherapeutics. Proton leak through UCP2 contributed significantly to the energetics of the Mx2 cells. Knockdown of UCP2 led to a significant decrease in both resting and state 4 (i.e., proton leak-dependent) respiration (~43% and 62%, respectively) in Mx2 cells. Similarly diamide inhibited proton leak-dependent respiration by ~64%. In contrast, diamide had very little effect on proton leak in HL-60 cells. Collectively, our observations indicate that manipulation of UCP2 glutathionylation status can serve as a therapeutic strategy for cancer treatment. Copyright © 2012 Elsevier B.V. All rights reserved.

Enhancement of therapeutic drug and DNA delivery into cells by electroporation* Enhancement of therapeutic drug and DNA delivery into cells by electroporation

NASA Astrophysics Data System (ADS)

Rabussay, Dietmar; Dev, Nagendu B.; Fewell, Jason; Smith, Louis C.; Widera, Georg; Zhang, Lei

2003-02-01

The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as `electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing `pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100-1500 V cm-1 generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes. The safety and pharmaco

Formulation development of smart gel periodontal drug delivery system for local delivery of chemotherapeutic agents with application of experimental design.

PubMed

Dabhi, Mahesh R; Nagori, Stavan A; Gohel, Mukesh C; Parikh, Rajesh K; Sheth, Navin R

2010-01-01

Smart gel periodontal drug delivery systems (SGPDDS) containing gellan gum (0.1-0.8% w/v), lutrol F127 (14, 16, and 18% w/v), and ornidazole (1% w/v) were designed for the treatment of periodontal diseases. Each formulation was characterized in terms of in vitro gelling capacity, viscosity, rheology, content uniformity, in vitro drug release, and syringeability. In vitro gelation time and the nature of the gel formed in simulated saliva for prepared formulations showed polymeric concentration dependency. Drug release data from all formulations was fitted to different kinetic models and the Korsemeyer-Peppas model was the best fit model. Drug release was significantly decreased as the concentration of each polymer component was increased. Increasing the concentration of each polymeric component significantly increased viscosity, syringeability, and time for 50%, 70%, and 90% drug release. In conclusion, the formulations described offer a wide range of physical and drug release characteristics. The formulation containing 0.8% w/v of gellan gum and 16% w/v of lutrol F127 exhibited superior physical characteristics.

Smart multifunctional drug delivery towards anticancer therapy harmonized in mesoporous nanoparticles.

PubMed

Baek, Seonmi; Singh, Rajendra K; Khanal, Dipesh; Patel, Kapil D; Lee, Eun-Jung; Leong, Kam W; Chrzanowski, Wojciech; Kim, Hae-Won

2015-09-14

Nanomedicine seeks to apply nanoscale materials for the therapy and diagnosis of diseased and damaged tissues. Recent advances in nanotechnology have made a major contribution to the development of multifunctional nanomaterials, which represents a paradigm shift from single purpose to multipurpose materials. Multifunctional nanomaterials have been proposed to enable simultaneous target imaging and on-demand delivery of therapeutic agents only to the specific site. Most advanced systems are also responsive to internal or external stimuli. This approach is particularly important for highly potent drugs (e.g. chemotherapeutics), which should be delivered in a discreet manner and interact with cells/tissues only locally. Both advances in imaging and precisely controlled and localized delivery are critically important in cancer treatment, and the use of such systems - theranostics - holds great promise to minimise side effects and boost therapeutic effectiveness of the treatment. Among others, mesoporous silica nanoparticles (MSNPs) are considered one of the most promising nanomaterials for drug delivery. Due to their unique intrinsic features, including tunable porosity and size, large surface area, structural diversity, easily modifiable chemistry and suitability for functionalization, and biocompatibility, MSNPs have been extensively utilized as multifunctional nanocarrier systems. The combination or hybridization with biomolecules, drugs, and other nanoparticles potentiated the ability of MSNPs towards multifunctionality, and even smart actions stimulated by specified signals, including pH, optical signal, redox reaction, electricity and magnetism. This paper provides a comprehensive review of the state-of-the-art of multifunctional, smart drug delivery systems centered on advanced MSNPs, with special emphasis on cancer related applications.

Smart multifunctional drug delivery towards anticancer therapy harmonized in mesoporous nanoparticles

NASA Astrophysics Data System (ADS)

Baek, Seonmi; Singh, Rajendra K.; Khanal, Dipesh; Patel, Kapil D.; Lee, Eun-Jung; Leong, Kam W.; Chrzanowski, Wojciech; Kim, Hae-Won

2015-08-01

Nanomedicine seeks to apply nanoscale materials for the therapy and diagnosis of diseased and damaged tissues. Recent advances in nanotechnology have made a major contribution to the development of multifunctional nanomaterials, which represents a paradigm shift from single purpose to multipurpose materials. Multifunctional nanomaterials have been proposed to enable simultaneous target imaging and on-demand delivery of therapeutic agents only to the specific site. Most advanced systems are also responsive to internal or external stimuli. This approach is particularly important for highly potent drugs (e.g. chemotherapeutics), which should be delivered in a discreet manner and interact with cells/tissues only locally. Both advances in imaging and precisely controlled and localized delivery are critically important in cancer treatment, and the use of such systems - theranostics - holds great promise to minimise side effects and boost therapeutic effectiveness of the treatment. Among others, mesoporous silica nanoparticles (MSNPs) are considered one of the most promising nanomaterials for drug delivery. Due to their unique intrinsic features, including tunable porosity and size, large surface area, structural diversity, easily modifiable chemistry and suitability for functionalization, and biocompatibility, MSNPs have been extensively utilized as multifunctional nanocarrier systems. The combination or hybridization with biomolecules, drugs, and other nanoparticles potentiated the ability of MSNPs towards multifunctionality, and even smart actions stimulated by specified signals, including pH, optical signal, redox reaction, electricity and magnetism. This paper provides a comprehensive review of the state-of-the-art of multifunctional, smart drug delivery systems centered on advanced MSNPs, with special emphasis on cancer related applications.

DNA origami as an in vivo drug delivery vehicle for cancer therapy.

PubMed

Zhang, Qian; Jiang, Qiao; Li, Na; Dai, Luru; Liu, Qing; Song, Linlin; Wang, Jinye; Li, Yaqian; Tian, Jie; Ding, Baoquan; Du, Yang

2014-07-22

Many chemotherapeutics used for cancer treatments encounter issues during delivery to tumors in vivo and may have high levels of systemic toxicity due to their nonspecific distribution. Various materials have been explored to fabricate nanoparticles as drug carriers to improve delivery efficiency. However, most of these materials suffer from multiple drawbacks, such as limited biocompatibility and inability to engineer spatially addressable surfaces that can be utilized for multifunctional activity. Here, we demonstrate that DNA origami possessed enhanced tumor passive targeting and long-lasting properties at the tumor region. Particularly, the triangle-shaped DNA origami exhibits optimal tumor passive targeting accumulation. The delivery of the known anticancer drug doxorubicin into tumors by self-assembled DNA origami nanostructures was performed, and this approach showed prominent therapeutic efficacy in vivo. The DNA origami carriers were prepared through the self-assembly of M13mp18 phage DNA and hundreds of complementary DNA helper strands; the doxorubicin was subsequently noncovalently intercalated into these nanostructures. After conducting fluorescence imaging and safety evaluation, the doxorubicin-containing DNA origami exhibited remarkable antitumor efficacy without observable systemic toxicity in nude mice bearing orthotopic breast tumors labeled with green fluorescent protein. Our results demonstrated the potential of DNA origami nanostructures as innovative platforms for the efficient and safe drug delivery of cancer therapeutics in vivo.

Buccal drug delivery.

PubMed

Smart, John D

2005-05-01

Buccal formulations have been developed to allow prolonged localised therapy and enhanced systemic delivery. The buccal mucosa, however, while avoiding first-pass effects, is a formidable barrier to drug absorption, especially for biopharmaceutical products (proteins and oligonucleotides) arising from the recent advances in genomics and proteomics. The buccal route is typically used for extended drug delivery, so formulations that can be attached to the buccal mucosa are favoured. The bioadhesive polymers used in buccal drug delivery to retain a formulation are typically hydrophilic macro-molecules containing numerous hydrogen bonding groups. Newer second-generation bioadhesives have been developed and these include modified or new polymers that allow enhanced adhesion and/or drug delivery, in addition to site-specific ligands such as lectins. Over the last 20 years a wide range of formulations has been developed for buccal drug delivery (tablet, patch, liquids and semisolids) but comparatively few have found their way onto the market. Currently, this route is restricted to the delivery of a limited number of small lipophilic molecules that readily cross the buccal mucosa. However, this route could become a significant means for the delivery of a range of active agents in the coming years, if the barriers to buccal drug delivery are overcome. In particular, patient acceptability and the successful systemic delivery of large molecules (proteins, oligonucleotides and polysaccharides) via this route remains both a significant opportunity and challenge, and new/improved technologies may be required to address these.

Polymer Nanocarriers to Enhance the Efficiency of Platinum-Based Chemotherapeutics

NASA Astrophysics Data System (ADS)

Callari, Manuela

The aim of this Thesis was to design and prepare polymer nanocarriers capable of encapsulating, carrying and delivering platinum-based chemotherapeutics. Polymer nanocarrier have been widely studied and employed as platinum drug delivery systems with the primary scope to overcome limitations presented by platinum-based chemotherapeutics. The conjugation of platinum onto polymers, however, presents some challenges, and, although there has been great progress in the field of drug delivery in the past years, to date only three polymer nanocarriers for platinum drugs have found their way to the clinic. In this Thesis, hydrophilic block copolymers were synthesised via reversible addition fragmentation chain transfer (RAFT) polymerisation or N-carboxyanhydride ring-opening polymerization (NCA-ROP). Upon attachment of a hydrophobic platinum drug the block copolymer becomes amphiphilic and can self-assemble in aqueous media into nanoparticles of different morphology depending on the block copolymer features. Spherical micelles consisting of a poly(methacrylic acid) core which conjugates and encapsulates the platinum chemotherapeutic and a hydrophilic shell made of sugar blocks were prepared and their biological activities compared in vitro. Among the sugars considered here, fructose based micelles showed promising results in terms of their targeting ability towards breast cancer cells. Consequently, fructose-shelled micelles were selected to explore the effect of different loading quantities of platinum drug. It was discovered that the amount of platinum in the core of the micelle highly influences the internal morphology of the micelle which, in turn, affects the micelle-cell interactions. Micelles with low dual drug loading had better cellular uptake and higher toxicity than the micelles with high drug loading, despite having the same fructose-based outer shell. Interestingly, this aspect had been neglected by literature so far, and is important to explore. Micelles made

Spatiotemporally synchronized cancer combination therapy using photo-activated nanoparticle drug delivery systems (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hasan, Tayyaba

2016-03-01

This talk will introduce a new nanotechnology platform for cancer combination therapy that utilizes near infrared light activation not only for photodynamic damage but also as an extrinsic mechanism to initiate release of complimentary drugs to suppress dynamic bursts in molecular signaling networks that promote tumor cell survival and treatment escape. The goal is to achieve co-delivery with concomitant activity of photodynamic, molecular inhibitor and chemotherapeutic agents, selectively within the tumor. This approach overcomes challenges in achieving synergistic interactions using sequential drug delivery. Conventional drug delivery is compromised by the differential pharmacokinetics of individual agents and potentially antagonistic effects—such as vascular shutdown by one agent that limits delivery of the second. Here, photodynamic damage—which efficiently kills drug-resistant cells via damage of common proteins involved in drug-resistance (such as anti-apoptosis factors and drug-efflux transporters)—is synchronized spatially and temporally with the photo-initiated release of complimentary agents—to enable full interaction amongst the individual therapies. This spatiotemporal synchronization offers new prospects for exploiting time-sensitive synergistic interactions. Specific implementations of these concepts will be presented in preclinical models of cancer. Strategies to enable molecular-targeting of cancer cells via site-specific attachment of targeting moieties to the outer lipid shell of these nanovehicles will also be discussed. If successful in humans, this new paradigm for synchronized, tumor-focused combination therapy will ultimately supersede the present use of chronic drug injection by increasing efficacy per cycle whilst reducing systemic exposure to toxic drugs.

Current trends in the use of vitamin E-based micellar nanocarriers for anticancer drug delivery.

PubMed

Muddineti, Omkara Swami; Ghosh, Balaram; Biswas, Swati

2017-06-01

Owing to the complexity of cancer pathogenesis, conventional chemotherapy can be an inadequate method of killing cancer cells effectively. Nanoparticle-based drug delivery systems have been widely exploited pre-clinically in recent years. Areas covered: Incorporation of vitamin-E in nanocarriers have the advantage of (1) improving the hydrophobicity of the drug delivery system, thereby improving the solubility of the loaded poorly soluble anticancer drugs, (2) enhancing the biocompatibility of the polymeric drug carriers, and (3) improving the anticancer potential of the chemotherapeutic agents by reversing the cellular drug resistance via simultaneous administration. In addition to being a powerful antioxidant, vitamin E demonstrated its anticancer potential by inducing apoptosis in various cancer cell lines. Various vitamin E analogs have proven their ability to cause marked inhibition of drug efflux transporters. Expert opinion: The review discusses the potential of incorporating vitamin E in the polymeric micelles which are designed to carry poorly water-soluble anticancer drugs. Current applications of various vitamin E-based polymeric micelles with emphasis on the use of α-tocopherol, D-α-tocopheryl succinate (α-TOS) and its conjugates such as D-α-tocopheryl polyethylene glycol-succinate (TPGS) in micellar system is delineated. Advantages of utilizing polymeric micelles for drug delivery and the challenges to treat cancer, including multiple drug resistance have been discussed.

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

Controlled Drug Delivery Using Microdevices

PubMed Central

Sanjay, Sharma T.; Dou, Maowei; Fu, Guanglei; Xu, Feng; Li, XiuJun

2016-01-01

Therapeutic drugs administered systematically are evenly distributed to the whole body through blood circulation and have to cross many biological barriers before reaching the pathological site. Conventional drug delivery may make drugs inactive or reduce their potency as they may be hydrolyzed or degraded enzymatically and are rapidly excreted through the urinary system resulting in suboptimal concentration of drugs at the desired site. Controlled drug delivery aims to localize the pharmacological activity of the drug to the desired site at desired release rates. The advances made by micro/nanofluidic technologies have provided new opportunities for better-controlled drug delivery. Various components of a drug delivery system can be integrated within a single tiny micro/nanofluidic chip. This article reviews recent advances of controlled drug delivery made by microfluidic/nanofluidic technologies. We first discuss microreservoir-based drug delivery systems. Then we highlight different kinds of microneedles used for controlled drug delivery, followed with a brief discussion about the current limitations and the future prospects of controlled drug delivery systems. PMID:26813304

Controlled Drug Delivery Using Microdevices.

PubMed

Sanjay, Sharma T; Dou, Maowei; Fu, Guanglei; Xu, Feng; Li, XiuJun

Therapeutic drugs administered systematically are evenly distributed to the whole body through blood circulation and have to cross many biological barriers before reaching the pathological site. Conventional drug delivery may make drugs inactive or reduce their potency as they may be hydrolyzed or degraded enzymatically and are rapidly excreted through the urinary system resulting in suboptimal concentration of drugs at the desired site. Controlled drug delivery aims to localize the pharmacological activity of the drug to the desired site at desired release rates. The advances made by micro/nanofluidic technologies have provided new opportunities for better-controlled drug delivery. Various components of a drug delivery system can be integrated within a single tiny micro/nanofluidic chip. This article reviews recent advances of controlled drug delivery made by microfluidic/nanofluidic technologies. We first discuss microreservoir-based drug delivery systems. Then we highlight different kinds of microneedles used for controlled drug delivery, followed with a brief discussion about the current limitations and the future prospects of controlled drug delivery systems.

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

MRI in ocular drug delivery

PubMed Central

Li, S. Kevin; Lizak, Martin J.; Jeong, Eun-Kee

2008-01-01

Conventional pharmacokinetic methods for studying ocular drug delivery are invasive and cannot be conveniently applied to humans. The advancement of MRI technology has provided new opportunities in ocular drug-delivery research. MRI provides a means to non-invasively and continuously monitor ocular drug-delivery systems with a contrast agent or compound labeled with a contrast agent. It is a useful technique in pharmacokinetic studies, evaluation of drug-delivery methods, and drug-delivery device testing. Although the current status of the technology presents some major challenges to pharmaceutical research using MRI, it has a lot of potential. In the past decade, MRI has been used to examine ocular drug delivery via the subconjunctival route, intravitreal injection, intrascleral injection to the suprachoroidal space, episcleral and intravitreal implants, periocular injections, and ocular iontophoresis. In this review, the advantages and limitations of MRI in the study of ocular drug delivery are discussed. Different MR contrast agents and MRI techniques for ocular drug-delivery research are compared. Ocular drug-delivery studies using MRI are reviewed. PMID:18186077

Strategies of targeting oral drug delivery systems to the colon and their potential use for the treatment of colorectal cancer.

PubMed

Krishnaiah, Yellela S R; Khan, Mansoor A

2012-01-01

Colorectal cancer (CRC) is the third most common cause of cancer-related death in both men and women. Often, surgical intervention remains the choice in treating CRC. Traditional dosage forms used for treating CRC deliver drug to wanted as well as unwanted sites of drug action resulting in several adverse side effects. Targeted oral drug delivery systems are being investigated to target and deliver chemotherapeutic and chemopreventive agents directly to colon and rectum. Site-specific delivery of a drug to colon increases its concentration at the target site, and thus requires a lower dose with reduced incidence of side effects. The major obstacle to be overcome for successful targeting of drug to colon through oral route is that drug absorption/degradation must be avoided in stomach and small intestine before the dosage form reaches colon. The review includes discussion of physiological factors that must be considered when targeting drugs directly to colorectal region, an outline on drugs used for treatment and prevention of CRC, and a brief description of various types of colon-targeted oral drug delivery systems. The focus is on the assessment of various formulation approaches being investigated for oral colon-specific delivery of drugs used in the treatment and prevention of CRC.

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.

PEG-detachable lipid-polymer hybrid nanoparticle for delivery of chemotherapy drugs to cancer cells.

PubMed

Du, Jiang-bo; Song, Yan-feng; Ye, Wei-liang; Cheng, Ying; Cui, Han; Liu, Dao-zhou; Liu, Miao; Zhang, Bang-le; Zhou, Si-yuan

2014-08-01

The experiment aimed to increase the drug-delivery efficiency of poly-lactic-co-glycolic acid (PLGA) nanoparticles. Lipid-polymer hybrid nanoparticles (LPNs-1) were prepared using PLGA as a hydrophobic core and FA-PEG-hyd-DSPE as an amphiphilic shell. Uniform and spherical nanoparticles with an average size of 185 nm were obtained using the emulsification solvent evaporation method. The results indicated that LPNs-1 showed higher drug loading compared with naked PLGA nanoparticles (NNPs). Drug release from LPNs-1 was faster in an acidic environment than in a neutral environment. LPNs-1 showed higher cytotoxicity on KB cells, A549 cells, MDA-MB-231 cells, and MDA-MB-231/ADR cells compared with free doxorubicin (DOX) and NNPs. The results also showed that, compared with free DOX and NNPs, LPNs-1 delivered more DOX to the nuclear of KB cells and MDA-MB-231/ADR cells. LPNs-1 induced apoptosis in KB cells and MDA-MB-231/ADR cells in a dose-dependent manner. The above data indicated that DOX-loaded LPNs-1 could kill not only normal tumor cells but also drug-resistant tumor cells. These results indicated that modification of PLGA nanoparticles with FA-PEG-hyd-DSPE could considerably increase the drug-delivery efficiency and LPNs-1 had potential in the delivery of chemotherapeutic agents in the treatment of cancer.

Non-Covalent Functionalization of Carbon Nanovectors with an Antibody Enables Targeted Drug Delivery

PubMed Central

Berlin, Jacob M.; Pham, Tam T.; Sano, Daisuke; Mohamedali, Khalid A.; Marcano, Daniela C.; Myers, Jeffrey N.; Tour, James M.

2011-01-01

Current chemotherapeutics are characterized by efficient tumor cell-killing and severe side effects mostly derived from off target toxicity. Hence targeted delivery of these drugs to tumor cells is actively sought. We previously demonstrated that poly(ethylene glycol)-functionalized carbon nanovectors are able to sequester paclitaxel, a widely used hydrophobic cancer drug, by simple physisorption and deliver the drug for killing of cancer cells. The cell-killing when these drug-loaded carbon nanoparticles were used was equivalent to when a commercial formulation of paclitaxel was used. Here we show that by further mixing the drug-loaded nanoparticles with Cetuximab, a monoclonal antibody that recognizes the epidermal growth factor receptor (EGFR), paclitaxel is preferentially targeted to EGFR+ tumor cells in vitro. This supports progressing to in vivo studies. Moreover, the construct is unusual in that all three components are assembled through non-covalent interactions. Such non-covalent assembly could enable high-throughput screening of drug/antibody combinations. PMID:21736358

Association between MDR1 gene of gastrointestinal tumors, the expression of P-glycoprotein and resistance to chemotherapeutic drugs.

PubMed

Su, Jian-Li; Wang, Cheng-Hong; Kang, Hong-Gang; Zhang, Jing; Wang, Bao-Zhong; Liu, Mei-Rong; Zhao, Jun; Liu, Lin

2017-09-01

The aim of the present study was to examine and discuss the association between multidrug resistance 1 gene ( MDR1 ) of gastrointestinal tumors, the expression of P-glycoprotein and resistance to chemotherapeutic drugs. In this study, 126 cases of patients with gastrointestinal tumors admitted to hospital from February 2013 to February 2015 were selected. The expression levels of MDR1 gene were obsreved in the control population and patients before and after treatment by fluoresecent quantitative PCR. The protein expression level of P-glycoprotein was determined using western blotting and enzyme-linked immunosorbent assay. In addition, drug resistance was assessed by ATP-TCA chemosensitivity experiments. The results showed that before treatment, the expression of mRNA in MDR1 of tissues of gastrointestinal tract of the 126 cases was 108-fold larger than that of the gastrointestinal tract of the controls (p<0.05), P-glycoprotein was 87-fold larger than the expression level of the controls (p<0.05). The sensitivity of 126 tumor tissues to different chemotherapeutic drugs was determined, and the results showed that most of the tumor tissues were sensitive to chemotherapeutic drugs, and the sensitivity rate reached 96.4%. Following chemotherapy, the expression of mRNA in MDR1 of tumor tissues and the expression of P-glycoprotein decreased (p<0.05). In conclusion, the MDR1 gene and P-glycoprotein have a positive correlation with the occurrence of gastrointestinal tumors, and a negative correlation between the MDR1 gene and P-glycoprotein with resistance of chemotherapeutic drugs. Therefore, the MDR1 gene and P-glycoprotein can be used as references in the identification and diagnosis of gastrointestinal tumors.

Low dosages: new chemotherapeutic weapons on the battlefield of immune-related disease

PubMed Central

Liu, Jing; Zhao, Jie; Hu, Liang; Cao, Yuchun; Huang, Bo

2011-01-01

Chemotherapeutic drugs eliminate tumor cells at relatively high doses and are considered weapons against tumors in clinics and hospitals. However, despite their ability to induce cellular apoptosis, chemotherapeutic drugs should probably be regarded more as a class of cell regulators than cell killers, if the dosage used and the fact that their targets are involved in basic molecular events are considered. Unfortunately, the regulatory properties of chemotherapeutic drugs are usually hidden or masked by the massive cell death induced by high doses. Recent evidence has begun to suggest that low dosages of chemotherapeutic drugs might profoundly regulate various intracellular aspects of normal cells, especially immune cells. Here, we discuss the immune regulatory roles of three kinds of chemotherapeutic drugs under low-dose conditions and propose low dosages as potential new chemotherapeutic weapons on the battlefield of immune-related disease. PMID:21423201

Liposomal systems as viable drug delivery technology for skin cancer sites with an outlook on lipid-based delivery vehicles and diagnostic imaging inputs for skin conditions'.

PubMed

Akhtar, Naseem; Khan, Riaz A

2016-10-01

Skin cancer is among one of the most common human malignancies wide-spread world-over with mortality statistics rising continuously at an alarming rate. The increasing frequency of these malignancies has marked the need for adopting effective treatment plan coupled with better and site-specific delivery options for the desired therapeutic agent's availability at the affected site. The concurrent delivery approaches to cancerous tissues are under constant challenge and, as a result, are evolving and gaining advancements in terms of delivery modes, therapeutic agents and site-specificity of the therapeutics delivery. The lipid-based liposomal drug delivery is an attractive and emerging option, and which is meticulously shaping up beyond a threshold level to a promising, and viable route for the effective delivery of therapeutic agents and other required injuctions to the skin cancer. An update on liposomal delivery of chemotherapeutic agents, natural-origin compounds, photosensitizer, and DNA repair enzymes as well as other desirable and typical delivery modes employed in drug delivery and in the treatment of skin cancers is discussed in details. Moreover, liposomal delivery of nucleic acid-based therapeutics, i.e., small interfering RNA (siRNA), mRNA therapy, and RGD-linked liposomes are among the other promising novel technology under constant development. The current clinical applicability, viable clinical plans, future prospects including transport feasibility of delivery vesicles and imaging techniques in conjunction with the therapeutic agents is also discussed. The ongoing innovations in liposomal drug delivery technology for skin cancers hold promise for further development of the methodology for better, more effective and site-specific delivery as part of the better treatment plan by ensuring faster drug transport, better and full payload delivery with enough and required concentration of the dose. Copyright © 2016 Elsevier B.V. All rights reserved.

Current Perspectives on Novel Drug Delivery Systems and Therapies for Management of Prostate Cancer: An Inclusive Review.

PubMed

Bhosale, Rohit R; Gangadharappa, H V; Hani, Umme; Ali M Osmani, Riyaz; Vaghela, Rudra; Kulkarni, P K; Koganti, Venkata Sairam

2017-01-01

Prostate cancer (PC) is a prostate gland cells carcinoma, the foremost reason of cancer deaths in men in developed countries, representing most common malignancy in adult males. The key obstacle to achieve practicable therapeutic effect of active drugs and capable hopeful agents including proteins and peptides, and nucleic acid for prostate cancer is the scarcity of targeted drug delivery to cells of prostate cancer. As a result, need for novel systems, strategies or therapeutic approaches to enhance the assortment of active agents meant for prostate cancer becomes an important criterion. Currently cancer research focuses on improving treatment of prostate cancer using various novel drug delivery systems of chemotherapeutic agents. These novel drug delivery systems comprise nanoparticles and liposomes. Also, strategies or therapeutic approaches intended for the prostate cancer include radiation therapy for localized prostate cancer, hormonal therapy for suppressing tumor growth, and gene-and-immunologic therapy. These systems and approaches can deliver the drugs to their selected or targeted cancer cells for the drug release in cancer atmosphere of prostate thereby enhancing the effectiveness of tumor penetration. The objective was to collect and report the recent research findings to manage the PC. Present review encloses existing diverse novel drug delivery systems and approaches intended for the management of PC. The reported miscellaneous novel drug delivery systems along with the diverse therapies are seem to be precise, secure and relatively effective; and in consequence could lead to a new track for obliteration of prostate cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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.

Multiple emulsions as effective platforms for controlled anti-cancer drug delivery.

PubMed

Dluska, Ewa; Markowska-Radomska, Agnieszka; Metera, Agata; Tudek, Barbara; Kosicki, Konrad

2017-09-01

Developing pH-responsive multiple emulsion platforms for effective glioblastoma multiforme therapy with reduced toxicity, a drug release study and modeling. Cancer cell line: U87 MG, multiple emulsions with pH-responsive biopolymer and encapsulated doxorubicin (DOX); preparation of multiple emulsions in a Couette-Taylor flow biocontactor, in vitro release study of DOX (fluorescence intensity analysis), in vitro cytotoxicity study (alamarBlue cell viability assay) and numerical simulation of DOX release rates. The multiple emulsions offered a high DOX encapsulation efficiency (97.4 ± 1%) and pH modulated release rates of a drug. Multiple emulsions with a low concentration of DOX (0.02 μM) exhibited broadly advanced cell (U87 MG) cytotoxicity than free DOX solution used at the same concentration. Emulsion platforms could be explored for potential delivery of chemotherapeutics in glioblastoma multiforme therapy.

Self-assembled nanoparticles based on PEGylated conjugated polyelectrolyte and drug molecules for image-guided drug delivery and photodynamic therapy.

PubMed

Yuan, Youyong; Liu, Bin

2014-09-10

A drug delivery system based on poly(ethylene glycol) (PEG) grafted conjugated polyelectrolyte (CPE) has been developed to serve as a polymeric photosensitizer and drug carrier for combined photodynamic and chemotherapy. The amphiphilic brush copolymer can self-assemble into micellar nanopaticles (NPs) in aqueous media with hydrophobic conjugated polyelectrolyte backbone as the core and hydrophilic PEG as the shell. The NPs have an average diameter of about 100 nm, with the absorption and emission maxima at 502 and 598 nm, respectively, making them suitable for bioimaging applications. Moreover, the CPE itself can serve as a photosensitizer, which makes the NPs not only a carrier for drug but also a photosensitizing unit for photodynamic therapy, resulting in the combination of chemo- and photodynamic therapy for cancer. The half-maximal inhibitory concentration (IC50) value for the combination therapy to U87-MG cells is 12.7 μg mL(-1), which is much lower than that for the solely photodynamic therapy (25.5 μg mL(-1)) or chemotherapy (132.8 μg mL(-1)). To improve the tumor specificity of the system, cyclic arginine-glycine-aspartic acid (cRGD) tripeptide as the receptor to integrin αvβ3 overexpressed cancer cells was further incorporated to the surface of the NPs. The delivery system based on PEGylated CPE is easy to fabricate, which integrates the merits of targeted cancer cell image, chemotherapeutic drug delivery, and photodynamic therapy, making it promising for cancer treatment.

Multifunctional aptamer-based nanoparticles for targeted drug delivery to circumvent cancer resistance.

PubMed

Liu, Juan; Wei, Tuo; Zhao, Jing; Huang, Yuanyu; Deng, Hua; Kumar, Anil; Wang, Chenxuan; Liang, Zicai; Ma, Xiaowei; Liang, Xing-Jie

2016-06-01

By its unique advantages over traditional medicine, nanomedicine has offered new strategies for cancer treatment. In particular, the development of drug delivery strategies has focused on nanoscale particles to improve bioavailability. However, many of these nanoparticles are unable to overcome tumor resistance to chemotherapeutic agents. Recently, new opportunities for drug delivery have been provided by oligonucleotides that can self-assemble into three-dimensional nanostructures. In this work, we have designed and developed functional DNA nanostructures to deliver the chemotherapy drug doxorubicin (Dox) to resistant cancer cells. These nanostructures have two components. The first component is a DNA aptamer, which forms a dimeric G-quadruplex nanostructure to target cancer cells by binding with nucleolin. The second component is double-stranded DNA (dsDNA), which is rich in -GC- base pairs that can be applied for Dox delivery. We demonstrated that Dox was able to efficiently intercalate into dsDNA and this intercalation did not affect the aptamer's three-dimensional structure. In addition, the Aptamer-dsDNA (ApS) nanoparticle showed good stability and protected the dsDNA from degradation in bovine serum. More importantly, the ApS&Dox nanoparticle efficiently reversed the resistance of human breast cancer cells to Dox. The mechanism circumventing doxorubicin resistance by ApS&Dox nanoparticles may be predominantly by cell cycle arrest in S phase, effectively increased cell uptake and decreased cell efflux of doxorubicin. Furthermore, the ApS&Dox nanoparticles could effectively inhibit tumor growth, while less cardiotoxicity was observed. Overall, this functional DNA nanostructure provides new insights into the design of nanocarriers to overcome multidrug resistance through targeted drug delivery. Copyright © 2016 Elsevier Ltd. All rights reserved.

Stimuli-free programmable drug release for combination chemo-therapy

NASA Astrophysics Data System (ADS)

Fan, Li; Jin, Boquan; Zhang, Silu; Song, Chaojun; Li, Quan

2016-06-01

Combinational chemotherapy capable of targeted delivery and programmable multi-drug release leads to enhanced drug efficacy, and is highly desired for cancer treatment. However, effective approaches for achieving both features in a single treatment are limited. In the present work, we demonstrated programmed delivery of both chemotherapeutic and immunotherapeutic agents with tumor cell targeting capability by using SiO2 based self-decomposable nanoparticulate systems. The programmable drug delivery is realized by manipulating drug loading configurations instead of relying on external stimuli. Both in vitro and in vivo results showed specific drug binding to FAT1-expressing colon cancer cells. The loaded dual drugs were demonstrated to be delivered in a sequential manner with specific time intervals between their peak releases, which maximize the synergistic effect of the chemotherapeutics. These features led to significantly enhanced drug efficacy and reduced system toxicity. The tumor weight decreased by 1/350, together with a moderate increase in rats' body weight, which were observed when adopting the dual drug loaded nanoparticles, as compared to those of the control groups. The present system provides a simple and feasible method for the design of targeting and combination chemotherapy with programmed drug release.Combinational chemotherapy capable of targeted delivery and programmable multi-drug release leads to enhanced drug efficacy, and is highly desired for cancer treatment. However, effective approaches for achieving both features in a single treatment are limited. In the present work, we demonstrated programmed delivery of both chemotherapeutic and immunotherapeutic agents with tumor cell targeting capability by using SiO2 based self-decomposable nanoparticulate systems. The programmable drug delivery is realized by manipulating drug loading configurations instead of relying on external stimuli. Both in vitro and in vivo results showed specific drug

Characterization of particulate drug delivery systems for oral delivery of Peptide and protein drugs.

PubMed

Christophersen, Philip Carsten; Fano, Mathias; Saaby, Lasse; Yang, Mingshi; Nielsen, Hanne Mørck; Mu, Huiling

2015-01-01

Oral drug delivery is a preferred route because of good patient compliance. However, most peptide/ protein drugs are delivered via parenteral routes because of the absorption barriers in the gastrointestinal (GI) tract such as enzymatic degradation by proteases and low permeability acrossthe biological membranes. To overcome these barriers, different formulation strategies for oral delivery of biomacromolecules have been proposed, including lipid based formulations and polymer-based particulate drug delivery systems (DDS). The aim of this review is to summarize the existing knowledge about oral delivery of peptide/protein drugs and to provide an overview of formulationand characterization strategies. For a better understanding of the challenges in oral delivery of peptide/protein drugs, the composition of GI fluids and the digestion processes of different kinds of excipients in the GI tract are summarized. Additionally, the paper provides an overview of recent studies on characterization of solid drug carriers for peptide/protein drugs, drug distribution in particles, drug release and stability in simulated GI fluids, as well as the absorption of peptide/protein drugs in cell-based models. The use of biorelevant media when applicable can increase the knowledge about the quality of DDS for oral protein delivery. Hopefully, the knowledge provided in this review will aid the establishment of improved biorelevant models capable of forecasting the performance of particulate DDS for oral peptide/protein delivery.

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

Mustard-inspired delivery shuttle for enhanced blood-brain barrier penetration and effective drug delivery in glioma therapy.

PubMed

Wang, Nan; Sun, Pei; Lv, Mingming; Tong, Gangsheng; Jin, Xin; Zhu, Xinyuan

2017-05-02

Effective penetration through the blood-brain barrier (BBB) remains a challenge for the treatment of many brain diseases. In this study, a small molecule, sinapic acid (SA), extracted from mustard, was selected as a novel bioinspired BBB-permeable ligand for efficient drug delivery in glioma treatment. SA was conjugated on the surface of zwitterionic polymer poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-encapsulated bovine serum albumin (BSA)-based nanoparticles, yielding nBSA-SA. The PMPC shell serves as a protective layer to prolong the in vivo blood circulation time with a better chance to cross the BBB. Furthermore, temozolomide (TMZ), which can be loaded onto the nanoparticles via electrostatic interactions with acrylic acid (AA) to generate AA-nBSA-SA-TMZ, was applied as an excellent chemotherapeutic drug for glioma therapy. The obtained nanoparticles with a distinct size show great BBB permeability. Through the mechanism study, it was found that the cell internalization of the SA-conjugated nanoparticles is an energy-dependent process with only transient disruption of the BBB. The biological evaluation results unambiguously suggest that drug-loaded nanoparticles can lead to strong apoptosis on the tumor site and increase the median survival time of glioma-bearing mice. Overall, this novel BBB-permeable ligand SA paves the way for the delivery of cargo into the brain and provides a powerful nanoplatform for glioma therapy via intravenous administration.

Measuring the Acoustic Release of a Chemotherapeutic Agent from Folate-Targeted Polymeric Micelles.

PubMed

Abusara, Ayah; Abdel-Hafez, Mamoun; Husseini, Ghaleb

2018-08-01

In this paper, we compare the use of Bayesian filters for the estimation of release and re-encapsulation rates of a chemotherapeutic agent (namely Doxorubicin) from nanocarriers in an acoustically activated drug release system. The study is implemented using an advanced kinetic model that takes into account cavitation events causing the antineoplastic agent's release from polymeric micelles upon exposure to ultrasound. This model is an improvement over the previous representations of acoustic release that used simple zero-, first- and second-order release and re-encapsulation kinetics to study acoustically triggered drug release from polymeric micelles. The new model incorporates drug release and micellar reassembly events caused by cavitation allowing for the controlled release of chemotherapeutics specially and temporally. Different Bayesian estimators are tested for this purpose including Kalman filters (KF), Extended Kalman filters (EKF), Particle filters (PF), and multi-model KF and EKF. Simulated and experimental results are used to verify the performance of the above-mentioned estimators. The proposed methods demonstrate the utility and high-accuracy of using estimation methods in modeling this drug delivery technique. The results show that, in both cases (linear and non-linear dynamics), the modeling errors are expensive but can be minimized using a multi-model approach. In addition, particle filters are more flexible filters that perform reasonably well compared to the other two filters. The study improved the accuracy of the kinetic models used to capture acoustically activated drug release from polymeric micelles, which may in turn help in designing hardware and software capable of precisely controlling the delivered amount of chemotherapeutics to cancerous tissue.

Dual-drug delivery by porous silicon nanoparticles for improved cellular uptake, sustained release, and combination therapy.

PubMed

Wang, Chang-Fang; Mäkilä, Ermei M; Kaasalainen, Martti H; Hagström, Marja V; Salonen, Jarno J; Hirvonen, Jouni T; Santos, Hélder A

2015-04-01

Dual-drug delivery of antiangiogenic and chemotherapeutic drugs can enhance the therapeutic effect for cancer therapy. Conjugation of methotrexate (MTX) to porous silicon (PSi) nanoparticles (MTX-PSi) with positively charged surface can improve the cellular uptake of MTX and inhibit the proliferation of cancer cells. Herein, MTX-PSi conjugates sustained the release of MTX up to 96 h, and the released fragments including MTX were confirmed by mass spectrometry. The intracellular distribution of the MTX-PSi nanoparticles was confirmed by transmission electron microscopy. Compared to pure MTX, the MTX-PSi achieved similar inhibition of cell proliferation in folate receptor (FR) over-expressing U87 MG cancer cells, and a higher effect in low FR-expressing EA.hy926 cells. Nuclear fragmentation analysis demonstrated programmed cell apoptosis of MTX-PSi in the high/low FR-expressing cancer cells, whereas PSi alone at the same dose had a minor effect on cell apoptosis. Finally, the porous structure of MTX-PSi enabled a successful concomitant loading of another anti-angiogenic hydrophobic drug, sorafenib, and considerably enhanced the dissolution rate of sorafenib. Overall, the MTX-PSi nanoparticles can be used as a platform for combination chemotherapy by simultaneously enhancing the dissolution rate of a hydrophobic drug and sustaining the release of a conjugated chemotherapeutic drug. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

A co-delivery nanosystem of chemotherapeutics and DNAzyme overcomes cancer drug resistance and metastasis

NASA Astrophysics Data System (ADS)

Sun, Shu-Pin; Liu, Ching-Ping; Huang, I.-Ping; Chu, Chia-Hui; Chung, Ming-Fang; Cheng, Shih-Hsun; Lin, Shu-Yi; Lo, Leu-Wei

2017-12-01

Multidrug resistance (MDR) constitutes a major problem in the management of cancer and cancer metastasized from primary-source tumor causes cancer-related deaths. Our new approach is the co-delivery of chemotherapy drugs with a transcription-factor-targeting genetic agent to simultaneously inhibit the growth and metastasis of cancer cells. C-Jun is a transcription factor that regulates multidrug resistance-associated protein 1 (MRP1) pump efflux transcription and tumor metastasis. In this work, we reported that mesoporous silica nanoparticles (MSNs) can be functionalized to co-deliver doxorubicin (Dox) and DNAzyme (Dz) to increase cancer cell killing in an additive fashion. The MSNs were sequentially conjugated with Dox into the MSNs’ nanochannels and Dz onto the MSNs’ outermost surface to target c-Jun as the Dox@MSN-Dz co-delivery system. The Dox-resistant PC-3 cells treated with Dox@MSN-Dz efficiently enhanced the intracellular Dox concentration due to the abrogation of Dox-induced MRP1 expression through the downregulation of c-Jun expression by Dz. Additionally, significant reductions in invasion and migration related to metastasis were also observed in cells treated with Dox@MSN-Dz. Therefore, our results contribute new insight to the treatment of MDR combined metastatic cancer cells, worthwhile for studying its potential for development in clinical translation.

Thermally targeted delivery of chemotherapeutics and anti-cancer peptides by elastin-like polypeptide.

PubMed

Raucher, Drazen; Massodi, Iqbal; Bidwell, Gene L

2008-03-01

Current chemotherapy treatment of solid tumors is limited due to a lack of specific delivery of the drugs to the tumor, leading to systemic toxicity. Therefore, it is necessary to develop targeted cancer therapies and tumor-targeted drug carriers. The authors review the development of elastin-like polypeptide (ELP) as a potential carrier for thermally targeted delivery of therapeutics. The authors searched Medline for articles concerning the application of ELP as a drug delivery vector for small molecule drugs and therapeutic peptides. ELP has been demonstrated to be a promising thermally targeted carrier. Further examination of the in vivo biodistribution and efficacy will provide the necessary data to advance ELP technology toward the ultimate goal of human therapeutics.

Polymers for Drug Delivery Systems

PubMed Central

Liechty, William B.; Kryscio, David R.; Slaughter, Brandon V.; Peppas, Nicholas A.

2012-01-01

Polymers have played an integral role in the advancement of drug delivery technology by providing controlled release of therapeutic agents in constant doses over long periods, cyclic dosage, and tunable release of both hydrophilic and hydrophobic drugs. From early beginnings using off-the-shelf materials, the field has grown tremendously, driven in part by the innovations of chemical engineers. Modern advances in drug delivery are now predicated upon the rational design of polymers tailored for specific cargo and engineered to exert distinct biological functions. In this review, we highlight the fundamental drug delivery systems and their mathematical foundations and discuss the physiological barriers to drug delivery. We review the origins and applications of stimuli-responsive polymer systems and polymer therapeutics such as polymer-protein and polymer-drug conjugates. The latest developments in polymers capable of molecular recognition or directing intracellular delivery are surveyed to illustrate areas of research advancing the frontiers of drug delivery. PMID:22432577

Enzyme responsive drug delivery system based on mesoporous silica nanoparticles for tumor therapy in vivo

NASA Astrophysics Data System (ADS)

Liu, Yun; Ding, Xingwei; Li, Jinghua; Luo, Zhong; Hu, Yan; Liu, Junjie; Dai, Liangliang; Zhou, Jun; Hou, Changjun; Cai, Kaiyong

2015-04-01

To reduce the toxic side effects of traditional chemotherapeutics in vivo, we designed and constructed a biocompatible, matrix metalloproteinases (MMPs) responsive drug delivery system based on mesoporous silica nanoparticles (MSNs). MMPs substrate peptide containing PLGLAR (sensitive to MMPs) was immobilized onto the surfaces of amino-functionalized MSNs via an amidation reaction, serving as MMPs sensitive intermediate linker. Bovine serum albumin was then covalently coupled to linker as end-cap for sealing the mesopores of MSNs. Lactobionic acid was further conjugated to the system as targeting motif. Doxorubicin hydrochloride was used as the model anticancer drug in this study. A series of characterizations revealed that the system was successfully constructed. The peptide-functionalized MSNs system demonstrated relatively high sensitivity to MMPs for triggering drug delivery, which was potentially important for tumor therapy since the tumor’s microenvironment overexpressed MMPs in nature. The in vivo experiments proved that the system could efficiently inhibit the tumor growth with minimal side effects. This study provides an approach for the development of the next generation of nanotherapeutics toward efficient cancer treatment.

Nanopharmaceutics: phytochemical-based controlled or sustained drug-delivery systems for cancer treatment.

PubMed

Jeetah, Roubeena; Bhaw-Luximon, Archana; Jhurry, Dhanjay

2014-09-01

This review is an attempt to assess the different classes of phytochemicals and some of their members which have been encapsulated into nanocarrier systems for their chemotherapeutic or chemopreventive properties. Given the broad spectrum of nanomedicines currently in clinical trial and clinical use from polymer-protein conjugates, through nanocrystals, nanogels, dendrimers to ethosomes, the focus of this review will be on block copolymer nanomicelles, nanoparticles, polymer-drug conjugates, liposomes and solid lipid nanocarriers (SLNs). The twenty phytochemicals investigated for encapsulation and targeted delivery were selected from a variety of classes intended to encompass the largest possible chemical compositions, namely flavonoids, aromatic acids, xanthones, terpenes, quinones, lignans and alkaloids. To the best of our knowledge, reviews on the nanoencapsulation of these phytochemicals and their delivery are not available. In this review, the issues associated with the limited use of each phytochemical in cancer therapy in humans are reviewed and the advantages of entrapment into nanocarriers are assessed in terms of drug loading efficiency, size of nanocarriers, drug release profiles and in vitro and/or in vivo testing specific to cancer research, e.g., cytotoxicity assay, cell inhibition/viability, scavenging of reactive oxygen species and biodistribution studies (elimination half-life and mean residence time).

Ocular drug delivery systems: An overview

PubMed Central

Patel, Ashaben; Cholkar, Kishore; Agrahari, Vibhuti; Mitra, Ashim K

2014-01-01

The major challenge faced by today’s pharmacologist and formulation scientist is ocular drug delivery. Topical eye drop is the most convenient and patient compliant route of drug administration, especially for the treatment of anterior segment diseases. Delivery of drugs to the targeted ocular tissues is restricted by various precorneal, dynamic and static ocular barriers. Also, therapeutic drug levels are not maintained for longer duration in target tissues. In the past two decades, ocular drug delivery research acceleratedly advanced towards developing a novel, safe and patient compliant formulation and drug delivery devices/techniques, which may surpass these barriers and maintain drug levels in tissues. Anterior segment drug delivery advances are witnessed by modulation of conventional topical solutions with permeation and viscosity enhancers. Also, it includes development of conventional topical formulations such as suspensions, emulsions and ointments. Various nanoformulations have also been introduced for anterior segment ocular drug delivery. On the other hand, for posterior ocular delivery, research has been immensely focused towards development of drug releasing devices and nanoformulations for treating chronic vitreoretinal diseases. These novel devices and/or formulations may help to surpass ocular barriers and associated side effects with conventional topical drops. Also, these novel devices and/or formulations are easy to formulate, no/negligibly irritating, possess high precorneal residence time, sustain the drug release, and enhance ocular bioavailability of therapeutics. An update of current research advancement in ocular drug delivery necessitates and helps drug delivery scientists to modulate their think process and develop novel and safe drug delivery strategies. Current review intends to summarize the existing conventional formulations for ocular delivery and their advancements followed by current nanotechnology based formulation developments

Ocular drug delivery systems: An overview.

PubMed

Patel, Ashaben; Cholkar, Kishore; Agrahari, Vibhuti; Mitra, Ashim K

The major challenge faced by today's pharmacologist and formulation scientist is ocular drug delivery. Topical eye drop is the most convenient and patient compliant route of drug administration, especially for the treatment of anterior segment diseases. Delivery of drugs to the targeted ocular tissues is restricted by various precorneal, dynamic and static ocular barriers. Also, therapeutic drug levels are not maintained for longer duration in target tissues. In the past two decades, ocular drug delivery research acceleratedly advanced towards developing a novel, safe and patient compliant formulation and drug delivery devices/techniques, which may surpass these barriers and maintain drug levels in tissues. Anterior segment drug delivery advances are witnessed by modulation of conventional topical solutions with permeation and viscosity enhancers. Also, it includes development of conventional topical formulations such as suspensions, emulsions and ointments. Various nanoformulations have also been introduced for anterior segment ocular drug delivery. On the other hand, for posterior ocular delivery, research has been immensely focused towards development of drug releasing devices and nanoformulations for treating chronic vitreoretinal diseases. These novel devices and/or formulations may help to surpass ocular barriers and associated side effects with conventional topical drops. Also, these novel devices and/or formulations are easy to formulate, no/negligibly irritating, possess high precorneal residence time, sustain the drug release, and enhance ocular bioavailability of therapeutics. An update of current research advancement in ocular drug delivery necessitates and helps drug delivery scientists to modulate their think process and develop novel and safe drug delivery strategies. Current review intends to summarize the existing conventional formulations for ocular delivery and their advancements followed by current nanotechnology based formulation developments

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

Biomaterials for drug delivery systems.

PubMed

Buckles, R G

1983-01-01

Drug delivery systems have unusual materials requirements which derive mainly from their therapeutic role: to administer drugs over prolonged periods of time at rates that are independent of patient-to-patient variables. The chemical nature of the surfaces of such devices may stimulate biorejection processes which can be enhanced or suppressed by the simultaneous presence of the drug that is being administered. Selection of materials for such systems is further complicated by the need for compatibility with the drug contained within the system. A review of selected drug delivery systems is presented. This leads to a definition of the technologies required to develop successfully such systems as well as to categorize the classes of drug delivery systems available to the therapist. A summary of the applications of drug delivery systems will also be presented. There are five major challenges to the biomaterials scientist: (1) how to minimize the influence on delivery rate of the transient biological response that accompanies implantation of any object; (2) how to select a composition, size, shape, and flexibility that optimizes biocompatibility; (3) how to make an intravascular delivery system that will retain long-term functionality; (4) how to make a percutaneous lead for those delivery systems that cannot be implanted but which must retain functionality for extended periods; and (5) how to make biosensors of adequate compatibility and stability to use with the ultimate drug delivery system-a system that operates with feedback control.

Methotrexate-F127 conjugated mesoporous zinc hydroxyapatite as an efficient drug delivery system for overcoming chemotherapy resistance in osteosarcoma cells.

PubMed

Meshkini, Azadeh; Oveisi, Hamid

2017-10-01

The resistance of cancer cells to chemotherapeutic agents and the poor selectivity of drugs toward tumor cells are regarded as the main impediments in successful cancer therapy. Currently, the design and fabrication of stimulus-responsive drug delivery systems with high specificity toward cancer cells are gaining increasing attention and they show a promising potential for clinical applications. In this study, mesoporous zinc-substituted hydroxyapatite has been synthesized and served as a drug delivery vehicle owing to its biocompatibility and high drug loading capacity. The mesoporous nanoparticles were decorated with F127 and subsequently conjugated with methotrexate (MTX) through a stable amide linkage. Since folate receptors are overexpressed on many tumor cell surfaces, MTX on the nanocarrier system plays a dual role as a targeting molecule and a chemotherapeutic drug. The evaluation of the drug release profile revealed that MTX was cleaved from the nanoparticles by a certain type of enzyme under low pH conditions that are meant to simulate the intracellular conditions in the lysosome. Cell viability studies on primary osteosarcoma cells (Saos-2) and MTX-resistance cell lines (RSaos-2/MTX) revealed that the drug-loaded nanoparticles possess high antitumor efficacy on both of the cell lines relative to free MTX. It was also found that the inhibition of P-glycoproteins by F127 and the release of Zn 2+ ions from the nanoparticles in an acidic environment effectively potentiate the antitumor efficacy of the drug-loaded nanoparticles, leading to caspase-mediated cell death. Based on these data, MTX-F127@ZnHAP nanoparticles are pH-responsive nanocarriers with precise controlled drug release and targeting effect. Therefore, they are considered to be promising candidates capable of overcoming resistance in osteosarcoma cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Plasmonic nanocarrier grid-enhanced Raman sensor for studies of anticancer drug delivery.

PubMed

Kurzątkowska, Katarzyna; Santiago, Ty; Hepel, Maria

2017-05-15

Targeted drug delivery systems using nanoparticle nanocarriers offer remarkable promise for cancer therapy by discriminating against devastating cytotoxicity of chemotherapeutic drugs to healthy cells. To aid in the development of new drug nanocarriers, we propose a novel plasmonic nanocarrier grid-enhanced Raman sensor which can be applied for studies and testing of drug loading onto the nanocarriers, attachment of targeting ligands, dynamics of drug release, assessment of nanocarrier stability in biological environment, and general capabilities of the nanocarrier. The plasmonic nanogrid sensor offers strong Raman enhancement due to the overlapping plasmonic fields emanating from the nearest-neighbor gold nanoparticle nanocarriers and creating the enhancement "hot spots". The sensor has been tested for immobilization of an anticancer drug gemcitabine (2',2'-difluoro-2'-deoxycytidine, GEM) which is used in treatment of pancreatic tumors. The drawbacks of currently applied treatment include high systemic toxicity, rapid drug decay, and low efficacy (ca. 20%). Therefore, the development of a targeted GEM delivery system is highly desired. We have demonstrated that the proposed nanocarrier SERS sensor can be utilized to investigate attachment of targeting ligands to nanocarriers (attachment of folic acid ligand recognized by folate receptors of cancer cells is described). Further testing of the nanocarrier SERS sensor involved drug release induced by lowering pH and increasing GSH levels, both occurring in cancer cells. The proposed sensor can be utilized for a variety of drugs and targeting ligands, including those which are Raman inactive, since the linkers can act as the Raman markers, as illustrated with mercaptobenzoic acid and para-aminothiophenol. Copyright © 2017 Elsevier B.V. All rights reserved.

Calcium silicate-based drug delivery systems.

PubMed

Zhu, Ying-Jie; Guo, Xiao-Xuan; Sham, Tsun-Kong

2017-02-01

Compared with other inorganic materials such as silica, metal oxides, noble metals and carbon, calcium silicate-based materials, especially nanostructured calcium silicate materials, have high biocompatibility, bioactivity and biodegradability, high specific surface area, nanoporous/hollow structure, high drug-loading capacity, pH-responsive drug release behavior and desirable drug release properties, and thus they are promising for the application in drug delivery. Calcium silicate-based drug delivery systems have a long drug-release time, which can significantly prolong the therapeutic effect of drugs. Another advantage of calcium silicate-based drug delivery systems is their pH-responsive drug release property, which can act as an ideal platform for targeted drug delivery. Areas covered: In recent years, studies have been carried out on calcium silicate-based drug delivery systems, and important results and insights have been documented. This article is not intended to offer a comprehensive review on the research on calcium silicate-based drug delivery systems, but presents some examples reported in the literature, and includes new insights obtained by tracking the interactions between drug molecules and calcium silicate carriers on the molecular level using the synchrotron-based X-ray spectroscopy. Expert opinion: Finally, our opinions on calcium silicate-based drug delivery systems are provided, and several research directions for the future studies are proposed.

Comparison of chemotherapeutic drug resistance in cells transfected with canine ABCG2 or feline ABCG2.

PubMed

Lewis, R S; Fidel, J; Dassanayake, S; Court, M H; Burke, N S; Mealey, K L

2017-06-01

ABCG2 (ATP binding cassette subfamily G, member 2) mediates resistance to a variety of cytotoxic agents. Although human ABCG2 is well characterized, the function of canine ABCG2 has not been studied previously. Feline ABCG2 has an amino acid substitution in the adenosine triphosphate-binding domain that decreases its transport capacity relative to human ABCG2. Our goal was to compare canine ABCG2-mediated chemotherapeutic drug resistance to feline ABCG2-mediated chemotherapeutic drug resistance. HEK-293 cells stably transfected with plasmid containing canine ABCG2, feline ABCG2 or no ABCG2 were exposed to carboplatin, doxorubicin, mitoxantrone, toceranib or vincristine, and cell survival was subsequently determined. Canine ABCG2 conferred a greater degree of chemotherapy resistance than feline ABCG2 for mitoxantrone. Neither canine nor feline ABCG2 conferred resistance to doxorubicin, vincristine or toceranib. Canine, but not feline, ABCG2 conferred resistance to carboplatin, a drug that is not reported to be a substrate for ABCG2 in other species. © 2015 John Wiley & Sons Ltd.

Regression of recurrent malignant gliomas with convection-enhanced delivery of topotecan.

PubMed

Bruce, Jeffrey N; Fine, Robert L; Canoll, Peter; Yun, Jonathan; Kennedy, Benjamin C; Rosenfeld, Steven S; Sands, Stephen A; Surapaneni, Krishna; Lai, Rose; Yanes, Candix L; Bagiella, Emilia; DeLaPaz, Robert L

2011-12-01

Convection-enhanced delivery of chemotherapeutics for the treatment of malignant glioma is a technique that delivers drugs directly into a tumor and the surrounding interstitium through continuous, low-grade positive-pressure infusion. This allows high local concentrations of drug while overcoming the limitations imposed by toxicity and the blood-brain barrier in systemic therapies that prevent the use of many potentially effective drugs. To examine the safety profile of a conventional chemotherapeutic agent, topotecan, via convection-enhanced delivery in the treatment of recurrent malignant gliomas and secondarily to assess radiographic response and survival. We performed a prospective, dose-escalation phase Ib study of the topoisomerase-I inhibitor topotecan given by convection-enhanced delivery in patients with recurrent malignant gliomas. Significant antitumor activity as described by radiographic changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated. A maximum tolerated dose was established for future phase II studies. Topotecan by convection-enhanced delivery has significant antitumor activity at concentrations that are nontoxic to normal brain. The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and III trials.

Microfabrication for Drug Delivery

PubMed Central

Koch, Brendan; Rubino, Ilaria; Quan, Fu-Shi; Yoo, Bongyoung; Choi, Hyo-Jick

2016-01-01

This review is devoted to discussing the application of microfabrication technologies to target challenges encountered in life processes by the development of drug delivery systems. Recently, microfabrication has been largely applied to solve health and pharmaceutical science issues. In particular, fabrication methods along with compatible materials have been successfully designed to produce multifunctional, highly effective drug delivery systems. Microfabrication offers unique tools that can tackle problems in this field, such as ease of mass production with high quality control and low cost, complexity of architecture design and a broad range of materials. Presented is an overview of silicon- and polymer-based fabrication methods that are key in the production of microfabricated drug delivery systems. Moreover, the efforts focused on studying the biocompatibility of materials used in microfabrication are analyzed. Finally, this review discusses representative ways microfabrication has been employed to develop systems delivering drugs through the transdermal and oral route, and to improve drug eluting implants. Additionally, microfabricated vaccine delivery systems are presented due to the great impact they can have in obtaining a cold chain-free vaccine, with long-term stability. Microfabrication will continue to offer new, alternative solutions for the development of smart, advanced drug delivery systems. PMID:28773770

In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery.

PubMed

Blagus, Tanja; Markelc, Bostjan; Cemazar, Maja; Kosjek, Tina; Preat, Veronique; Miklavcic, Damijan; Sersa, Gregor

2013-12-28

Electroporation (EP) is a physical method for the delivery of molecules into cells and tissues, including the skin. In this study, in order to control the degree of transdermal and topical drug delivery, EP at different amplitudes of electric pulses was evaluated. A new in vivo real-time monitoring system based on fluorescently labeled molecules was developed, for the quantification of transdermal and topical drug delivery. EP of the mouse skin was performed with new non-invasive multi-array electrodes, delivering different amplitudes of electric pulses ranging from 70 to 570 V, between the electrode pin pairs. Patches, soaked with 4 kDa fluorescein-isothiocyanate labeled dextran (FD), doxorubicin (DOX) or fentanyl (FEN), were applied to the skin before and after EP. The new monitoring system was developed based on the delivery of FD to and through the skin. FD relative quantity was determined with fluorescence microscopy imaging, in the treated region of the skin for topical delivery and in a segment of the mouse tail for transdermal delivery. The application of electric pulses for FD delivery resulted in enhanced transdermal delivery. Depending on the amplitude of electric pulses, it increased up to the amplitude of 360 V, and decreased at higher amplitudes (460 and 570 V). Topical delivery steadily enhanced with increasing the amplitude of the delivered electric pulses, being even higher than after tape stripping used as a positive control. The non-invasive monitoring of the delivery of DOX, a fluorescent chemotherapeutic drug, qualitatively and quantitatively confirmed the effects of EP at 360 and 570 V pulse amplitudes on topical and transdermal drug delivery. Delivery of FEN at 360 and 570 V pulse amplitudes verified the observed effects as obtained with FD and DOX, by the measured physiological responses of the mice as well as FEN plasma concentration. This study demonstrates that with the newly developed non-invasive multi-array electrodes and with the

Localized delivery of chemotherapy to the cervix for radiosensitization.

PubMed

Hodge, Lucy S; Downs, Levi S; Chura, Justin C; Thomas, Sajeena G; Callery, Patrick S; Soisson, A Patrick; Kramer, Paul; Wolfe, Stephen S; Tracy, Timothy S

2012-10-01

Chemoradiation is the mainstay of therapy for advanced cervical cancer, with the most effective treatment regimens involving combinations of radiosensitizing agents. However, administration of radiosensitizing chemotherapeutics concurrently with pelvic radiation is not without side effects. The aim of this study was to examine the utility of localized drug delivery as a means of improving drug targeting of radiosensitizing chemotherapeutics to the cervix while limiting systemic toxicities. An initial proof-of-concept study was performed in 14 healthy women following local administration of diazepam utilizing a novel cervical delivery device (CerviPrep™). Uterine vein and peripheral blood samples were collected and diazepam was measured using a GC-MS method. In the follow-up study, gemcitabine was applied to the cervix in 17 women undergoing hysterectomy for various gynecological malignancies. Cervical tissue, uterine vein blood samples, and peripheral plasma were collected, and gemcitabine and its deaminated metabolite 2',2'-difluorodeoxyuridine (dFdU) were measured using HPLC-UV and LC/MS methods. Targeted delivery of diazepam to the cervix was consistent with parent drug detectable in the uterine vein of 13 of 14 women. In the second study, pharmacologically relevant concentrations of gemcitabine (0.01-6.6 nmol/g tissue) were detected in the cervical tissue of 11 of 16 available specimens with dFdU measureable in 15 samples (0.04-8.8 nmol/g tissue). Neither gemcitabine nor its metabolites were detected in the peripheral plasma of any subject. Localized drug delivery to the cervix is possible and may be useful in limiting toxicity associated with intravenous administration of chemotherapeutics for radiosensitization. Copyright © 2012 Elsevier Inc. All rights reserved.

Intracochlear Drug Delivery Systems

PubMed Central

Borenstein, Jeffrey T.

2011-01-01

Introduction Advances in molecular biology and in the basic understanding of the mechanisms associated with sensorineural hearing loss and other diseases of the inner ear, are paving the way towards new approaches for treatments for millions of patients. However, the cochlea is a particularly challenging target for drug therapy, and new technologies will be required to provide safe and efficacious delivery of these compounds. Emerging delivery systems based on microfluidic technologies are showing promise as a means for direct intracochlear delivery. Ultimately, these systems may serve as a means for extended delivery of regenerative compounds to restore hearing in patients suffering from a host of auditory diseases. Areas covered in this review Recent progress in the development of drug delivery systems capable of direct intracochlear delivery is reviewed, including passive systems such as osmotic pumps, active microfluidic devices, and systems combined with currently available devices such as cochlear implants. The aim of this article is to provide a concise review of intracochlear drug delivery systems currently under development, and ultimately capable of being combined with emerging therapeutic compounds for the treatment of inner ear diseases. Expert Opinion Safe and efficacious treatment of auditory diseases will require the development of microscale delivery devices, capable of extended operation and direct application to the inner ear. These advances will require miniaturization and integration of multiple functions, including drug storage, delivery, power management and sensing, ultimately enabling closed-loop control and timed-sequence delivery devices for treatment of these diseases. PMID:21615213

Increasing the cytotoxicity of doxorubicin in breast cancer MCF-7 cells with multidrug resistance using a mesoporous silica nanoparticle drug delivery system.

PubMed

Wang, Xin; Teng, Zhaogang; Wang, Haiyan; Wang, Chunyan; Liu, Ying; Tang, Yuxia; Wu, Jiang; Sun, Jin; Wang, Hai; Wang, Jiandong; Lu, Guangming

2014-01-01

Resistance to cytotoxic chemotherapy is the main cause of therapeutic failure and death in women with breast cancer. Overexpression of various members of the superfamily of adenosine triphosphate binding cassette (ABC)-transporters has been shown to be associated with multidrug resistance (MDR) phenotype in breast cancer cells. MDR1 protein promotes the intracellular efflux of drugs. A novel approach to address cancer drug resistance is to take advantage of the ability of nanocarriers to sidestep drug resistance mechanisms by endosomal delivery of chemotherapeutic agents. Doxorubicin (DOX) is an anthracycline antibiotic commonly used in breast cancer chemotherapy and a substrate for ABC-mediated drug efflux. In the present study, we developed breast cancer MCF-7 cells with overexpression of MDR1 and designed mesoporous silica nanoparticles (MSNs) which were used as a drug delivery system. We tested the efficacy of DOX in the breast cancer cell line MCF-7/MDR1 and in a MCF-7/MDR1 xenograft nude mouse model using the MSNs drug delivery system. Our data show that drug resistance in the human breast cancer cell line MCF-7/MDR1 can be overcome by treatment with DOX encapsulated within mesoporous silica nanoparticles.

Oral Drug Delivery Systems Comprising Altered Geometric Configurations for Controlled Drug Delivery

PubMed Central

Moodley, Kovanya; Pillay, Viness; Choonara, Yahya E.; du Toit, Lisa C.; Ndesendo, Valence M. K.; Kumar, Pradeep; Cooppan, Shivaan; Bawa, Priya

2012-01-01

Recent pharmaceutical research has focused on controlled drug delivery having an advantage over conventional methods. Adequate controlled plasma drug levels, reduced side effects as well as improved patient compliance are some of the benefits that these systems may offer. Controlled delivery systems that can provide zero-order drug delivery have the potential for maximizing efficacy while minimizing dose frequency and toxicity. Thus, zero-order drug release is ideal in a large area of drug delivery which has therefore led to the development of various technologies with such drug release patterns. Systems such as multilayered tablets and other geometrically altered devices have been created to perform this function. One of the principles of multilayered tablets involves creating a constant surface area for release. Polymeric materials play an important role in the functioning of these systems. Technologies developed to date include among others: Geomatrix® multilayered tablets, which utilizes specific polymers that may act as barriers to control drug release; Procise®, which has a core with an aperture that can be modified to achieve various types of drug release; core-in-cup tablets, where the core matrix is coated on one surface while the circumference forms a cup around it; donut-shaped devices, which possess a centrally-placed aperture hole and Dome Matrix® as well as “release modules assemblage”, which can offer alternating drug release patterns. This review discusses the novel altered geometric system technologies that have been developed to provide controlled drug release, also focusing on polymers that have been employed in such developments. PMID:22312236

Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs

PubMed Central

Braidwood, Lynne; Graham, Sheila V; Graham, Alex; Conner, Joe

2013-01-01

Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVexGM-CSF]), is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with “standard-of-care” drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with “standard-of-care” drugs merits further investigation, both preclinically and in the clinic. Numerous publications report such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions

Gx1-conjugated endostar nanoparticle: a new drug delivery system for anti-colorectal cancer in vivo

NASA Astrophysics Data System (ADS)

Zhang, Qian; Du, Yang; Li, Yaqian; Liang, Xiaolong; Yang, Xin; Tian, Jie

2014-03-01

In this study we describe a new theranostic nanostytem to combine those functions together. GX1, the peptide identified by phage display technology, is a tumor vasculature endothelium specific ligand. Endostar, a novel recombinant human endostatin, has been proved to inhibit tumor angiogenesis. In this study, Endostar-loaded PLA nanoparticles (EPNPs) were first prepared, and then GX1 was coupled to the surface of EPNPs for targeting therapy, last a near infrared (NIR) dye IRDye 800CW was conjugated to the surface of EPNPs for monitoring the biodistributon. This GX1-EPNPs-NIR dye IRDye 800CW (GEN) multifunction drug delivery system not only facilitates efficient delivery of chemotherapeutic agents to tumor site, while minimizing systemic toxicity and side effects, but also enables to real time monitor tumor targeting in vivo. Compare to the Endostar and EPNPs, the GEN inhibited the subcutaneous colon tumor more obviously both in tumor volume and bioluminescence imaging (BLI) light intensity during the 10 days drug treatment.

Protein-Based Nanomedicine Platforms for Drug Delivery

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

Ma Ham, Aihui; Tang, Zhiwen; Wu, Hong

2009-08-03

Drug delivery systems have been developed for many years, however some limitations still hurdle the pace of going to clinical phase, for example, poor biodistribution, drug molecule cytotoxicity, tissue damage, quick clearance from the circulation system, solubility and stability of drug molecules. To overcome the limitations of drug delivery, biomaterials have to be developed and applied to drug delivery to protect the drug molecules and to enhance the drug’s efficacy. Protein-based nanomedicine platforms for drug delivery are platforms comprised of naturally self-assembled protein subunits of the same protein or a combination of proteins making up a complete system. They aremore » ideal for drug delivery platforms due to their biocompatibility and biodegradability coupled with low toxicity. A variety of proteins have been used and characterized for drug delivery systems including the ferritin/apoferritin protein cage, plant derived viral capsids, the small Heat shock protein (sHsp) cage, albumin, soy and whey protein, collagen, and gelatin. There are many different types and shapes that have been prepared to deliver drug molecules using protein-based platforms including the various protein cages, microspheres, nanoparticles, hydrogels, films, minirods and minipellets. There are over 30 therapeutic compounds that have been investigated with protein-based drug delivery platforms for the potential treatment of various cancers, infectious diseases, chronic diseases, autoimmune diseases. In protein-based drug delivery platforms, protein cage is the most newly developed biomaterials for drug delivery and therapeutic applications. Their uniform sizes, multifunctions, and biodegradability push them to the frontier for drug delivery. In this review, the recent strategic development of drug delivery has been discussed with a special emphasis upon the polymer based, especially protein-based nanomedicine platforms for drug delivery. The advantages and disadvantages are

Mesoporous silica for drug delivery: Interactions with model fluorescent lipid vesicles and live cells.

PubMed

Bardhan, Munmun; Majumdar, Anupa; Jana, Sayantan; Ghosh, Tapas; Pal, Uttam; Swarnakar, Snehasikta; Senapati, Dulal

2018-01-01

Formulated mesoporous silica nanoparticle (MSN) systems offer the best possible drug delivery system through the release of drug molecules from the accessible pores. In the present investigation, steady state and time resolved fluorescence techniques along with the fluorescence imaging were applied to investigate the interactions of dye loaded MSN with fluorescent unilamellar vesicles and live cells. Here 1,2-dimyristoyl-sn-glycero-3-phospocholine (DMPC) was used to prepare Small Unilamellar Vesicles (SUVs) as the model membrane with fluorescent 1,6-diphenyl-1,3,5-hexatriene (DPH) molecule incorporated inside the lipid bilayer. The interaction of DPH incorporated DMPC membrane with Fluorescein loaded MSN lead to the release of Fluorescein (Fl) dye from the interior pores of MSN systems. The extent of release of Fl and spatial distribution of the DPH molecule has been explored by monitoring steady-state fluorescence intensity and fluorescence lifetime at physiological condition. To investigate the fate of drug molecule released from MSN, fluorescence anisotropy has been used. The drug delivery efficiency of the MSN as a carrier for doxorubicin (DOX), a fluorescent chemotherapeutic drug, has also been investigated at physiological conditions. The study gives a definite confirmation for high uptake and steady release of DOX in primary oral mucosal non-keratinized squamous cells in comparison to naked DOX treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Microspheres and Nanotechnology for Drug Delivery.

PubMed

Jóhannesson, Gauti; Stefánsson, Einar; Loftsson, Thorsteinn

2016-01-01

Ocular drug delivery to the posterior segment of the eye can be accomplished by invasive drug injections into different tissues of the eye and noninvasive topical treatment. Invasive treatment involves the risks of surgical trauma and infection, and conventional topical treatments are ineffective in delivering drugs to the posterior segment of the eye. In recent years, nanotechnology has become an ever-increasing part of ocular drug delivery. In the following, we briefly review microspheres and nanotechnology for drug delivery to the eye, including different forms of nanotechnology such as nanoparticles, microparticles, liposomes, microemulsions and micromachines. The permeation barriers and anatomical considerations linked to ocular drug delivery are discussed and a theoretical overview on drug delivery through biological membranes is given. Finally, in vitro, in vivo and human studies of x03B3;-cyclodextrin nanoparticle eyedrop suspensions are discussed as an example of nanotechnology used for drug delivery to the eye. © 2016 S. Karger AG, Basel.

Hierarchical pulmonary target nanoparticles via inhaled administration for anticancer drug delivery.

PubMed

Chen, Rui; Xu, Liu; Fan, Qin; Li, Man; Wang, Jingjing; Wu, Li; Li, Weidong; Duan, Jinao; Chen, Zhipeng

2017-11-01

Inhalation administration, compared with intravenous administration, significantly enhances chemotherapeutic drug exposure to the lung tissue and may increase the therapeutic effect for pulmonary anticancer. However, further identification of cancer cells after lung deposition of inhaled drugs is necessary to avoid side effects on normal lung tissue and to maximize drug efficacy. Moreover, as the action site of the major drug was intracellular organelles, drug target to the specific organelle is the final key for accurate drug delivery. Here, we designed a novel multifunctional nanoparticles (MNPs) for pulmonary antitumor and the material was well-designed for hierarchical target involved lung tissue target, cancer cell target, and mitochondrial target. The biodistribution in vivo determined by UHPLC-MS/MS method was employed to verify the drug concentration overwhelmingly increasing in lung tissue through inhaled administration compared with intravenous administration. Cellular uptake assay using A549 cells proved the efficient receptor-mediated cell endocytosis. Confocal laser scanning microscopy observation showed the location of MNPs in cells was mitochondria. All results confirmed the intelligent material can progressively play hierarchical target functions, which could induce more cell apoptosis related to mitochondrial damage. It provides a smart and efficient nanocarrier platform for hierarchical targeting of pulmonary anticancer drug. So far, this kind of material for pulmonary mitochondrial-target has not been seen in other reports.

Protein-Based Drug-Delivery Materials

PubMed Central

Jao, Dave; Xue, Ye; Medina, Jethro; Hu, Xiao

2017-01-01

There is a pressing need for long-term, controlled drug release for sustained treatment of chronic or persistent medical conditions and diseases. Guided drug delivery is difficult because therapeutic compounds need to survive numerous transport barriers and binding targets throughout the body. Nanoscale protein-based polymers are increasingly used for drug and vaccine delivery to cross these biological barriers and through blood circulation to their molecular site of action. Protein-based polymers compared to synthetic polymers have the advantages of good biocompatibility, biodegradability, environmental sustainability, cost effectiveness and availability. This review addresses the sources of protein-based polymers, compares the similarity and differences, and highlights characteristic properties and functionality of these protein materials for sustained and controlled drug release. Targeted drug delivery using highly functional multicomponent protein composites to guide active drugs to the site of interest will also be discussed. A systematical elucidation of drug-delivery efficiency in the case of molecular weight, particle size, shape, morphology, and porosity of materials will then be demonstrated to achieve increased drug absorption. Finally, several important biomedical applications of protein-based materials with drug-delivery function—including bone healing, antibiotic release, wound healing, and corneal regeneration, as well as diabetes, neuroinflammation and cancer treatments—are summarized at the end of this review. PMID:28772877

Protein-Based Drug-Delivery Materials.

PubMed

Jao, Dave; Xue, Ye; Medina, Jethro; Hu, Xiao

2017-05-09

There is a pressing need for long-term, controlled drug release for sustained treatment of chronic or persistent medical conditions and diseases. Guided drug delivery is difficult because therapeutic compounds need to survive numerous transport barriers and binding targets throughout the body. Nanoscale protein-based polymers are increasingly used for drug and vaccine delivery to cross these biological barriers and through blood circulation to their molecular site of action. Protein-based polymers compared to synthetic polymers have the advantages of good biocompatibility, biodegradability, environmental sustainability, cost effectiveness and availability. This review addresses the sources of protein-based polymers, compares the similarity and differences, and highlights characteristic properties and functionality of these protein materials for sustained and controlled drug release. Targeted drug delivery using highly functional multicomponent protein composites to guide active drugs to the site of interest will also be discussed. A systematical elucidation of drug-delivery efficiency in the case of molecular weight, particle size, shape, morphology, and porosity of materials will then be demonstrated to achieve increased drug absorption. Finally, several important biomedical applications of protein-based materials with drug-delivery function-including bone healing, antibiotic release, wound healing, and corneal regeneration, as well as diabetes, neuroinflammation and cancer treatments-are summarized at the end of this review.

Enhanced Delivery of Chemotherapy to Tumors Using a Multi-Component Nanochain with Radiofrequency-Tunable Drug Release

PubMed Central

Peiris, Pubudu M.; Bauer, Lisa; Toy, Randall; Tran, Emily; Pansky, Jenna; Doolittle, Elizabeth; Schmidt, Erik; Hayden, Elliott; Mayer, Aaron; Keri, Ruth A.; Griswold, Mark A.; Karathanasis, Efstathios

2012-01-01

While nanoparticles maximize the amount of chemotherapeutic drug in tumors relative to normal tissues, nanoparticle-based drugs are not accessible to the majority of cancer cells because nanoparticles display patchy, near-perivascular accumulation in tumors. To overcome the limitations of current drugs in their molecular or nanoparticle form, we developed a nanoparticle based on multi-component nanochains to deliver drug to the majority of cancer cells throughout a tumor while reducing off-target delivery. The nanoparticle is composed of three magnetic nanospheres and one doxorubicin-loaded liposome assembled in a 100-nm-long chain. These nanoparticles display prolonged blood circulation and significant intratumoral deposition in tumor models in rodents. Furthermore, the magnetic particles of the chains serve as a mechanical transducer to transfer radiofrequency energy to the drug-loaded liposome. The defects on the liposomal walls trigger the release of free drug capable of spreading throughout the entire tumor, which results in a wide-spread anticancer effect. PMID:22486623

MEMS: Enabled Drug Delivery Systems.

PubMed

Cobo, Angelica; Sheybani, Roya; Meng, Ellis

2015-05-01

Drug delivery systems play a crucial role in the treatment and management of medical conditions. Microelectromechanical systems (MEMS) technologies have allowed the development of advanced miniaturized devices for medical and biological applications. This Review presents the use of MEMS technologies to produce drug delivery devices detailing the delivery mechanisms, device formats employed, and various biomedical applications. The integration of dosing control systems, examples of commercially available microtechnology-enabled drug delivery devices, remaining challenges, and future outlook are also discussed. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Epithelial cell adhesion molecule aptamer functionalized PLGA-lecithin-curcumin-PEG nanoparticles for targeted drug delivery to human colorectal adenocarcinoma cells.

PubMed

Li, Lei; Xiang, Dongxi; Shigdar, Sarah; Yang, Wenrong; Li, Qiong; Lin, Jia; Liu, Kexin; Duan, Wei

2014-01-01

To improve the efficacy of drug delivery, active targeted nanotechnology-based drug delivery systems are gaining considerable attention as they have the potential to reduce side effects, minimize toxicity, and improve efficacy of anticancer treatment. In this work CUR-NPs (curcumin-loaded lipid-polymer-lecithin hybrid nanoparticles) were synthesized and functionalized with ribonucleic acid (RNA) Aptamers (Apts) against epithelial cell adhesion molecule (EpCAM) for targeted delivery to colorectal adenocarcinoma cells. These CUR-encapsulated bioconjugates (Apt-CUR-NPs) were characterized for particle size, zeta potential, drug encapsulation, stability, and release. The in vitro specific cell binding, cellular uptake, and cytotoxicity of Apt-CUR-NPs were also studied. The Apt-CUR-NP bioconjugates exhibited increased binding to HT29 colon cancer cells and enhancement in cellular uptake when compared to CUR-NPs functionalized with a control Apt (P<0.01). Furthermore, a substantial improvement in cytotoxicity was achieved toward HT29 cells with Apt-CUR-NP bioconjugates. The encapsulation of CUR in Apt-CUR-NPs resulted in the increased bioavailability of delivered CUR over a period of 24 hours compared to that of free CUR in vivo. These results show that the EpCAM Apt-functionalized CUR-NPs enhance the targeting and drug delivery of CUR to colorectal cancer cells. Further development of CUR-encapsulated, nanosized carriers will lead to improved targeted delivery of novel chemotherapeutic agents to colorectal cancer cells.

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.

Permeation enhancer strategies in transdermal drug delivery.

PubMed

Marwah, Harneet; Garg, Tarun; Goyal, Amit K; Rath, Goutam

2016-01-01

Today, ∼74% of drugs are taken orally and are not found to be as effective as desired. To improve such characteristics, transdermal drug delivery was brought to existence. This delivery system is capable of transporting the drug or macromolecules painlessly through skin into the blood circulation at fixed rate. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive techniques of drug delivery. Several important advantages of transdermal drug delivery are prevention from hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. Human skin surface, as a site of drug application for both local and systemic effects, is the most eligible candidate available. New controlled transdermal drug delivery systems (TDDS) technologies (electrically-based, structure-based and velocity-based) have been developed and commercialized for the transdermal delivery of troublesome drugs. This review article covers most of the new active transport technologies involved in enhancing the transdermal permeation via effective drug delivery system.

[Effects of traditional Tibetan drug Liu Tea on proliferation and chemotherapeutic sensitivity of drug-resistant human gastric cancer cell BGC823/5-FU].

PubMed

Cheng, Yan; Hasiqi, Mei-Ge; Qin, Xiao-Zhen; Tang, Xiang-You; Chen, Jian-Nan; Wang, Hui-Yin; Gao, Ao

2016-02-01

To investigate the effects of Liu Tea extracts(LTE) on proliferation, apoptosis and drug sensitivity of drug-resistant gastric cancer cell BGC823/5-FU. MTT assay was used to analyze effect of LTE on cell growth and sensitivity chemotherapeutic drugs, and synergistic effect of the combination of LTE with 5-FU on BGC823/5-FU cells. Combination index (CI) was calculated by CompuSyn. Cell apoptosis was measured by flow cytometry (FCM). Protein expressions of P-gp, Bcl-2, Bax and Caspase-3 (17KD) were detected by Western blot at different concentrations of LTE in BGC823/5-FU cells (100, 200, 400 mg•L⁻¹). The results showed that LTE had an inhibitory effect on growth of BGC823/5-FU cell in a dose-time-dependent manner and significantly reduced IC₅₀ of 5-FU, CDDP, PTX and ADM to BGC823/5-FU cells(P<0.05), indicating it could reverse tolerance of drug resistant cells to chemotherapeutic drugs, with reversion multiples of 2.35, 1.68, 1.96, 0.52. The combination of LTE with 5-FU had positive synergistic effect on the BGC-823 cell line. FCM assay suggested that LTE could induce BGC823/5-FU apoptosis. The apoptosis rate was up to 46.2% when the cells were treated with 800 mg•L⁻¹ LTE after 24 h(P<0.01). According to the protein detection results, with the increase in concentration of LTE, the protein expression of Bcl-2 was gradually decreased(P<0.01), the expression of Bax and Caspase-3 were extremely increased(P<0.01), with statistical significance in difference(P<0.01) but no difference in the expression of P-gp between experiment group and control group. LTE can inhibit the growth of drug-resistant human gastric cancer cell BGC823/5-FU and reverse its chemotherapeutic tolerance to some extent. Inhibition of antiapoptotic proteins, activation of proapoptotic proteins and induction of apoptosis of resistant cells may be its main mechanisms. Copyright© by the Chinese Pharmaceutical Association.

Designed Synthesis of Nanostructured Magnetic Hydroxyapatite Based Drug Nanocarrier for Anti-Cancer Drug Delivery toward the Treatment of Human Epidermoid Carcinoma

PubMed Central

Govindan, Bharath; Swarna Latha, Beeseti; Nagamony, Ponpandian; Ahmed, Faheem; Saifi, Muheet Alam; Harrath, Abdel Halim; Alwasel, Saleh; Mansour, Lamjed; Alsharaeh, Edreese H.

2017-01-01

Superparamagnetic Fe3O4 nanoparticles on hydroxyapatite nanorod based nanostructures (Fe3O4/HAp) were synthesized using hydrothermal techniques at 180 °C for 12 h and were used as drug delivery nanocarriers for cancer cell therapeutic applications. The synthesized Fe3O4/HAp nanocomposites were characterized by X-ray diffraction analysis (XRD), Field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR), Brunauer-Emmett-Teller (BET)-analysis, and vibrating sample magnetometry (VSM). The morphologies of the Fe3O4/HAp nanocomposites show 15 nm Fe3O4 nanoparticles dispersed in the form of rods. The BET result shows that the synthesized samples have a high specific surface area of 80 m2 g−1 with mesoporous structures. Magnetic measurements revealed that the sample has high saturation magnetization of 18 emu/g with low coercivity. The Fe3O4/HAp nanocomposites had a large specific surface area (SSA), high mesoporous volume, and good magnetic property, which made it a suitable nanocarrier for targeted drug delivery systems. The chemotherapeutic agent, andrographolide, was used to investigate the drug delivery behavior of the Fe3O4/HAp nanocomposites. The human epidermoid skin cancer cells (A431) were used as the model targeting cell lines by treating with andrographolide loaded Fe3O4/HAp nanosystems and were further evaluated for their antiproliferative activities and the induction of apoptosis. Also, the present nanocomposite shows better biocompatibility, therefore it can be used as suitable drug vehicle for cancer therapy applications. PMID:28587317

Fabrication of Polymeric Micelles with Aggregation-Induced Emission and Forster Resonance Energy Transfer for Anticancer Drug Delivery.

PubMed

Hao, Na; Sun, Changzhen; Wu, Zhengfei; Xu, Long; Gao, Wenxia; Cao, Jun; Li, Li; He, Bin

2017-07-19

With the aim of obtaining effective cancer therapy with simultaneous cellular imaging, dynamic drug-release monitoring, and chemotherapeutic treatment, a polymeric micelle with aggregation-induced emission (AIE) imaging and a Forster resonance energy transfer (FRET) effect was fabricated as the drug carrier. An amphiphilic conjugate of 1H-pyrrole-1-propanoicacid (MAL)-poly(ethylene glycol) (PEG)-Tripp-bearing AIE molecules were synthesized and self-assembled into micelles to load the anticancer drug doxorubicin (DOX). Spherical DOX-loaded micelles with the mean size of 106 nm were obtained with good physiological stability (CMC, 12.5 μg/mL), high drug-loading capacity (10.4%), and encapsulation efficiency (86%). The cellular uptake behavior of DOX-loaded MAL-PEG-Tripp micelles was visible for high-quality intracellular imaging due to the AIE property. The delivery of DOX from the drug-loaded micelles was dynamic monitored by the FRET effect between the DOX and MAL-PEG-Tripp. Both in vitro (IC50, 2.36 μg/mL) and in vivo anticancer activity tests revealed that the DOX-loaded MAL-PEG-Tripp micelles exhibited promising therapeutic efficacy to cancer with low systematic toxicity. In summary, this micelle provided an effective way to fabricate novel nanoplatform for intracellular imaging, drug-delivery tracing, and chemotherapy.

131I-Traced PLGA-Lipid Nanoparticles as Drug Delivery Carriers for the Targeted Chemotherapeutic Treatment of Melanoma

NASA Astrophysics Data System (ADS)

Wang, Haiyan; Sheng, Weizhong

2017-05-01

Herein, folic acid (FA) conjugated Poly(d,l-lactide-co-glycolide) (PLGA)-lipid composites (FA-PL) were developed as nanocarriers for the targeted delivery of insoluble anti-cancer drug paclitaxel (PTX), resulting FA-PLP nanoparticles. Furthermore, 131I, as a radioactive tracer, was used to label FA-PLP nanoparticles (FA-PLP-131I) to evaluate their cell uptake activity, in vivo blood circulation, and biodistribution. The FA-PLP-131I nanoparticles had a spherical morphology with great stability, a narrow size distribution (165.6 and 181.2 nm), and -22.1 mV in average zeta potential. Confocal laser scanning microscopy indicated that the targeting molecule FA promotes PLP-131I uptake by melanoma B16F10 cells, which was further confirmed by the cell incorporation rate via 131I activity detection as measured by a gamma counter. FA-PLP-131I without PTX (FA-PL-131I) shows minor cytotoxicity, good biocompatibility, while FA-PLP-131I was demonstrated to have efficient cell viability suppression compared to free PTX and PLP-131I. Following intravenous injection, the blood circulation half-life of free PTX ( t 1/2 = 5.4 ± 0.23 h) was prolonged to 18.5 ± 0.5 h by FA-PLP-131I. Through FA targeting, the tumor uptake of FA-PLP-131I was approximately 4.41- and 12.8-fold higher compared to that of PLP-131I and free PTX-131I, respectively. Moreover, following 40 days of treatment, FA-PLP-131I showed an improved tumor inhibition effect compared to free PTX and PLP-131I, with no relapse and no remarkable systemic in vivo toxicity. The results demonstrate that the 131I-labeled PLGA-lipid nanoparticle can be simultaneously applied for targeted drug delivery and reliable tracking of drugs in vivo.

Nanobiotechnology-based drug delivery in brain targeting.

PubMed

Dinda, Subas C; Pattnaik, Gurudutta

2013-01-01

Blood brain barrier (BBB) found to act as rate limiting factor in drug delivery to brain in combating the central nervous system (CNS) disorders. Such limiting physiological factors include the reticuloendothelial system and protein opsonization, which present across BBB, play major role in reducing the passage of drug. Several approaches employed to improve the drug delivery across the BBB. Nanoparticles (NP) are the solid colloidal particle ranges from 1 to 1000 nm in size utilized as career for drug delivery. At present NPs are found to play a significant advantage over the other methods of available drug delivery systems to deliver the drug across the BBB. Nanoparticles may be because of its size and functionalization characteristics able to penetrate and facilitate the drug delivery through the barrier. There are number of mechanisms and strategies found to be involved in this process, which are based on the type of nanomaterials used and its combination with therapeutic agents, such materials include liposomes, polymeric nanoparticles and non-viral vectors of nano-sizes for CNS gene therapy, etc. Nanotechnology is expected to reduce the need for invasive procedures for delivery of therapeutics to the CNS. Some devices such as implanted catheters and reservoirs however will still be needed to overcome the problems in effective drug delivery to the CNS. Nanomaterials are found to improve the safety and efficacy level of drug delivery devices in brain targeting. Nanoegineered devices are found to be delivering the drugs at cellular levels through nono-fluidic channels. Different drug delivery systems such as liposomes, microspheres, nanoparticles, nonogels and nonobiocapsules have been used to improve the bioavailability of the drug in the brain, but microchips and biodegradable polymeric nanoparticulate careers are found to be more effective therapeutically in treating brain tumor. The physiological approaches also utilized to improve the transcytosis capacity

Microprocessor controlled transdermal drug delivery.

PubMed

Subramony, J Anand; Sharma, Ashutosh; Phipps, J B

2006-07-06

Transdermal drug delivery via iontophoresis is reviewed with special focus on the delivery of lidocaine for local anesthesia and fentanyl for patient controlled acute therapy such as postoperative pain. The role of the microprocessor controller in achieving dosimetry, alternating/reverse polarity, pre-programmed, and sensor-based delivery is highlighted. Unique features such as the use of tactile signaling, telemetry control, and pulsatile waveforms in iontophoretic drug delivery are described briefly.

Beta-lactams and their potential use as novel anticancer chemotherapeutics drugs.

PubMed

Kuhn, Deborah; Coates, Cristina; Daniel, Kenyon; Chen, Di; Bhuiyan, Mohammad; Kazi, Aslamuzzaman; Turos, Edward; Dou, Q Ping

2004-09-01

The discovery of natural and synthetic antibiotics is one of the most important medical breakthroughs in human history. Many diseases, such as bacterial meningitis, pneumonia, and septicemia, are now curable with the use of antibiotics. Antibiotics are efficacious, generally well tolerated in patients, and have a low toxicity level. It is for these reasons antibiotics remain an attractive target for drug discovery. Traditional beta-lactam antibiotics (e.g. penicillins, penems, cephalosporins) have a bicyclic ring structure that is conformationally rigid and functions to inhibit bacterial cell wall synthesis. In addition to the bactericidal action of antibiotics, it has been discovered that many antibiotics are capable of inhibiting tumor cell growth. There are currently many antitumor antibiotics approved for cancer therapy, which work to inhibit tumor cell growth by DNA intercalation. The use of beta-lactams as prodrugs has also met with success by aiding delivery of the chemotherapeutic directly to tumor sites. Recently, a novel class of N-thiolated monobactams, so termed because they possess a monocyclic ring instead of the bicyclic ring, has been found to induce apoptosis potently and specifically in many tumor cell lines but not in normal, non-transformed cell lines. Other beta-lactams, such as the polyaromatics, have been found to slow or inhibit tumor cell growth, and the 4-alkylidene beta-lactams are capable of inhibiting matrix metalloproteinases and leukocyte elactase activity. These data indicate that synthesis and evaluation of beta-lactams are a promising area for further development in anticancer research.

Chemotherapeutic Drug Based Metal-Organic Particles for Microvesicle-Mediated Deep Penetration and Programmable pH/NIR/Hypoxia Activated Cancer Photochemotherapy.

PubMed

Zhang, Da; Wu, Ming; Cai, Zhixiong; Liao, Naishun; Ke, Kun; Liu, Hongzhi; Li, Ming; Liu, Gang; Yang, Huanghao; Liu, Xiaolong; Liu, Jingfeng

2018-02-01

A novel metal-organic particle (MOP) based nanodrug formed by mild self-assembly of chemotherapeutic drugs, including banoxantrone and doxorubicin, through Cu(II)-mediated coordination effects, is reported. In this nanodrug, Cu(II) acts as a bridge to join AQ4N and DOX, and then, self-assembly of [-AQ4N-Cu(II)-(DOX) 2 -Cu(II)-] n complexes forms nanosized MOPs (referred to as ADMOPs) through multiple interactions including host-metal-guest coordination, hydrophobic interactions, π-stacking, and van der Waals force. The ADMOPs reported here have several important features over conventional drugs, including tumor microenvironment pH-sensitive drug release that can be tracked by "turning on" the fluorescence of AQ4N or DOX through proton competition with Cu(II) to break the coordination bonds and much deeper penetration into solid tumors via microvesicle-mediated intercellular transfer. Most strikingly, the ADMOPs can serve as stimuli-responsive nanocarriers to efficiently load the photosensitizer phthalocyanine due to their inherent highly porous characteristics. Thus, the ADMOPs significantly enhance the chemotherapeutic efficacy by "on-demand" photodynamic therapy, which further induces a hypoxic environment that enhances the reduction of AQ4N to systematically increase the therapeutic efficiency. Taken together, the designed ADMOPs composed of chemotherapeutic drugs may serve as a potential programmable controlled synergistic agent for cancer 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.

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

PubMed Central

Sun, Tao; Zhang, Yongzhi; Power, Chanikarn; Alexander, Phillip M.; Sutton, Jonathan T.; Aryal, Muna; Vykhodtseva, Natalia; Miller, Eric L.; McDannold, Nathan J.

2017-01-01

Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood–brain barrier (BBB) for treating many neurological disorders. Unlike ultrasound thermal therapies, during which magnetic resonance thermometry can serve as a reliable treatment control modality, real-time control of modulated BBB disruption with undetectable vascular damage remains a challenge. Here a closed-loop cavitation controlling paradigm that sustains stable cavitation while suppressing inertial cavitation behavior was designed and validated using a dual-transducer system operating at the clinically relevant ultrasound frequency of 274.3 kHz. Tests in the normal brain and in the F98 glioma model in vivo demonstrated that this controller enables reliable and damage-free delivery of a predetermined amount of the chemotherapeutic drug (liposomal doxorubicin) into the brain. The maximum concentration level of delivered doxorubicin exceeded levels previously shown (using uncontrolled sonication) to induce tumor regression and improve survival in rat glioma. These results confirmed the ability of the controller to modulate the drug delivery dosage within a therapeutically effective range, while improving safety control. It can be readily implemented clinically and potentially applied to other cavitation-enhanced ultrasound therapies. PMID:29133392

EMP-induced BBB-disruption enhances drug delivery to glioma and increases treatment efficacy in rats.

PubMed

Li, Kangchu; Zhang, Keying; Xu, Shenglong; Wang, Xiaowu; Zhou, Yongchun; Zhou, Yan; Gao, Peng; Lin, Jiajin; Ding, Guirong; Guo, Guozhen

2018-01-01

Chemotherapy on gliomas is not satisfactorily efficient because the presence of blood-brain barriers (BBB) leads to inadequate exposure of tumor cells to administered drugs. In order to facilitate chemotherapeutics to penetrate BBB and increase the treatment efficacy of gliomas, electromagnetic pulse (EMP) was applied and the 1-(2-Chlorethyl)-cyclohexyl-nitrosourea (CCNU) lomustine concentration in tumor tissue, tumor size, tumor apoptosis, and side effects were measured in glioma-bearing rat model. The results showed that EMP exposure could enhance the delivery of CCNU to tumor tissue, facilitate tumor apoptosis, and inhibit tumor growth without obvious side effects. The data indicated that EMP-induced BBB disruption could enhance delivery of CCNU to glioblastoma multiforme and increase treatment efficacy in glioma-bearing rats. Bioelectromagnetics. 39:60-67, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Drug Delivery to CNS: Challenges and Opportunities with Emphasis on Biomaterials Based Drug Delivery Strategies.

PubMed

Khambhla, Ekta; Shah, Viral; Baviskar, Kalpesh

2016-01-01

The current epoch has witnessed a lifestyle impregnated with stress, which is a major cause of several neurological disorders. High morbidity and mortality rate due to neurological diseases and disorders have generated a huge social impact. Despite voluminous research, patients suffering from fatal and/or debilitating CNS diseases such as brain tumors, HIV, encephalopathy, Alzheimer's, epilepsy, Parkinson's, migraine and multiple sclerosis outnumbered those suffering from systemic cancer or heart diseases. The brain being a highly sensitive neuronal organ, has evolved with vasculature barriers, which regulates the efflux and influx of substances to CNS. Treatment of CNS diseases/disorders is challenging because of physiologic, metabolic and biochemical obstacles created by these barriers which comprise mainly of BBB and BCFB. The inability of achieving therapeutically active concentration has become the bottleneck level difficulty, hampering the therapeutic efficiency of several promising drug candidates for CNS related disorders. Parallel maturation of an effective CNS drug delivery strategy with CNS drug discovery is the need of the hour. Recently, the focus of the pharmaceutical community has aggravated in the direction of developing novel and more efficient drug delivery systems, giving the potential of more effective and safer CNS therapies. The present review outlines several hurdles in drug delivery to the CNS along with ideal physicochemical properties desired in drug substance/formulation for CNS delivery. The review also focuses on different conventional and novel strategies for drug delivery to the CNS. The article also assesses and emphasizes on possible benefits of biomaterial based formulations for drug delivery to the CNS.

Drug delivery across length scales.

PubMed

Delcassian, Derfogail; Patel, Asha K; Cortinas, Abel B; Langer, Robert

2018-02-20

Over the last century, there has been a dramatic change in the nature of therapeutic, biologically active molecules available to treat disease. Therapies have evolved from extracted natural products towards rationally designed biomolecules, including small molecules, engineered proteins and nucleic acids. The use of potent drugs which target specific organs, cells or biochemical pathways, necessitates new tools which can enable controlled delivery and dosing of these therapeutics to their biological targets. Here, we review the miniaturisation of drug delivery systems from the macro to nano-scale, focussing on controlled dosing and controlled targeting as two key parameters in drug delivery device design. We describe how the miniaturisation of these devices enables the move from repeated, systemic dosing, to on-demand, targeted delivery of therapeutic drugs and highlight areas of focus for the future.

Polypeptides and polyaminoacids in drug delivery.

PubMed

González-Aramundiz, José Vicente; Lozano, María Victoria; Sousa-Herves, Ana; Fernandez-Megia, Eduardo; Csaba, Noemi

2012-02-01

Advances achieved over the last few years in drug delivery have provided novel and versatile possibilities for the treatment of various diseases. Among the biomaterials applied in this field, it is worth highlighting the increasing importance of polyaminoacids and polypeptides. The appealing properties of these polymers are very promising for the design of novel compositions in a variety of drug delivery applications. This review provides an overview on the general characteristics of polyaminoacids and polypeptides and briefly discusses different synthetic pathways for their production. This is followed by a detailed description of different drug delivery applications of these polymers, emphasizing those examples that already reached advanced preclinical development or have entered clinical trials. Polyaminoacids and polypeptides are gaining much attention in drug delivery due to their exceptional properties. Their application as polymers for drug delivery purposes has been sped up by the significant achievements related to their synthesis. Certainly, cancer therapy has benefited the most from these advances, although other fields such as vaccine delivery and alternative administration routes are also being successfully explored. The design of new entities based on polyaminoacids and polypeptides and the improved insight gained in drug delivery guarantee exciting findings in the near future.

Spectroscopic detection of chemotherapeutics and antioxidants

NASA Astrophysics Data System (ADS)

Latka, Ines; Grüner, Roman; Matthäus, Christian; Dietzek, Benjamin; Werncke, W.; Lademann, Jürgen; Popp, Jürgen

2012-06-01

The hand-foot-syndrome presents a severe dermal side-effect of chemotherapeutic cancer treatment. The cause of this side-effect is the elimination of systemically administered chemotherapeutics with the sweat. Transported to the skin surface, the drugs subsequently penetrate into the skin in the manner of topically applied substances. Upon accumulation of the chemotherapeutics in the skin the drugs destroy cells and tissue - in the same way as they are supposed to act in cancer cells. Aiming at the development of strategies to illuminate the molecular mechanism underlying the handfoot- syndrome (and, in a second step, strategies to prevent this severe side-effect), it might be important to evaluate the concentration and distribution of chemotherapeutics and antioxidants in the human skin. The latter can be estimated by the carotenoid concentration, as carotenoids serve as marker substances for the dermal antioxidative status.Following the objectives outlined above, this contribution presents a spectroscopic study aiming at the detection and quantification of carotenoids and selected chemotherapeutics in human skin. To this end, spontaneous Raman scattering and coherent anti-Stokes Raman scattering (CARS) microspectroscopy are combined with two-photon excited fluorescence. While the latter technique is Please verify that (1) all pages are present, (2) all figures are correct, (3) all fonts and special characters are correct, and (4) all text and figures fit within the red margin lines shown on this review document. Complete formatting information is available at http://SPIE.org/manuscripts Return to your MySPIE To Do List at http://myspie.org and approve or disapprove this submission. Your manuscript will not be published without this approval.restricted to the detection of fluorescent chemotherapeutics, e.g., doxorubicin, the vibrational spectroscopic techniques can - in principle - be applied to any type of analyte molecules. Furthermore, we will present the

Graphene as multifunctional delivery platform in cancer therapy.

PubMed

Nejabat, Mojgan; Charbgoo, Fahimeh; Ramezani, Mohammad

2017-08-01

The biomedical applications of graphene-based nanomaterials including drug and gene delivery have grown rapidly in the past few years. This is due to its high surface area that results in high cargo loading capacity. It is demonstrated that graphene can improve drug efficacy without increasing the dose of the chemotherapeutic agent in cancer treatment. Considering these valuable benefits of graphene, this review focused on the newest advancements in drug and gene delivery systems using graphene and unveiling advantages and disadvantages of different graphene-based materials in introducing an effective cargo delivery system for cancer therapy. Different approaches for reducing cytotoxic impacts of graphene oxide and production of biocompatible delivery platform were also reviewed. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2355-2367, 2017. © 2017 Wiley Periodicals, Inc.

Drug Delivery in Cancer Therapy, Quo Vadis?

PubMed

Lu, Zheng-Rong; Qiao, Peter

2018-03-22

The treatment of malignancies has undergone dramatic changes in the past few decades. Advances in drug delivery techniques and nanotechnology have allowed for new formulations of old drugs, so as to improve the pharmacokinetics, to enhance accumulation in solid tumors, and to reduce the significant toxic effects of these important therapeutic agents. Here, we review the published clinical data in cancer therapy of several major drug delivery systems, including targeted radionuclide therapy, antibody-drug conjugates, liposomes, polymer-drug conjugates, polymer implants, micelles, and nanoparticles. The clinical outcomes of these delivery systems from various phases of clinical trials are summarized. The success and limitations of the drug delivery strategies are discussed based on the clinical observations. In addition, the challenges in applying drug delivery for efficacious cancer therapy, including physical barriers, tumor heterogeneity, drug resistance, and metastasis, are discussed along with future perspectives of drug delivery in cancer therapy. In doing so, we intend to underscore that efficient delivery of cancer therapeutics to solid malignancies remains a major challenge in cancer therapy, and requires a multidisciplinary approach that integrates knowledge from the diverse fields of chemistry, biology, engineering, and medicine. The overall objective of this review is to improve our understanding of the clinical fate of commonly investigated drug delivery strategies, and to identify the limitations that must be addressed in future drug delivery strategies, toward the pursuit of curative therapies for cancer.

Smart Polymers in Nasal Drug Delivery

PubMed Central

Chonkar, Ankita; Nayak, Usha; Udupa, N.

2015-01-01

Nasal drug delivery has now been recognized as a promising route for drug delivery due to its capability of transporting a drug to systemic circulation and central nervous system. Though nasal mucosa offers improved bioavailability and quick onset of action of the drug, main disadvantage associated with nasal drug delivery is mucocilliary clearance due to which drug particles get cleared from the nose before complete absorption through nasal mucosa. Therefore, mucoadhesive polymeric approach can be successfully used to enhance the retention of the drug on nasal mucosal surface. Here, some of the aspects of the stimuli responsive polymers have been discussed which possess liquid state at the room temperature and in response to nasal temperature, pH and ions present in mucous, can undergo in situ gelation in nasal cavity. In this review, several temperature responsive, pH responsive and ion responsive polymers used in nasal delivery, their gelling mechanisms have been discussed. Smart polymers not only able to enhance the retention of the drug in nasal cavity but also provide controlled release, ease of administration, enhanced permeation of the drug and protection of the drug from mucosal enzymes. Thus smart polymeric approach can be effectively used for nasal delivery of peptide drugs, central nervous system dugs and hormones. PMID:26664051

Ion-Responsive Drug Delivery Systems.

PubMed

Yoshida, Takayuki; Shakushiro, Kohsuke; Sako, Kazuhiro

2018-02-08

Some kinds of cations and anions are contained in body fluids such as blood, interstitial fluid, gastrointestinal juice, and tears at relatively high concentration. Ionresponsive drug delivery is available to design the unique dosage formulations which provide optimized drug therapy with effective, safe and convenient dosing of drugs. The objective of the present review was to collect, summarize, and categorize recent research findings on ion-responsive drug delivery systems. Ions in body fluid/formulations caused structural changes of polymers/molecules contained in the formulations, allow formulations exhibit functions. The polymers/molecules responding to ions were ion-exchange resins/fibers, anionic or cationic polymers, polymers exhibiting transition at lower critical solution temperature, self-assemble supramolecular systems, peptides, and metalorganic frameworks. The functions of ion-responsive drug delivery systems were categorized to controlled drug release, site-specific drug release, in situ gelation, prolonged retention at the target sites, and enhancement of drug permeation. Administration of the formulations via oral, ophthalmic, transdermal, and nasal routes has showed significant advantages in the recent literatures. Many kinds of drug delivery systems responding to ions have been reported recently for several administration routes. Improvement and advancement of these systems can maximize drugs potential and contribute to patients in the world. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Colloidal drug delivery system: amplify the ocular delivery.

PubMed

Ali, Javed; Fazil, Mohd; Qumbar, Mohd; Khan, Nazia; Ali, Asgar

2016-01-01

The ocular perceivers are the most voluntarily accessible organs in terms of location in the body, yet drug distribution to these tissues is one of the most intriguing and challenging endeavors and problematic to the pharmaceutical scientist. The most of ocular diseases are treated with topical application of conventional formulation, i.e. solutions, suspensions and ointment. Typically on installation of these conventional formulations, only <5% of the applied dose penetrates the cornea and reaches intraocular tissues, while a major fraction of the instilled dose is wastage due to the presence of many ocular barriers like external barriers, rapid loss of the instilled solution from the precorneal area and nasolacrimal drainage system. Systemic absorption caused systemic side effects varying from mild to life-threatening events. The main objective of this review is to explore the role of colloidal delivery of drug to minimize the drawbacks associated with them. This review provides an insight into the various constraints associated with ocular drug delivery, summarizes recent findings and applications of colloidal delivery systems, i.e. nanoparticles, nanosuspensions, liposomes, niosomes, dendrimers and contact lenses containing nanoparticles have the capacity to distribute ocular drugs to categorical target sites and hold promise to revolutionize the therapy of many ocular perceiver diseases and minimized the circumscription of conventional delivery. Form the basis of literature review, it has been found that the novel delivery system have greater impact to maximize ocular drug absorption, and minimize systemic absorption and side effects.

Towards magnetic-enhanced cellular uptake, MRI and chemotherapeutics delivery by magnetic mesoporous silica nanoparticles.

PubMed

Liu, Qian; Zhang, Jixi; Xia, Weiliang; Gu, Hongchen

2012-10-01

A type of nanoparticle with three functional modalities was prepared with the aim of providing a multifunctional drug delivery system. The nanoparticle was 50 nm in size, with 2.7 nm mesopores and a magnetic nanocrystal core, which was further doped with FITC to enable the tracking of cellular uptake. We demonstrated that the internalization of the nanoparticles in tumor cells could be enhanced by applying an external magnetic field and furthermore, this kind of nanoparticle could be used in magnetic targeted drug delivery. With high transverse relaxivity, the magnetic nanoparticles shortened proton relaxation time and induced high magnetic resonance imaging contrast in tumor cells. Studies on anticancer drug loading and delivery capacity of anticancer drugs also showed that this type of nanoparticles could load water-soluble doxorubicin, and produce a prominent inhibitive effect against tumor cells. Taken together, the presented nanoparticles could become a promising agent in cancer theranostics.

Epithelial cell adhesion molecule aptamer functionalized PLGA-lecithin-curcumin-PEG nanoparticles for targeted drug delivery to human colorectal adenocarcinoma cells

PubMed Central

Li, Lei; Xiang, Dongxi; Shigdar, Sarah; Yang, Wenrong; Li, Qiong; Lin, Jia; Liu, Kexin; Duan, Wei

2014-01-01

To improve the efficacy of drug delivery, active targeted nanotechnology-based drug delivery systems are gaining considerable attention as they have the potential to reduce side effects, minimize toxicity, and improve efficacy of anticancer treatment. In this work CUR-NPs (curcumin-loaded lipid-polymer-lecithin hybrid nanoparticles) were synthesized and functionalized with ribonucleic acid (RNA) Aptamers (Apts) against epithelial cell adhesion molecule (EpCAM) for targeted delivery to colorectal adenocarcinoma cells. These CUR-encapsulated bioconjugates (Apt-CUR-NPs) were characterized for particle size, zeta potential, drug encapsulation, stability, and release. The in vitro specific cell binding, cellular uptake, and cytotoxicity of Apt-CUR-NPs were also studied. The Apt-CUR-NP bioconjugates exhibited increased binding to HT29 colon cancer cells and enhancement in cellular uptake when compared to CUR-NPs functionalized with a control Apt (P<0.01). Furthermore, a substantial improvement in cytotoxicity was achieved toward HT29 cells with Apt-CUR-NP bioconjugates. The encapsulation of CUR in Apt-CUR-NPs resulted in the increased bioavailability of delivered CUR over a period of 24 hours compared to that of free CUR in vivo. These results show that the EpCAM Apt-functionalized CUR-NPs enhance the targeting and drug delivery of CUR to colorectal cancer cells. Further development of CUR-encapsulated, nanosized carriers will lead to improved targeted delivery of novel chemotherapeutic agents to colorectal cancer cells. PMID:24591829

Ultrasound mediated transdermal drug delivery.

PubMed

Azagury, Aharon; Khoury, Luai; Enden, Giora; Kost, Joseph

2014-06-01

Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injections. However, the stratum corneum serves as a barrier that limits the penetration of substances to the skin. Application of ultrasound (US) irradiation to the skin increases its permeability (sonophoresis) and enables the delivery of various substances into and through the skin. This review presents the main findings in the field of sonophoresis in transdermal drug delivery as well as transdermal monitoring and the mathematical models associated with this field. Particular attention is paid to the proposed enhancement mechanisms and future trends in the fields of cutaneous vaccination and gene therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

HSA/PSS coated gold nanorods as thermo-triggered drug delivery vehicles for combined cancer photothermal therapy and chemotherapy

NASA Astrophysics Data System (ADS)

Tu, Ting-Yu; Yang, Shu-Jyuan; Wang, Chung-Hao; Lee, Shin-Yu; Shieh, Ming-Jium

2018-02-01

Drug delivery systems combined multimodal therapy strategies are very promising in cancer theranostic applications. In this work, a new drug-delivery vehicles based on human serum albumin (HSA)-coated gold nanorods (GNR/PSS/HSA NPs) was developed. The success of coating was verified by transmission electron microscopy (TEM), zeta potential and fourier transform infrared spectroscopy (FTIR). Furthermore, it is demonstrated that doxorubicin (DOX) is successfully loaded among multilayered gold nanorods by the electrostatic and hydrophobic force, and DOX@GNR/PSS/HSA NPs were highly biocompatible and stable in various physiological solutions. The NPs possess strong absorbance in nearinfrared (NIR) region, and high photothermal conversion efficiency for outstanding photothermal therapy applications. A bimodal drug release triggered by proteinase or NIR irradiation has been revealed, resulting in a significant chemotherapeutic effect in tumor sites because of the preferential drug accumulation and triggered release. Importantly, the in vitro and in vivo experiments demonstrated that DOX@GNR/PSS/HSA NPs, which combined photothermal and chemotherapy for cancer therapy, revealing a remarkably superior synergistic anticancer effect over either monotherapy. All these results suggested a considerable potential of DOX@GNR/PSS/HSA NPs nano-platform for antitumor therapy.

Ultrasound-guided drug delivery in cancer

PubMed Central

2017-01-01

Recent advancements in ultrasound and microbubble (USMB) mediated drug delivery technology has shown that this approach can improve spatially confined delivery of drugs and genes to target tissues while reducing systemic dose and toxicity. The mechanism behind enhanced delivery of therapeutics is sonoporation, the formation of openings in the vasculature, induced by ultrasound-triggered oscillations and destruction of microbubbles. In this review, progress and challenges of USMB mediated drug delivery are summarized, with special focus on cancer therapy. PMID:28607323

Limited Efficiency of Drug Delivery to Specific Intracellular Organelles Using Subcellularly "Targeted" Drug Delivery Systems.

PubMed

Maity, Amit Ranjan; Stepensky, David

2016-01-04

Many drugs have been designed to act on intracellular targets and to affect intracellular processes inside target cells. For the desired effects to be exerted, these drugs should permeate target cells and reach specific intracellular organelles. This subcellular drug targeting approach has been proposed for enhancement of accumulation of these drugs in target organelles and improved efficiency. This approach is based on drug encapsulation in drug delivery systems (DDSs) and/or their decoration with specific targeting moieties that are intended to enhance the drug/DDS accumulation in the intracellular organelle of interest. During recent years, there has been a constant increase in interest in DDSs targeted to specific intracellular organelles, and many different approaches have been proposed for attaining efficient drug delivery to specific organelles of interest. However, it appears that in many studies insufficient efforts have been devoted to quantitative analysis of the major formulation parameters of the DDSs disposition (efficiency of DDS endocytosis and endosomal escape, intracellular trafficking, and efficiency of DDS delivery to the target organelle) and of the resulting pharmacological effects. Thus, in many cases, claims regarding efficient delivery of drug/DDS to a specific organelle and efficient subcellular targeting appear to be exaggerated. On the basis of the available experimental data, it appears that drugs/DDS decoration with specific targeting residues can affect their intracellular fate and result in preferential drug accumulation within an organelle of interest. However, it is not clear whether these approaches will be efficient in in vivo settings and be translated into preclinical and clinical applications. Studies that quantitatively assess the mechanisms, barriers, and efficiencies of subcellular drug delivery and of the associated toxic effects are required to determine the therapeutic potential of subcellular DDS targeting.

Dacarbazine in melanoma: from a chemotherapeutic drug to an immunomodulating agent.

PubMed

Ugurel, Selma; Paschen, Annette; Becker, Jürgen C

2013-02-01

Chemotherapeutic drugs are clinically used to treat cancer because of their cytotoxic activities against tumor cells. Recently, however, evidence is accumulating-including the report of Hervieu et al. (2012) in the current issue of The Journal of Investigative Dermatology-indicating that at least some of these drugs have broader activities and that they should also be considered immunomodulatory agents. Indeed, Hervieu demonstrates that dacarbazine (DTIC) exerts immunostimulatory effects by inducing local activation of natural killer (NK) and T cells, suggesting that upon treatment with DTIC, the tumor participates in the initiation of an immune response: (i) DTIC treatment elicits the expression of ligands of the immunoreceptor NKG2D on melanoma cells; (ii) engagement of the ligands by NKG2D on NK cells leads to their activation, allowing enhanced tumor-cell killing and the release of IFN-γ; and (iii) IFN-γ in turn upregulates major histocompatibility complex class I expression on tumor cells, which favors their recognition by cytotoxic CD8+ T lymphocytes (CTLs).

Recent advances in ophthalmic drug delivery

PubMed Central

Kompella, Uday B; Kadam, Rajendra S; Lee, Vincent HL

2011-01-01

Topical ocular drug bioavailability is notoriously poor, in the order of 5% or less. This is a consequence of effective multiple barriers to drug entry, comprising nasolacrimal drainage, epithelial drug transport barriers and clearance from the vasculature in the conjunctiva. While sustained drug delivery to the back of the eye is now feasible with intravitreal implants such as Vitrasert™ (~6 months), Retisert™ (~3 years) and Iluvien™ (~3 years), currently there are no marketed delivery systems for long-term drug delivery to the anterior segment of the eye. The purpose of this article is to summarize the resurgence in interest to prolong and improve drug entry from topical administration. These approaches include mucoadhesives, viscous polymer vehicles, transporter-targeted prodrug design, receptor-targeted functionalized nanoparticles, iontophoresis, punctal plug and contact lens delivery systems. A few of these delivery systems might be useful in treating diseases affecting the back of the eye. Their effectiveness will be compared against intravitreal implants (upper bound of effectiveness) and trans-scleral systems (lower bound of effectiveness). Refining the animal model by incorporating the latest advances in microdialysis and imaging technology is key to expanding the knowledge central to the design, testing and evaluation of the next generation of innovative ocular drug delivery systems. PMID:21399724

Advancements in ocular drug delivery.

PubMed

Weiner, Alan L; Gilger, Brian C

2010-11-01

This review covers both noninvasive and invasive ophthalmic drug delivery systems that can have application to therapy of veterinary ophthalmic diseases. Noninvasive approaches include gel technologies, permeation enhancement via pro-drug development, solubilization agents and nanoparticle technologies, iontophoresis, microneedles, drug-eluting contact lenses and eye misters, and microdroplets. More invasive systems include both eroding implants and noneroding technologies that encompass diffusion based systems, active pumps, intraocular lenses, suprachoroidal drug delivery, and episcleral reservoirs. In addition to addressing the physiologic challenges of achieving the necessary duration of delivery, tissue targeting and patient compliance, the commercial development factors of biocompatibility, sterilization, manufacturability and long-term stability will be discussed. © 2010 American College of Veterinary Ophthalmologists.

Combination Chemotherapeutic Dry Powder Aerosols via Controlled Nanoparticle Agglomeration

PubMed Central

El-Gendy, Nashwa; Berkland, Cory

2014-01-01

Purpose To develop an aerosol system for efficient local lung delivery of chemotherapeutics where nanotechnology holds tremendous potential for developing more valuable cancer therapies. Concurrently, aerosolized chemotherapy is generating interest as a means to treat certain types of lung cancer more effectively with less systemic exposure to the compound. Methods Nanoparticles of the potent anticancer drug, paclitaxel, were controllably assembled to form low density microparticles directly after preparation of the nanoparticle suspension. The amino acid, L-leucine, was used as a colloid destabilizer to drive the assembly of paclitaxel nanoparticles. A combination chemotherapy aerosol was formed by assembling the paclitaxel nanoparticles in the presence of cisplatin in solution. Results Freeze-dried powders of the combination chemotherapy possessed desirable aerodynamic properties for inhalation. In addition, the dissolution rates of dried nanoparticle agglomerate formulations (~60% to 66% after 8 h) were significantly faster than that of micronized paclitaxel powder as received (~18% after 8 h). Interestingly, the presence of the water soluble cisplatin accelerated the dissolution of paclitaxel. Conclusions Nanoparticle agglomerates of paclitaxel alone or in combination with cisplatin may serve as effective chemotherapeutic dry powder aerosols to enable regional treatment of certain lung cancers. PMID:19415471

Co-delivery of platinum drug and siNotch1 with micelleplex for enhanced hepatocellular carcinoma therapy.

PubMed

Shen, Song; Sun, Chun-Yang; Du, Xiao-Jiao; Li, Hong-Jun; Liu, Yang; Xia, Jin-Xing; Zhu, Yan-Hua; Wang, Jun

2015-11-01

As part of HCC tumor cellularity, cancer stem cells (CSCs) are considered a major obstacle to eradicate hepatocellular carcinoma (HCC), which is the third most common cause of cancer-related death worldwide, and the accumulation of chemotherapeutic drug-resistant CSCs invariably accounts for poor prognosis and HCC relapse. In the present study, we explored the efficacy of co-delivery of platinum drug and siRNA targeting Notch1 to treat CSCs-harboring HCC. To overcome the challenging obstacles of platinum drug and siRNA in the systemic administration, we developed a micellar nanoparticle (MNP) to deliver platinum(IV) prodrug and siNotch1, hereafter referred to as (Pt(IV))MNP/siNotch1. We demonstrated that (Pt(IV))MNP/siNotch1 was able to efficiently deliver two drugs into both non-CSCs and CSCs of SMMC7721, a HCC cell line. We further found that siRNA-mediated inhibition of Notch1 suppression can increase the sensitivity of HCC cells to platinum drugs and decrease the percentage of HCC CSCs, and consequently resulting in enhanced proliferation inhibition and apoptosis induction in HCC cells in vitro. Moreover, our results indicated that the combined drug delivery system can remarkably augment drug enrichment in tumor tissues, substantially suppressing the tumor growth while avoiding the accumulation of CSCs in a synergistic manner in the SMMC7721 xenograft model. Copyright © 2015 Elsevier Ltd. All rights reserved.

Characterization of the interaction forces in a drug carrier complex of doxorubicin with a drug-binding peptide.

PubMed

Gocheva, Gergana; Ilieva, Nina; Peneva, Kalina; Ivanova, Anela

2018-04-01

Polypeptide-based materials are used as building blocks for drug delivery systems aimed at toxicity decrease in chemotherapeutics. A molecular-level approach is adopted for investigating the non-covalent interactions between doxorubicin and a recently synthesized drug-binging peptide as a key part of a system for delivery to neoplastic cells. Molecular dynamics simulations in aqueous solution at room and body temperature are applied to investigate the structure and the binding modes within the drug-peptide complex. The tryptophans are outlined as the main chemotherapeutic adsorption sites, and the importance of their placement in the peptide sequence is highlighted. The drug-peptide binging energy is evaluated by density functional theory calculations. Principal component analysis reveals comparable importance of several types of interaction for the binding strength. π-Stacking is dominant, but other factors are also significant: intercalation, peptide backbone stacking, electrostatics, dispersion, and solvation. Intra- and intermolecular H-bonding also stabilizes the complexes. The influence of solvent molecules on the binding energy is mild. The obtained data characterize the drug-to-peptide attachment as a mainly attractive collective process with interactions spanning a broad range of values. These results explain with atomistic detail the experimentally registered doxorubicin-binging ability of the peptide and outline the complex as a prospective carrying unit that can be employed in design of drug delivery systems. © 2017 John Wiley & Sons A/S.

Smart Drug Delivery Systems in Cancer Therapy.

PubMed

Unsoy, Gozde; Gunduz, Ufuk

2018-02-08

Smart nanocarriers have been designed for tissue-specific targeted drug delivery, sustained or triggered drug release and co-delivery of synergistic drug combinations to develop safer and more efficient therapeutics. Advances in drug delivery systems provide reduced side effects, longer circulation half-life and improved pharmacokinetics. Smart drug delivery systems have been achieved successfully in the case of cancer. These nanocarriers can serve as an intelligent system by considering the differences of tumor microenvironment from healthy tissue, such as low pH, low oxygen level, or high enzymatic activity of matrix metalloproteinases. The performance of anti-cancer agents used in cancer diagnosis and therapy is improved by enhanced cellular internalization of smart nanocarriers and controlled drug release. Here, we review targeting, cellular internalization; controlled drug release and toxicity of smart drug delivery systems. We are also emphasizing the stimulus responsive controlled drug release from smart nanocarriers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Polypeptide nanogels with hydrophobic moieties in the cross-linked ionic cores: Synthesis, characterization and implications for anticancer drug delivery

PubMed Central

Kim, Jong Oh; Oberoi, Hardeep S.; Desale, Swapnil; Kabanov, Alexander V.; Bronich, Tatiana K.

2014-01-01

Polymer nanogels have gained considerable attention as a potential platform for drug delivery applications. Here we describe the design and synthesis of novel polypeptide-based nanogels with hydrophobic moieties in the cross-linked ionic cores. Diblock copolymer, poly(ethylene glycol)-b-poly(L-glutamic acid), hydrophobically modified with L-phenylalanine methyl ester moieties was used for controlled template synthesis of nanogels with small size (ca. 70 nm in diameter) and narrow particle size distribution. Steady-state and time-resolved fluorescence studies using coumarin C153 indicated the existence of hydrophobic domains in the ionic cores of the nanogels. Stable doxorubicin-loaded nanogels were prepared at high drug capacity (30 w/w%). We show that nanogels are enzymatically-degradable leading to accelerated drug release under simulated lysosomal acidic pH. Furthermore, we demonstrate that the nanogel-based formulation of doxorubicin is well tolerated and exhibit an improved antitumor activity compared to a free doxorubicin in an ovarian tumor xenograft mouse model. Our results signify the point to a potential of these biodegradable nanogels as attractive carriers for delivery of chemotherapeutics. PMID:23998716

Advancements in the oral delivery of Docetaxel: challenges, current state-of-the-art and future trends

PubMed Central

Sohail, Muhammad Farhan; Rehman, Mubashar; Sarwar, Hafiz Shoaib; Naveed, Sara; Salman, Omer; Bukhari, Nadeem Irfan; Hussain, Irshad; Webster, Thomas J; Shahnaz, Gul

2018-01-01

The oral delivery of cancer chemotherapeutic drugs is challenging due to low bioavailability, gastrointestinal side effects, first-pass metabolism and P-glycoprotein efflux pumps. Thus, chemotherapeutic drugs, including Docetaxel, are administered via an intravenous route, which poses many disadvantages of its own. Recent advances in pharmaceutical research have focused on designing new and efficient drug delivery systems for site-specific targeting, thus leading to improved bioavailability and pharmacokinetics. A decent number of studies have been reported for the safe and effective oral delivery of Docetaxel. These nanocarriers, including liposomes, polymeric nanoparticles, metallic nanoparticles, hybrid nanoparticles, dendrimers and so on, have shown promising results in research papers and clinical trials. The present article comprehensively reviews the research efforts made so far in designing various advancements in the oral delivery of Docetaxel. Different strategies to improve oral bioavailability, prevent first-pass metabolism and inhibition of efflux pumping leading to improved pharmacokinetics and anticancer activity are discussed. The final portion of this review article presents key issues such as safety of nanomaterials, regulatory approval and future trends in nanomedicine research. PMID:29922053

Advancements in the oral delivery of Docetaxel: challenges, current state-of-the-art and future trends.

PubMed

Sohail, Muhammad Farhan; Rehman, Mubashar; Sarwar, Hafiz Shoaib; Naveed, Sara; Salman, Omer; Bukhari, Nadeem Irfan; Hussain, Irshad; Webster, Thomas J; Shahnaz, Gul

2018-01-01

The oral delivery of cancer chemotherapeutic drugs is challenging due to low bioavailability, gastrointestinal side effects, first-pass metabolism and P-glycoprotein efflux pumps. Thus, chemotherapeutic drugs, including Docetaxel, are administered via an intravenous route, which poses many disadvantages of its own. Recent advances in pharmaceutical research have focused on designing new and efficient drug delivery systems for site-specific targeting, thus leading to improved bioavailability and pharmacokinetics. A decent number of studies have been reported for the safe and effective oral delivery of Docetaxel. These nanocarriers, including liposomes, polymeric nanoparticles, metallic nanoparticles, hybrid nanoparticles, dendrimers and so on, have shown promising results in research papers and clinical trials. The present article comprehensively reviews the research efforts made so far in designing various advancements in the oral delivery of Docetaxel. Different strategies to improve oral bioavailability, prevent first-pass metabolism and inhibition of efflux pumping leading to improved pharmacokinetics and anticancer activity are discussed. The final portion of this review article presents key issues such as safety of nanomaterials, regulatory approval and future trends in nanomedicine research.

Heterocyclic Drug-polymer Conjugates for Cancer Targeted Drug Delivery.

PubMed

Kaur, Harmeet; Desai, Sapna D; Kumar, Virender; Rathi, Pooja; Singh, Jasbir

2016-01-01

New polymer therapeutics like polymer-drug conjugates (PDCs) are developing day by day. Heterocyclic drugs with excellent cytotoxic properties are available, but lack of their specificity makes them available to the normal cells also, which is the main cause of their toxicity. Drugs in the form of PDCs make delivery possible to the specific sites. Most of the PDCs are designed with the aim to either target and/or to get activated in specific cancer microenvironments. Therefore, the most exploited targets for cancer drug delivery are; cancer cell enzymes, heat shock protein 90 (HSP90), multi-drug resistance (MDR) proteins, angiogenesis, apoptosis and cell membrane receptors (e.g., folates, transferrin, etc.). In this review, we will summarize PDCs of heterocyclic drugs, like doxorubicin (DOX), daunorubicin, paclitaxel (PTX), docetaxel (DTX), cisplatin, camptothecin (CPT), geldanamycin (GDM), etc., and some of their analogs for efficient delivery of drugs to cancer cells.

Expression of long non-coding RNA LINC00973 is consistently increased upon treatment of colon cancer cells with different chemotherapeutic drugs.

PubMed

Zinovieva, Olga L; Grineva, Evgenia N; Prokofjeva, Maria M; Karpov, Dmitry S; Zheltukhin, Andrei O; Krasnov, George S; Snezhkina, Anastasiya V; Kudryavtseva, Anna V; Chumakov, Peter M; Mashkova, Tamara D; Prassolov, Vladimir S; Lisitsyn, Nikolai A

2018-06-02

Early prediction of tumor relapse depends on the identification of new prognostic cancer biomarkers, which are suitable for monitoring tumor response to different chemotherapeutic drugs. Using RNA-Seq, RT-qPCR, bioinformatics, and studies utilizing the murine tumor xenograft model, we have found significant and consistent changes in the abundance of five lincRNAs (LINC00973, LINC00941, CASC19, CCAT1, and BCAR4) upon treatment of both HT-29 and HCT-116 cells with 5-fluorouracil, oxaliplatin, and irinotecan at different doses and durations; both in vitro and in vivo. The most frequent changes were detected for LINC00973, whose content is most strongly and consistently increased upon treatment of both colon cancer cell lines with all three chemotherapeutic drugs. Additional studies are required in order to determine the molecular mechanisms by which anticancer drugs affect LINC00973 expression and to define the consequences of its upregulation on drug resistance of cancer cells. Copyright © 2018. Published by Elsevier B.V.

Photomechanical drug delivery

NASA Astrophysics Data System (ADS)

Doukas, Apostolos G.; Lee, Shun

2000-05-01

Photomechanical waves (PW) are generated by Q-switched or mode-locked lasers. Ablation is a reliable method for generating PWs with consistent characteristics. Depending on the laser wavelength and target material, PWs with different parameters can be generated which allows the investigation of PWs with cells and tissue. PWs have been shown to permeabilize the stratum corneum (SC) in vivo and facilitate the transport of drugs into the skin. Once a drug has diffused into the dermis it can enter the vasculature, thus producing a systemic effect. Fluorescence microscopy of biopsies show that 40-kDa molecules can be delivered to a depth of > 300 micrometers into the viable skin of rats. Many important drugs such as insulin, and erythropoietin are smaller or comparable in size, making the PWs attractive for transdermal drug delivery. There are three possible pathways through the SC: Transappendageal via hair follicles or other appendages, transcellular through the corneocytes, and intercellular via the extracellular matrix. The intracellular route appears to be the most likely pathway of drug delivery through the SC.

Recent advances in oral pulsatile drug delivery.

PubMed

Kalantzi, Lida E; Karavas, Evangelos; Koutris, Efthimios X; Bikiaris, Dimitrios N

2009-01-01

Pulsatile drug delivery aims to release drugs on a programmed pattern i.e.: at appropriate time and/or at appropriate site of action. Currently, it is gaining increasing attention as it offers a more sophisticated approach to the traditional sustained drug delivery i.e: a constant amount of drug released per unit time or constant blood levels. Technically, pulsatile drug delivery systems administered via the oral route could be divided into two distinct types, the time controlled delivery systems and the site-specific delivery systems. The simplest pulsatile formulation is a two layer press coated tablet consisted of polymers with different dissolution rates. Homogenicity of the coated barrier is mandatory in order to assure the predictability of the lag time. The disadvantage of such formulation is that the rupture time cannot be always adequately manipulated as it is strongly correlated with the physicochemical properties of the polymer. Gastric retentive systems, systems where the drug is released following a programmed lag phase, chronopharmaceutical drug delivery systems matching human circadian rhythms, multiunit or multilayer systems with various combinations of immediate and sustained-release preparation, are all classified under pulsatile drug delivery systems. On the other hand, site-controlled release is usually controlled by factors such as the pH of the target site, the enzymes present in the intestinal tract and the transit time/pressure of various parts of the intestine. In this review, recent patents on pulsatile drug delivery of oral dosage forms are summarized and discussed.

Nanomaterials in cancer-therapy drug delivery system.

PubMed

Zhang, Gen; Zeng, Xin; Li, Ping

2013-05-01

Nanomaterials can enhance the delivery and treatment efficiency of anti-cancer drugs, and the mechanisms of the tumor-reducing activity of nanomaterials with cancer drug have been investigated. The task for drug to reach pathological areas has facilitated rapid advances in nanomedicine. Herein, we summarize promising findings with respect to cancer therapeutics based on nano-drug delivery vectors. Relatively high toxicity of uncoated nanoparticles restricts the use of these materials in humans. In order to reduce toxicity, many approaches have focused on the encapsulation of nanoparticles with biocompatible materials. Efficient delivery systems have been developed that utilized nanoparticles loaded with high dose of cancer drug in the presence of bilayer molecules. Well-established nanotechnologies have been designed for drug delivery with specific bonding. Surface-modified nanoparticles as vehicles for drug delivery system that contains multiple nano-components, each specially designed to achieve aimed task for the emerging application delivery of therapeutics. Drug-coated polymer nanoparticles could efficiently increase the intracellular accumulation of anti-cancer drugs. This review also introduces the nanomaterials with drug on the induction of apoptosis in cancer cells in vitro and in vivo. Direct interactions between the particles and cellular molecules to cause adverse biological responses are also discussed.

The significance of transferrin receptors in oncology: the development of functional nano-based drug delivery systems.

PubMed

Tortorella, Stephanie; Karagiannis, Tom C

2014-01-01

Anticancer therapeutic research aims to improve clinical management of the disease through the development of strategies that involve currently-relevant treatment options and targeted delivery. Tumour-specific and -targeted delivery of compounds to the site of malignancy allows for enhanced cellular uptake, increased therapeutic benefit with high intratumoural drug concentrations, and decreased systemic exposure. Due to the upregulation of transferrin receptor expression in a wide variety of cancers, its function and its highly efficient recycling pathway, strategies involving the selective targeting of the receptor are well documented. Direct conjugation and immunotoxin studies using the transferrin peptide or anti-transferrin receptor antibodies as the targeting moiety have established the capacity to enhance cellular uptake, cross the blood brain barrier, limit systemic toxicity and reverse multi-drug resistance. Limitations in direct conjugation, including the difficulty in linking an adequate amount of therapeutic compound to the ligand or antibody have identified the requirement to develop novel delivery methods. The application of nanoparticulate theory in the development of functional drug delivery systems has proven to be most promising, with the ability to selectively modify size-dependent properties and surface chemistry. The transferrin modification on a range of nanoparticle formulations enhances selective cellular uptake through transferrin-mediated processes, and increases therapeutic benefit through the ability to encapsulate high concentrations of relevant drug to the tumour site. Although ineffective in crossing the blood brain barrier in its free form, chemotherapeutic compounds including doxorubicin, may be loaded into transferrin-conjugated nanocarriers and impart cytotoxic effects in glioma cells in vitro and in vivo. Additionally, transferrin-targeted nanoparticles may be used in selective diagnostic applications with enhanced selectivity and

Nanomedicine Drug Delivery across Mucous Membranes

NASA Astrophysics Data System (ADS)

Lancina, Michael George, III

Control over the distribution of therapeutic compounds is a complex and somewhat overlooked field of pharmaceutical research. When swallowing a pill or receiving an injection, it is commonly assumed that drug will spread throughout the body in a more or less uniform concentration and find its way to wherever it is needed. In truth, drug biodistribuition is highly non-uniform and dependent on a large number of factors. The development of advanced drug delivery systems to control biodistribution can produce significant advances in clinical treatments without the need to discover new therapeutic compounds. This work focuses on a number of nanostructured materials designed to improve drug delivery by direct and efficient transfer of drugs across one of the body's external mucous membranes. Chapter 1 outlines the central concept that unites these studies: nanomaterials and cationic particles can be used to delivery therapeutic compounds across mucous membranes. Special attention is given to dendritic nanoparticles. In chapter 2, uses for dendrimers in ocular drug delivery are presented. The studies are divided into two main groups: topical and injectable formulations. Chapter 3 does not involve dendrimers but instead another cationic particle used in transmembrane drug delivery, chitosan. Next, a dendrimer based nanofiber mat was used to deliver anti-glaucoma drugs in chapter 4. A three week in vivo efficacy trial showed dendrimer nanofiber mats outperformed traditional eye drops in terms of intra-ocular pressure decrease in a normotensive rat model. Finally, we have developed a new dendrimer based anti-glaucoma drug in chapter 5. Collectively, these studies demonstrate some of the potential applications for nanotechnology to improve transmembrane drug delivery. These particles and fibers are able to readily adhere and penetrate across epithelial cell lays. Utilizing these materials to improve drug absorption through these portals has the potential to improve the

Solid lipid nanoparticles for ocular drug delivery.

PubMed

Seyfoddin, Ali; Shaw, John; Al-Kassas, Raida

2010-01-01

Ocular drug delivery remains challenging because of the complex nature and structure of the eye. Conventional systems, such as eye drops and ointments, are inefficient, whereas systemic administration requires high doses resulting in significant toxicity. There is a need to develop novel drug delivery carriers capable of increasing ocular bioavailability and decreasing both local and systemic cytotoxicity. Nanotechnology is expected to revolutionize ocular drug delivery. Many nano-structured systems have been employed for ocular drug delivery and yielded some promising results. Solid lipid nanoparticles (SLNs) have been looked at as a potential drug carrier system since the 1990s. SLNs do not show biotoxicity as they are prepared from physiological lipids. SLNs are especially useful in ocular drug delivery as they can enhance the corneal absorption of drugs and improve the ocular bioavailability of both hydrophilic and lipophilic drugs. SLNs have another advantage of allowing autoclave sterilization, a necessary step towards formulation of ocular preparations. This review outlines in detail the various production, characterization, sterilization, and stabilization techniques for SLNs. In-vitro and in-vivo methods to study the drug release profile of SLNs have been explained. Special attention has been given to the nature of lipids and surfactants commonly used for SLN production. A summary of previous studies involving the use of SLNs in ocular drug delivery is provided, along with a critical evaluation of SLNs as a potential ocular delivery system.

Enhancing Tumor Cell Response to Chemotherapy through the Targeted Delivery of Platinum Drugs Mediated by Highly Stable, Multifunctional Carboxymethylcellulose-Coated Magnetic Nanoparticles.

PubMed

Medříková, Zdenka; Novohradsky, Vojtech; Zajac, Juraj; Vrána, Oldřich; Kasparkova, Jana; Bakandritsos, Aristides; Petr, Martin; Zbořil, Radek; Brabec, Viktor

2016-07-04

The fabrication of nanoparticles using different formulations, and which can be used for the delivery of chemotherapeutics, has recently attracted considerable attention. We describe herein an innovative approach that may ultimately allow for the selective delivery of anticancer drugs to tumor cells by using an external magnet. A conventional antitumor drug, cisplatin, has been incorporated into new carboxymethylcellulose-stabilized magnetite nanoparticles conjugated with the fluorescent marker Alexa Fluor 488 or folic acid as targeting agent. The magnetic nanocarriers possess exceptionally high biocompatibility and colloidal stability. These cisplatin-loaded nanoparticles overcome the resistance mechanisms typical of free cisplatin. Moreover, experiments aimed at the localization of the nanoparticles driven by an external magnet in a medium that mimics physiological conditions confirmed that this localization can inhibit tumor cell growth site-specifically. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biomimetics in drug delivery systems: A critical review.

PubMed

Sheikhpour, Mojgan; Barani, Leila; Kasaeian, Alibakhsh

2017-05-10

Today, the advanced drug delivery systems have been focused on targeted drug delivery fields. The novel drug delivery is involved with the improvement of the capacity of drug loading in drug carriers, cellular uptake of drug carriers, and the sustained release of drugs within target cells. In this review, six groups of therapeutic drug carriers including biomimetic hydrogels, biomimetic micelles, biomimetic liposomes, biomimetic dendrimers, biomimetic polymeric carriers and biomimetic nanostructures, are studied. The subject takes advantage of the biomimetic methods of productions or the biomimetic techniques for the surface modifications, similar to what accrues in natural cells. Moreover, the effects of these biomimetic approaches for promoting the drug efficiency in targeted drug delivery are visible. The study demonstrates that the fabrication of biomimetic nanocomposite drug carriers could noticeably promote the efficiency of drugs in targeted drug delivery systems. Copyright © 2017 Elsevier B.V. All rights reserved.

PLGA: a unique polymer for drug delivery.

PubMed

Kapoor, Deepak N; Bhatia, Amit; Kaur, Ripandeep; Sharma, Ruchi; Kaur, Gurvinder; Dhawan, Sanju

2015-01-01

Biodegradable polymers have played an important role in the delivery of drugs in a controlled and targeted manner. Polylactic-co-glycolic acid (PLGA) is one of the extensively researched synthetic biodegradable polymers due to its favorable properties. It is also known as a 'Smart Polymer' due to its stimuli sensitive behavior. A wide range of PLGA-based drug delivery systems have been reported for the treatment or diagnosis of various diseases and disorders. The present review provides an overview of the chemistry, physicochemical properties, biodegradation behavior, evaluation parameters and applications of PLGA in drug delivery. Different drug-polymer combinations developed into drug delivery or carrier systems are enumerated and discussed.

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

Dendrimers for Drug Delivery.

PubMed

Chauhan, Abhay Singh

2018-04-18

Dendrimers have come a long way in the last 25 years since their inception. Originally created as a wonder molecule of chemistry, dendrimer is now in the fourth class of polymers. Dr. Donald Tomalia first published his seminal work on Poly(amidoamine) (PAMAM) dendrimers in 1985. Application of dendrimers as a drug delivery system started in late 1990s. Dendrimers for drug delivery are employed using two approaches: (i) formulation and (ii) nanoconstruct. In the formulation approach, drugs are physically entrapped in a dendrimer using non-covalent interactions, whereas drugs are covalently coupled on dendrimers in the nanoconstruct approach. We have demonstrated the utility of PAMAM dendrimers for enhancing solubility, stability and oral bioavailability of various drugs. Drug entrapment and drug release from dendrimers can be controlled by modifying dendrimer surfaces and generations. PAMAM dendrimers are also shown to increase transdermal permeation and specific drug targeting. Dendrimer platforms can be engineered to attach targeting ligands and imaging molecules to create a nanodevice. Dendrimer nanotechnology, due to its multifunctional ability, has the potential to create next generation nanodevices.

Porous Inorganic Drug Delivery Systems-a Review.

PubMed

Sayed, E; Haj-Ahmad, R; Ruparelia, K; Arshad, M S; Chang, M-W; Ahmad, Z

2017-07-01

Innovative methods and materials have been developed to overcome limitations associated with current drug delivery systems. Significant developments have led to the use of a variety of materials (as excipients) such as inorganic and metallic structures, marking a transition from conventional polymers. Inorganic materials, especially those possessing significant porosity, are emerging as good candidates for the delivery of a range of drugs (antibiotics, anticancer and anti-inflammatories), providing several advantages in formulation and engineering (encapsulation of drug in amorphous form, controlled delivery and improved targeting). This review focuses on key selected developments in porous drug delivery systems. The review provides a short broad overview of porous polymeric materials for drug delivery before focusing on porous inorganic materials (e.g. Santa Barbara Amorphous (SBA) and Mobil Composition of Matter (MCM)) and their utilisation in drug dosage form development. Methods for their preparation and drug loading thereafter are detailed. Several examples of porous inorganic materials, drugs used and outcomes are discussed providing the reader with an understanding of advances in the field and realistic opportunities.

Topical drug delivery systems: a patent review.

PubMed

Singh Malik, Deepinder; Mital, Neeraj; Kaur, Gurpreet

2016-01-01

Topical administration is the favored route for local delivery of therapeutic agents due to its convenience and affordability. The specific challenge of designing a therapeutic system is to achieve an optimal concentration of a certain drug at its site of action for an appropriate duration. This review summarizes innovations from the past 3 years (2012-2015) in the field of topical drug delivery for the treatment of local infections of the vagina, nose, eye and skin. The review also throws some light on the anatomy and physiology of these organs and their various defensive barriers which affect the delivery of drugs administered topically. Topical administration has been gaining attention over the last few years. However, conventional topical drug delivery systems suffer from drawbacks such as poor retention and low bioavailability. The successful formulation of topical delivery products requires the careful manipulation of defensive barriers and selection of a soluble drug carrier. Extensive research is required to develop newer topical drug delivery systems aiming either to improve the efficacy or to reduce side effects compared to current patented systems.

Ultrasound-mediated drug delivery for cardiovascular disease

PubMed Central

Sutton, Jonathan T; Haworth, Kevin J; Pyne-Geithman, Gail; Holland, Christy K

2014-01-01

Introduction Ultrasound (US) has been developed as both a valuable diagnostic tool and a potent promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. These effects can be mediated by mechanical oscillations of circulating microbubbles, or US contrast agents, which may also encapsulate and shield a therapeutic agent in the bloodstream. Oscillating microbubbles can create stresses directly on nearby tissue or induce fluid effects that effect drug penetration into vascular tissue, lyse thrombi or direct drugs to optimal locations for delivery. Areas covered The present review summarizes investigations that have provided evidence for US-mediated drug delivery as a potent method to deliver therapeutics to diseased tissue for cardiovascular treatment. In particular, the focus will be on investigations of specific aspects relating to US-mediated drug delivery, such as delivery vehicles, drug transport routes, biochemical mechanisms and molecular targeting strategies. Expert opinion These investigations have spurred continued research into alternative therapeutic applications, such as bioactive gas delivery and new US technologies. Successful implementation of US-mediated drug delivery has the potential to change the way many drugs are administered systemically, resulting in more effective and economical therapeutics, and less-invasive treatments. PMID:23448121

Polymeric micelles for multi-drug delivery in cancer.

PubMed

Cho, Hyunah; Lai, Tsz Chung; Tomoda, Keishiro; Kwon, Glen S

2015-02-01

Drug combinations are common in cancer treatment and are rapidly evolving, moving beyond chemotherapy combinations to combinations of signal transduction inhibitors. For the delivery of drug combinations, i.e., multi-drug delivery, major considerations are synergy, dose regimen (concurrent versus sequential), pharmacokinetics, toxicity, and safety. In this contribution, we review recent research on polymeric micelles for multi-drug delivery in cancer. In concurrent drug delivery, polymeric micelles deliver multi-poorly water-soluble anticancer agents, satisfying strict requirements in solubility, stability, and safety. In sequential drug delivery, polymeric micelles participate in pretreatment strategies that "prime" solid tumors and enhance the penetration of secondarily administered anticancer agent or nanocarrier. The improved delivery of multiple poorly water-soluble anticancer agents by polymeric micelles via concurrent or sequential regimens offers novel and interesting strategies for drug combinations in cancer treatment.

Nanocomposite thin films for triggerable drug delivery.

PubMed

Vannozzi, Lorenzo; Iacovacci, Veronica; Menciassi, Arianna; Ricotti, Leonardo

2018-05-01

Traditional drug release systems normally rely on a passive delivery of therapeutic compounds, which can be partially programmed, prior to injection or implantation, through variations in the material composition. With this strategy, the drug release kinetics cannot be remotely modified and thus adapted to changing therapeutic needs. To overcome this issue, drug delivery systems able to respond to external stimuli are highly desirable, as they allow a high level of temporal and spatial control over drug release kinetics, in an operator-dependent fashion. Areas covered: On-demand drug delivery systems actually represent a frontier in this field and are attracting an increasing interest at both research and industrial level. Stimuli-responsive thin films, enabled by nanofillers, hold a tremendous potential in the field of triggerable drug delivery systems. The inclusion of responsive elements in homogeneous or heterogeneous thin film-shaped polymeric matrices strengthens and/or adds intriguing properties to conventional (bare) materials in film shape. Expert opinion: This Expert Opinion review aims to discuss the approaches currently pursued to achieve an effective on-demand drug delivery, through nanocomposite thin films. Different triggering mechanisms allowing a fine control on drug delivery are described, together with current challenges and possible future applications in therapy and surgery.

Hydrogel-Based Drug Delivery Systems for Poorly Water-Soluble Drugs.

PubMed

McKenzie, Matthew; Betts, David; Suh, Amy; Bui, Kathryn; Kim, London Doyoung; Cho, Hyunah

2015-11-13

Hydrogels are three-dimensional materials that can withstand a great amount of water incorporation while maintaining integrity. This allows hydrogels to be very unique biomedical materials, especially for drug delivery. Much effort has been made to incorporate hydrophilic molecules in hydrogels in the field of drug delivery, while loading of hydrophobic drugs has not been vastly studied. However, in recent years, research has also been conducted on incorporating hydrophobic molecules within hydrogel matrices for achieving a steady release of drugs to treat various ailments. Here, we summarize the types of hydrogels used as drug delivery vehicles, various methods to incorporate hydrophobic molecules in hydrogel matrices, and the potential therapeutic applications of hydrogels in cancer.

Digesting a Path Forward: The Utility of Collagenase Tumor Treatment for Improved Drug Delivery.

PubMed

Dolor, Aaron; Szoka, Francis C

2018-06-04

Collagen and hyaluronan are the most abundant components of the extracellular matrix (ECM) and their overexpression in tumors is linked to increased tumor growth and metastasis. These ECM components contribute to a protective tumor microenvironment by supporting a high interstitial fluid pressure and creating a tortuous setting for the convection and diffusion of chemotherapeutic small molecules, antibodies, and nanoparticles in the tumor interstitial space. This review focuses on the research efforts to deplete extracellular collagen with collagenases to normalize the tumor microenvironment. Although collagen synthesis inhibitors are in clinical development, the use of collagenases is contentious and clinically untested in cancer patients. Pretreatment of murine tumors with collagenases increased drug uptake and diffusion 2-10-fold. This modest improvement resulted in decreased tumor growth, but the benefits of collagenase treatment are confounded by risks of toxicity from collagen breakdown in healthy tissues. In this review, we evaluate the published in vitro and in vivo benefits and limitations of collagenase treatment to improve drug delivery.

Enhancing Tumor Drug Delivery by Laser-Activated Vascular Barrier Disruption

DTIC Science & Technology

2006-12-01

increased, which leads to normal tissue toxicity . This delivery problem not only limits the clinical application of existing chemotherapeutics, but also...principles and uses photochemical reactions to generate biological effectors, such as reactive oxygen species (ROS), which cause oxidative damage to...liposomes, mi- celles, and biodegradable nanoparticles , or conju- gated with hydrophilic polymers.6 It is likely that although some level of

Recent advances of controlled drug delivery using microfluidic platforms.

PubMed

Sanjay, Sharma T; Zhou, Wan; Dou, Maowei; Tavakoli, Hamed; Ma, Lei; Xu, Feng; Li, XiuJun

2018-03-15

Conventional systematically-administered drugs distribute evenly throughout the body, get degraded and excreted rapidly while crossing many biological barriers, leaving minimum amounts of the drugs at pathological sites. Controlled drug delivery aims to deliver drugs to the target sites at desired rates and time, thus enhancing the drug efficacy, pharmacokinetics, and bioavailability while maintaining minimal side effects. Due to a number of unique advantages of the recent microfluidic lab-on-a-chip technology, microfluidic lab-on-a-chip has provided unprecedented opportunities for controlled drug delivery. Drugs can be efficiently delivered to the target sites at desired rates in a well-controlled manner by microfluidic platforms via integration, implantation, localization, automation, and precise control of various microdevice parameters. These features accordingly make reproducible, on-demand, and tunable drug delivery become feasible. On-demand self-tuning dynamic drug delivery systems have shown great potential for personalized drug delivery. This review presents an overview of recent advances in controlled drug delivery using microfluidic platforms. The review first briefly introduces microfabrication techniques of microfluidic platforms, followed by detailed descriptions of numerous microfluidic drug delivery systems that have significantly advanced the field of controlled drug delivery. Those microfluidic systems can be separated into four major categories, namely drug carrier-free micro-reservoir-based drug delivery systems, highly integrated carrier-free microfluidic lab-on-a-chip systems, drug carrier-integrated microfluidic systems, and microneedles. Microneedles can be further categorized into five different types, i.e. solid, porous, hollow, coated, and biodegradable microneedles, for controlled transdermal drug delivery. At the end, we discuss current limitations and future prospects of microfluidic platforms for controlled drug delivery. Copyright �

Nanoparticles in the ocular drug delivery

PubMed Central

Zhou, Hong-Yan; Hao, Ji-Long; Wang, Shuang; Zheng, Yu; Zhang, Wen-Song

2013-01-01

Ocular drug transport barriers pose a challenge for drug delivery comprising the ocular surface epithelium, the tear film and internal barriers of the blood-aqueous and blood-retina barriers. Ocular drug delivery efficiency depends on the barriers and the clearance from the choroidal, conjunctival vessels and lymphatic. Traditional drug administration reduces the clinical efficacy especially for poor water soluble molecules and for the posterior segment of the eye. Nanoparticles (NPs) have been designed to overcome the barriers, increase the drug penetration at the target site and prolong the drug levels by few internals of drug administrations in lower doses without any toxicity compared to the conventional eye drops. With the aid of high specificity and multifunctionality, DNA NPs can be resulted in higher transfection efficiency for gene therapy. NPs could target at cornea, retina and choroid by surficial applications and intravitreal injection. This review is concerned with recent findings and applications of NPs drug delivery systems for the treatment of different eye diseases. PMID:23826539

Colloidal microgels in drug delivery applications

PubMed Central

Vinogradov, Serguei V.

2005-01-01

Colloidal microgels have recently received attention as environmentally responsive systems and now are increasingly used in applications as carriers for therapeutic drugs and diagnostic agents. Synthetic microgels consist of a crosslinked polymer network that provides a depot for loaded drugs, protection against environmental hazards and template for post-synthetic modification or vectorization of the drug carriers. The aim of this manuscript is to review recent attempts to develop new microgel formulations for oral drug delivery, to design metal-containing microgels for diagnostic and therapeutic applications, and to advance approaches including the systemic administration of microgels. Novel nanogel drug delivery systems developed in the authors’ laboratory are discussed in details including aspects of their synthesis, vectorization and recent applications for encapsulation of low molecular weight drugs or formulation of biological macromolecules. The findings reviewed here are encouraging for further development of the nanogels as intelligent drug carriers with such features as targeted delivery and triggered drug release. PMID:17168773

1,3-Bis(2-chloroethyl)-1-nitrosourea-loaded bovine serum albumin nanoparticles with dual magnetic resonance-fluorescence imaging for tracking of chemotherapeutic agents.

PubMed

Wei, Kuo-Chen; Lin, Feng-Wei; Huang, Chiung-Yin; Ma, Chen-Chi M; Chen, Ju-Yu; Feng, Li-Ying; Yang, Hung-Wei

To date, knowing how to identify the location of chemotherapeutic agents in the human body after injection is still a challenge. Therefore, it is urgent to develop a drug delivery system with molecular imaging tracking ability to accurately understand the distribution, location, and concentration of a drug in living organisms. In this study, we developed bovine serum albumin (BSA)-based nanoparticles (NPs) with dual magnetic resonance (MR) and fluorescence imaging modalities (fluorescein isothiocyanate [FITC]-BSA-Gd/1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU] NPs) to deliver BCNU for inhibition of brain tumor cells (MBR 261-2). These BSA-based NPs are water dispersible, stable, and biocompatible as confirmed by XTT cell viability assay. In vitro phantoms and in vivo MR and fluorescence imaging experiments show that the developed FITC-BSA-Gd/BCNU NPs enable dual MR and fluorescence imaging for monitoring cellular uptake and distribution in tumors. The T1 relaxivity (R1) of FITC-BSA-Gd/BCNU NPs was 3.25 mM(-1) s(-1), which was similar to that of the commercial T1 contrast agent (R1 =3.36 mM(-1) s(-1)). The results indicate that this multifunctional drug delivery system has potential bioimaging tracking of chemotherapeutic agents ability in vitro and in vivo for cancer therapy.

Synthetic Tumor Networks for Screening Drug Delivery Systems

PubMed Central

Prabhakarpandian, Balabhaskar; Shen, Ming-Che; Nichols, Joseph B.; Garson, Charles J.; Mills, Ivy R.; Matar, Majed M.; Fewell, Jason G.; Pant, Kapil

2015-01-01

Tumor drug delivery is a complex phenomenon affected by several elements in addition to drug or delivery vehicle’s physico-chemical properties. A key factor is tumor microvasculature with complex effects including convective transport, high interstitial pressure and enhanced vascular permeability due to the presence of “leaky vessels”. Current in vitro models of the tumor microenvironment for evaluating drug delivery are oversimplified and, as a result, show poor correlation with in vivo performance. In this study, we report on the development of a novel microfluidic platform that models the tumor microenvironment more accurately, with physiologically and morphologically realistic microvasculature including endothelial cell lined leaky capillary vessels along with 3D solid tumors. Endothelial cells and 3D spheroids of cervical tumor cells were co-cultured in the networks. Drug vehicle screening was demonstrated using GFP gene delivery by different formulations of nanopolymers. The synthetic tumor network was successful in predicting in vivo delivery efficiencies of the drug vehicles. The developed assay will have critical applications both in basic research, where it can be used to develop next generation delivery vehicles, and in drug discovery where it can be used to study drug transport and delivery efficacy in realistic tumor microenvironment, thereby enabling drug compound and/or delivery vehicle screening. PMID:25599856

Non-invasive systemic drug delivery through mucosal routes.

PubMed

Goyal, Amit K; Singh, Ranjit; Chauhan, Gaurav; Rath, Goutam

2018-04-24

Science of drug delivery has achieved tremendous milestones in the last few decades. Emergence of novel drug delivery techniques and the most popular nanotechnology directed the drug delivery to another level. Without any doubt, present technology holds the proficiency to approach even the intercellular targets. Between all these success auras, there lies wads of giant challenges. One such challenge is delivering the molecule directly to the blood stream. Parenteral route is considered as the most effective route for delivering active pharmaceutical substances, but is associated with major disadvantages of painful drug delivery. Modern drug delivery suggests several approaches to outstrip this painful phenomenon. In the present article, we represent a new systematic vision to understand the ability and desirability of mucosal sites to achieve painless drug delivery. Human mucosa presents supreme proximity to the blood circulation that one can even observe with naked eye. Advances in drug delivery provide numerous approaches to exploit the mucosa for systemic reach. However, the revolutionary success is still unapproachable, with an understandable reason of associated complexities and challenges. This manuscript summarizes the significance of each mucosal site, on the basis of anatomical-physiological grounds. Particular attention is given to rationalize the selection of disease and a suitable drug delivery approach for its treatment.

The Research Progress of Targeted Drug Delivery Systems

NASA Astrophysics Data System (ADS)

Zhan, Jiayin; Ting, Xizi Liang; Zhu, Junjie

2017-06-01

Targeted drug delivery system (DDS) means to selectively transport drugs to targeted tissues, organs, and cells through a variety of drugs carrier. It is usually designed to improve the pharmacological and therapeutic properties of conventional drugs and to overcome problems such as limited solubility, drug aggregation, poor bio distribution and lack of selectivity, controlling drug release carrier and to reduce normal tissue damage. With the characteristics of nontoxic and biodegradable, it can increase the retention of drug in lesion site and the permeability, improve the concentration of the drug in lesion site. at present, there are some kinds of DDS using at test phase, such as slow controlled release drug delivery system, targeted drug delivery systems, transdermal drug delivery system, adhesion dosing system and so on. This paper makes a review for DDS.

Biocompatible and biodegradable fibrinogen microspheres for tumor-targeted doxorubicin delivery

PubMed Central

Joo, Jae Yeon; Park, Gil Yong; An, Seong Soo A

2015-01-01

In the development of effective drug delivery carriers, many researchers have focused on the usage of nontoxic and biocompatible materials and surface modification with targeting molecules for tumor-specific drug delivery. Fibrinogen (Fbg), an abundant glycoprotein in plasma, could be a potential candidate for developing drug carriers because of its biocompatibility and tumor-targeting property via arginine–glycine–aspartate (RGD) peptide sequences. Doxorubicin (DOX), a chemotherapeutic agent, was covalently conjugated to Fbg, and the microspheres were prepared. Acid-labile and non-cleavable linkers were used for the conjugation of DOX to Fbg, resulting in an acid-triggered drug release under a mild acidic condition and a slow-controlled drug release, respectively. In vitro cytotoxicity tests confirmed low cytotoxicity in normal cells and high antitumor effect toward cancer cells. In addition, it was discovered that a longer linker could make the binding of cells to Fbg drug carriers easier. Therefore, DOX–linker–Fbg microspheres could be a suitable drug carrier for safer and effective drug delivery. PMID:26366073

Novel drug delivery systems for glaucoma

PubMed Central

Lavik, E; Kuehn, M H; Kwon, Y H

2011-01-01

Reduction of intraocular pressure (IOP) by pharmaceutical or surgical means has long been the standard treatment for glaucoma. A number of excellent drugs are available that are effective in reducing IOP. These drugs are typically applied as eye drops. However, patient adherence can be poor, thus reducing the clinical efficacy of the drugs. Several novel delivery systems designed to address the issue of adherence and to ensure consistent reduction of IOP are currently under development. These delivery systems include contact lenses-releasing glaucoma medications, injectables such as biodegradable micro- and nanoparticles, and surgically implanted systems. These new technologies are aimed at increasing clinical efficacy by offering multiple delivery options and are capable of managing IOP for several months. There is also a desire to have complementary neuroprotective approaches for those who continue to show progression, despite IOP reduction. Many potential neuroprotective agents are not suitable for traditional oral or drop formulations. Their potential is dependent on developing suitable delivery systems that can provide the drugs in a sustained, local manner to the retina and optic nerve. Drug delivery systems have the potential to improve patient adherence, reduce side effects, increase efficacy, and ultimately, preserve sight for glaucoma patients. In this review, we discuss benefits and limitations of the current systems of delivery and application, as well as those on the horizon. PMID:21475311

Intracarotid Delivery of Drugs: The Potential and the Pitfalls

PubMed Central

Joshi, Shailendra; Meyers, Phillip M.; Ornstein, Eugene

2014-01-01

The major efforts to selectively deliver drugs to the brain in the last decade have relied on smart molecular techniques to penetrate the blood brain barrier while intraarterial drug delivery has drawn relatively little attention. In the last decade there have been rapid advances in endovascular techniques. Modern endovascular procedures can permit highly targeted drug delivery by intracarotid route. Intracarotid drug delivery can be the primary route of drug delivery or it could be used to facilitate the delivery of smart-neuropharmaceuticals. There have been few attempts to systematically understand the kinetics of intracarotid drugs. Anecdotal data suggests that intracarotid drug delivery is effective in the treatment of cerebral vasospasm, thromboembolic strokes, and neoplasms. Neuroanesthesiologists are frequently involved in the care of such high-risk patients. Therefore, it is necessary to understand the applications of intracarotid drug delivery and the unusual kinetics of intracarotid drugs. PMID:18719453

Nanocrystal for ocular drug delivery: hope or hype.

PubMed

Sharma, Om Prakash; Patel, Viral; Mehta, Tejal

2016-08-01

The complexity of the structure and nature of the eye emanates a challenge for drug delivery to formulation scientists. Lower bioavailability concern of conventional ocular formulation provokes the interest of researchers in the development of novel drug delivery system. Nanotechnology-based formulations have been extensively investigated and found propitious in improving bioavailability of drugs by overcoming ocular barriers prevailing in the eye. The advent of nanocrystals helped in combating the problem of poorly soluble drugs specifically for oral and parenteral drug delivery and led to development of various marketed products. Nanocrystal-based formulations explored for ocular drug delivery have been found successful in achieving increase in retention time, bioavailability, and permeability of drugs across the corneal and conjunctival epithelium. In this review, we have highlighted the ocular physiology and barriers in drug delivery. A comparative analysis of various nanotechnology-based ocular formulations is done with their pros and cons. Consideration is also given to various methods of preparation of nanocrystals with their patented technology. This article highlights the success achieved in conquering various challenges of ocular delivery by the use of nanocrystals while emphasizing on its advantages and application for ocular formulation. The perspectives of nanocrystals as an emerging flipside to explore the frontiers of ocular drug delivery are discussed.

Microencapsulation: A promising technique for controlled drug delivery.

PubMed

Singh, M N; Hemant, K S Y; Ram, M; Shivakumar, H G

2010-07-01

MICROPARTICLES OFFER VARIOUS SIGNIFICANT ADVANTAGES AS DRUG DELIVERY SYSTEMS, INCLUDING: (i) an effective protection of the encapsulated active agent against (e.g. enzymatic) degradation, (ii) the possibility to accurately control the release rate of the incorporated drug over periods of hours to months, (iii) an easy administration (compared to alternative parenteral controlled release dosage forms, such as macro-sized implants), and (iv) Desired, pre-programmed drug release profiles can be provided which match the therapeutic needs of the patient. This article gives an overview on the general aspects and recent advances in drug-loaded microparticles to improve the efficiency of various medical treatments. An appropriately designed controlled release drug delivery system can be a foot ahead towards solving problems concerning to the targeting of drug to a specific organ or tissue, and controlling the rate of drug delivery to the target site. The development of oral controlled release systems has been a challenge to formulation scientist due to their inability to restrain and localize the system at targeted areas of gastrointestinal tract. Microparticulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. The objective of this paper is to take a closer look at microparticles as drug delivery devices for increasing efficiency of drug delivery, improving the release profile and drug targeting. In order to appreciate the application possibilities of microcapsules in drug delivery, some fundamental aspects are briefly reviewed.

Microencapsulation: A promising technique for controlled drug delivery

PubMed Central

Singh, M.N.; Hemant, K.S.Y.; Ram, M.; Shivakumar, H.G.

2010-01-01

Microparticles offer various significant advantages as drug delivery systems, including: (i) an effective protection of the encapsulated active agent against (e.g. enzymatic) degradation, (ii) the possibility to accurately control the release rate of the incorporated drug over periods of hours to months, (iii) an easy administration (compared to alternative parenteral controlled release dosage forms, such as macro-sized implants), and (iv) Desired, pre-programmed drug release profiles can be provided which match the therapeutic needs of the patient. This article gives an overview on the general aspects and recent advances in drug-loaded microparticles to improve the efficiency of various medical treatments. An appropriately designed controlled release drug delivery system can be a foot ahead towards solving problems concerning to the targeting of drug to a specific organ or tissue, and controlling the rate of drug delivery to the target site. The development of oral controlled release systems has been a challenge to formulation scientist due to their inability to restrain and localize the system at targeted areas of gastrointestinal tract. Microparticulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. The objective of this paper is to take a closer look at microparticles as drug delivery devices for increasing efficiency of drug delivery, improving the release profile and drug targeting. In order to appreciate the application possibilities of microcapsules in drug delivery, some fundamental aspects are briefly reviewed. PMID:21589795

Advanced Analgesic Drug Delivery and Nanobiotechnology.

PubMed

Stoicea, Nicoleta; Fiorda-Diaz, Juan; Joseph, Nicholas; Shabsigh, Muhammad; Arias-Morales, Carlos; Gonzalez-Zacarias, Alicia A; Mavarez-Martinez, Ana; Marjoribanks, Stephen; Bergese, Sergio D

2017-07-01

Transdermal administration of analgesic medications offers several benefits over alternative routes of administration, including a decreased systemic drug load with fewer side effects, and avoidance of drug degradation by the gastrointestinal tract. Transdermal administration also offers a convenient mode of drug administration over an extended period of time, particularly desirable in pain medicine. A transdermal administration route may also offer increased safety for drugs with a narrow therapeutic window. The primary barrier to transdermal drug absorption is the skin itself. Transdermal nanotechnology offers a novel method of achieving enhanced dermal penetration with an extended delivery profile for analgesic drugs, due to their small size and relatively large surface area. Several materials have been used to enhance drug duration and transdermal penetration. The application of nanotechnology in transdermal delivery of analgesics has raised new questions regarding safety and ethical issues. The small molecular size of nanoparticles enables drug delivery to previously inaccessible body sites. To ensure safety, the interaction of nanoparticles with the human body requires further investigation on an individual drug basis, since different formulations have unique properties and side effects.

Reservoir-Based Drug Delivery Systems Utilizing Microtechnology

PubMed Central

Stevenson, Cynthia L.; Santini, John T.; Langer, Robert

2012-01-01

This review covers reservoir-based drug delivery systems that incorporate microtechnology, with an emphasis on oral, dermal, and implantable systems. Key features of each technology are highlighted such as working principles, fabrication methods, dimensional constraints, and performance criteria. Reservoir-based systems include a subset of microfabricated drug delivery systems and provide unique advantages. Reservoirs, whether external to the body or implanted, provide a well-controlled environment for a drug formulation, allowing increased drug stability and prolonged delivery times. Reservoir systems have the flexibility to accommodate various delivery schemes, including zero order, pulsatile, and on demand dosing, as opposed to a standard sustained release profile. Furthermore, the development of reservoir-based systems for targeted delivery for difficult to treat applications (e.g., ocular) has resulted in potential platforms for patient therapy. PMID:22465783

Drug delivery with microsecond laser pulses into gelatin

NASA Astrophysics Data System (ADS)

Shangguan, Hanqun; Casperson, Lee W.; Shearin, Alan; Gregory, Kenton W.; Prahl, Scott A.

1996-07-01

Photoacoustic drug delivery is a technique for localized drug delivery by laser-induced hydrodynamic pressure following cavitation bubble expansion and collapse. Photoacoustic drug delivery was investigated on gelatin-based thrombus models with planar and cylindrical geometries by use of one microsecond laser pulses. Solutions of a hydrophobic dye in mineral oil permitted monitoring of delivered colored oil into clear gelatin-based thrombus models. Cavitation bubble development and photoacoustic drug delivery were visualized with flash photography. This study demonstrated that cavitation is the governing mechanism for photoacoustic drug delivery, and the deepest penetration of colored oil in gels followed the bubble collapse. Spatial distribution measurements revealed that colored oil could be driven a few millimeters into the gels in both axial and radial directions, and the penetration was less than 500 mu m when the gelatin structure was not fractured. localized drug delivery, cavitation bubble, laser thrombolysis.

Advanced Drug Delivery Systems for Transdermal Delivery of Non-Steroidal Anti-Inflammatory Drugs: A Review.

PubMed

Kumar, Lalit; Verma, Shivani; Singh, Mehakjot; Tamanna, Tamanna; Utreja, Puneet

2018-06-04

Transdermal route of delivery of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) has several advantages over other routes like reduced adverse effects, less systemic absorption, and avoidance of first pass effect and degradation in the gastrointestinal tract (GIT). Transdermal route is also beneficial for drugs having a narrow therapeutic index. The skin acts as the primary barrier for transdermal delivery of various therapeutic molecules. Various advanced nanocarrier systems offer several advantages like improved dermal penetration along with an extended drug release profile due to their smaller size and high surface area. Various nanocarrier explored for transdermal delivery of NSAIDs are liposomes, niosomes, ethosomes, polymeric nanoparticles (NPs), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), dendrimers, nanosuspensions/nanoemulsion, and nanofibers Objectives: In the present review, our major aim was to explore the therapeutic potential of advanced nanocarrier systems enlisted above for transdermal delivery of NSAIDs. All literature search regarding advanced nanocarrier systems for transdermal delivery of NSAIDs was done using Google Scholar and Pubmed. Advanced nanocarrier have shown various advantages like reduced side effect, low dosing frequency, high skin permeation, and ease of application over conventional transdermal delivery systems of NSAIDs in various preclinical studies. However, clinical exploration of advanced nanocarrier systems for transdermal delivery of NSAIDs is still a challenge. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Biopolymers as transdermal drug delivery systems in dermatology therapy.

PubMed

Basavaraj, K H; Johnsy, George; Navya, M A; Rashmi, R; Siddaramaiah

2010-01-01

The skin is considered a complex organ for drug delivery because of its structure. Drug delivery systems are designed for the controlled release of drugs through the skin into the systemic circulation, maintaining consistent efficacy and reducing the dose of the drugs and their related side effects. Transdermal drug delivery represents one of the most rapidly advancing areas of novel drug delivery. The excellent impervious nature of the skin is the greatest challenge that must be overcome for successful drug delivery. Today, polymers have been proven to be successful for long-term drug delivery applications as no single polymer can satisfy all of the requirements. Biopolymers in the field of dermal application are rare and the mechanisms that affect skin absorption are almost unknown. Biopolymers are widely used as drug delivery systems, but as such the use of biopolymers as drug delivery systems in dermatologic therapy is still in progress. Commonly used biopolymers include hydrocolloids, alginates, hydrogels, polyurethane, collagen, poly(lactic-co-glycolic acid), chitosan, proteins and peptides, pectin, siRNAs, and hyaluronic acid. These new and exciting methods for drug delivery are already increasing the number and quality of dermal and transdermal therapies. This article reviews current research on biopolymers and focuses on their potential as drug carriers, particularly in relation to the dermatologic aspects of their use.

Spray-on transdermal drug delivery systems.

PubMed

Ibrahim, Sarah A

2015-02-01

Transdermal drug delivery possesses superior advantages over other routes of administration, particularly minimizing first-pass metabolism. Transdermal drug delivery is challenged by the barrier nature of skin. Numerous technologies have been developed to overcome the relatively low skin permeability, including spray-on transdermal systems. A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug-solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin. TSS is easily applied, delivering flexible drug dosage and associated with lower incidence of skin irritation. TSS provides a fast-drying product where the volatile solvent enables uniform drug distribution with minimal vehicle deposition on skin. TSS ensures precise dose administration that is aesthetically appealing and eliminates concerns of residual drug associated with transdermal patches. Furthermore, it provides a better alternative to traditional transdermal products due to ease of product development and manufacturing.

Light-switchable systems for remotely controlled drug delivery.

PubMed

Shim, Gayong; Ko, Seungbeom; Kim, Dongyoon; Le, Quoc-Viet; Park, Gyu Thae; Lee, Jaiwoo; Kwon, Taekhyun; Choi, Han-Gon; Kim, Young Bong; Oh, Yu-Kyoung

2017-12-10

Light-switchable systems have recently received attention as a new mode of remotely controlled drug delivery. In the past, a multitude of nanomedicine studies have sought to enhance the specificity of drug delivery to target sites by focusing on receptors overexpressed on malignant cells or environmental features of diseases sites. Despite these immense efforts, however, there are few clinically available nanomedicines. We need a paradigm shift in drug delivery. One strategy that may overcome the limitations of pathophysiology-based drug delivery is the use of remotely controlled delivery technology. Unlike pathophysiology-based active drug targeting strategies, light-switchable systems are not affected by the heterogeneity of cells, tissue types, and/or microenvironments. Instead, they are triggered by remote light (i.e., near-infrared) stimuli, which are absorbed by photoresponsive molecules or three-dimensional nanostructures. The sequential conversion of light to heat or reactive oxygen species can activate drug release and allow it to be spatio-temporally controlled. Light-switchable systems have been used to activate endosomal drug escape, modulate the release of chemical and biological drugs, and alter nanoparticle structures to control the release rates of drugs. This review will address the limitations of pathophysiology-based drug delivery systems, the current status of light-based remote-switch systems, and future directions in the application of light-switchable systems for remotely controlled drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

Bilirubin Nanoparticle-Assisted Delivery of a Small Molecule-Drug Conjugate for Targeted Cancer Therapy.

PubMed

Lee, Soyoung; Lee, Yonghyun; Kim, Hyungjun; Lee, Dong Yun; Jon, Sangyong

2018-06-11

Despite growing interest in targeted cancer therapy with small molecule drug conjugates (SMDCs), the short half-life of these conjugates in blood associated with their small size has limited their efficacy in cancer therapy. In this report, we propose a new approach for improving the antitumor efficacy of SMDCs based on nanoparticle-assisted delivery. Ideally, a nanoparticle-based delivery vehicle would prolong the half-life of an SMDC in blood and then release it in response to stimuli in the tumor microenvironment (TME). In this study, PEGylated bilirubin-based nanoparticles (BRNPs) were chosen as an appropriate delivery carrier because of their ability to release drugs in response to TME-associated reactive oxygen species (ROS) through rapid particle disruption. As a model SMDC, ACUPA-SN38 was synthesized by linking the prostate-specific membrane antigen (PSMA)-targeting ligand, ACUPA, to the chemotherapeutic agent, SN38. ACUPA-SN38 was loaded into BRNPs using a film-formation and rehydration method. The resulting ACUPA-SN38@BRNPs exhibited ROS-mediated particle disruption and rapid release of the SMDC, resulting in greater cytotoxicity toward PSMA-overexpressing prostate cancer cells (LNCaP) than toward ROS-unresponsive ACUPA-SN38@Liposomes. In a pharmacokinetic study, the circulation time of ACUPA-SN38@BRNPs in blood was prolonged by approximately 2-fold compared with that of the SMDC-based micellar nanoparticles. Finally, ACUPA-SN38@BRNPs showed greater antitumor efficacy in a PSMA-overexpressing human prostate xenograft tumor model than SN38@BRNPs or the SMDC alone. Collectively, these findings suggest that BRNPs are a viable delivery carrier option for various cancer-targeting SMDCs that suffer from short circulation half-life and limited therapeutic efficacy.

Recent advances in chitosan-based nanoparticulate pulmonary drug delivery

NASA Astrophysics Data System (ADS)

Islam, Nazrul; Ferro, Vito

2016-07-01

The advent of biodegradable polymer-encapsulated drug nanoparticles has made the pulmonary route of administration an exciting area of drug delivery research. Chitosan, a natural biodegradable and biocompatible polysaccharide has received enormous attention as a carrier for drug delivery. Recently, nanoparticles of chitosan (CS) and its synthetic derivatives have been investigated for the encapsulation and delivery of many drugs with improved targeting and controlled release. Herein, recent advances in the preparation and use of micro-/nanoparticles of chitosan and its derivatives for pulmonary delivery of various therapeutic agents (drugs, genes, vaccines) are reviewed. Although chitosan has wide applications in terms of formulations and routes of drug delivery, this review is focused on pulmonary delivery of drug-encapsulated nanoparticles of chitosan and its derivatives. In addition, the controversial toxicological effects of chitosan nanoparticles for lung delivery will also be discussed.

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

Pharmacology and pharmacogenetics of chemotherapeutic agents.

PubMed

Dawood, Shaheenah; Leyland-Jones, Brian

2009-06-01

The last decade the field of oncology has seen the introduction of several efficacious chemotherapeutic agents. However the benefits achieved have been modest at best. The choice of chemotherapeutic agent is often empirical and geared to fit the average patient with the result that approximately 40% of patients may be receiving the wrong drug. With greater understanding of the mechanisms behind the heterogeneity observed across patient populations, both in terms of efficacy and toxicity of a variety of therapeutic agents, research has now focused on individualizing treatment strategies by incorporating a combination of physiological variables, genetic characteristics and environmental factors together with the traditional tumor characteristics that currently drives clinical decision making. This review focuses on defining some of the principle components of personalized medicine. In addition we will review the pharmacological and pharmacogenetic predictors of toxic effects of chemotherapeutic agents drawing on examples of commonly used agents in oncology.

Multifunctional targeted liposomal drug delivery for efficient glioblastoma treatment

PubMed Central

Belhadj, Zakia; Zhan, Changyou; Ying, Man; Wei, Xiaoli; Xie, Cao; Yan, Zhiqiang; Lu, Weiyue

2017-01-01

Glioblastoma multiforme (GBM) has been considered to be the most malignant brain tumors. Due to the existence of various barriers including the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB) greatly hinder the accumulation and deep penetration of chemotherapeutics, the treatment of glioma remains to be the most challenging task in clinic. In order to circumvent these hurdles, we developed a multifunctional liposomal glioma-targeted drug delivery system (c(RGDyK)/pHA-LS) modified with cyclic RGD (c(RGDyK)) and p-hydroxybenzoic acid (pHA) in which c(RGDyK) could target integrin αvβ3 overexpressed on the BBTB and glioma cells and pHA could target dopamine receptors on the BBB. In vitro, c(RGDyK)/pHA-LS could target glioblastoma cells (U87), brain capillary endothelial cells (bEnd.3) and umbilical vein endothelial cells (HUVECs) through a comprehensive pathway. Besides, c(RGDyK)/pHA-LS could also increase the cytotoxicity of doxorubicin encapsulated in liposomes on glioblastoma cells, and was able to penetrate inside the glioma spheroids after traversing the in vitro BBB and BBTB. In vivo, we demonstrated the targeting ability of c(RGDyK)/pHA-LS to intracranial glioma. As expected, c(RGDyK)/pHA-LS/DOX showed a median survival time of 35 days, which was 2.31-, 1.76- and 1.5-fold higher than that of LS/DOX, c(RGDyK)-LS/DOX, and pHA-LS/DOX, respectively. The findings here suggested that the multifunctional glioma-targeted drug delivery system modified with both c(RGDyK) and pHA displayed strong antiglioma efficiency in vitro and in vivo, representing a promising platform for glioma therapy. PMID:28978003

A multifunctional β-CD-modified Fe3O4@ZnO:Er(3+),Yb(3+) nanocarrier for antitumor drug delivery and microwave-triggered drug release.

PubMed

Peng, Hongxia; Cui, Bin; Li, Guangming; Wang, Yingsai; Li, Nini; Chang, Zhuguo; Wang, Yaoyu

2015-01-01

We constructed a novel core-shell structured Fe3O4@ZnO:Er(3+),Yb(3+)@(β-CD) nanoparticles used as drug carrier to investigate the loading and controllable release properties of the chemotherapeutic drug etoposide (VP-16). The cavity of β-cyclodextrin is chemically inert, it can store etoposide molecules by means of hydrophobic interactions. The Fe3O4 core and ZnO:Er(3+),Yb(3+) shell functioned successfully for magnetic targeting and up-conversion fluorescence imaging, respectively. In addition, the ZnO:Er(3+),Yb(3+) shell acts as a good microwave absorber with excellent microwave thermal response property for microwave triggered drug release (the VP-16 release of 18% under microwave irradiation for 15 min outclass the 2% within 6h without microwave irradiation release). The release profile could be controlled by the duration and number of cycles of microwave application. This material therefore promises to be a useful noninvasive, externally controlled drug-delivery system in cancer therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Drug delivery technologies for autoimmune disease.

PubMed

Phillips, Brett E; Giannoukakis, Nick

2010-11-01

Targeting autoimmune disease poses two main challenges. The first is to identify unique targets to suppress directly or indirectly autoreactive cells exclusively. The second is to penetrate target tissues to deliver specifically drugs to desired cells that can achieve a therapeutic outcome. Herein, the range of drug delivery methods available and under development and how they can be useful to treat autoimmune diseases are discussed. Polymer delivery methods, as well as biological methods that include fusion proteins, targeted antibodies, recombinant viruses and cell products are compared. Readers will gain insight into the progression of clinical trials for different technologies and drug delivery methods useful for targeting and modulating the function of autoreactive immune cells. Several tissue-specific polymer-based and biologic drug delivery systems are now in Phase II/III clinical trials. Although these trials are focused mainly on cancer treatment, lessons from these trials can guide the use of the same agents for autoimmunity therapeutics.

Controlled drug delivery systems: past forward and future back.

PubMed

Park, Kinam

2014-09-28

Controlled drug delivery technology has progressed over the last six decades. This progression began in 1952 with the introduction of the first sustained release formulation. The 1st generation of drug delivery (1950-1980) focused on developing oral and transdermal sustained release systems and establishing controlled drug release mechanisms. The 2nd generation (1980-2010) was dedicated to the development of zero-order release systems, self-regulated drug delivery systems, long-term depot formulations, and nanotechnology-based delivery systems. The latter part of the 2nd generation was largely focused on studying nanoparticle formulations. The Journal of Controlled Release (JCR) has played a pivotal role in the 2nd generation of drug delivery technologies, and it will continue playing a leading role in the next generation. The best path towards a productive 3rd generation of drug delivery technology requires an honest, open dialog without any preconceived ideas of the past. The drug delivery field needs to take a bold approach to designing future drug delivery formulations primarily based on today's necessities, to produce the necessary innovations. The JCR provides a forum for sharing the new ideas that will shape the 3rd generation of drug delivery technology. Copyright © 2014 Elsevier B.V. All rights reserved.

Introduction for Design of Nanoparticle Based Drug Delivery Systems.

PubMed

Edgar, Jun Yan Chan; Wang, Hui

2017-01-01

Conventional drug delivery systems contain numerous limitations such as limited targeting, low therapeutic indices, poor water solubility, and the induction of drug resistances. In order to overcome the drawbacks of conventional pathway of drug delivery, nanoparticle delivery systems are therefore designed and used as the drug carriers. Nanoparticle based drug delivery systems have been rapidly growing and are being applied to various sections of biomedicine. Drug nanocarriers based on dendrimers, liposomes, self-assembling peptides, watersoluble polymers, and block copolymer micelles are the most extensively studied types of drug delivery systems and some of them are being used in clinical therapy. In particular for cancer therapy, antineoplastic drugs are taking advantage of nanoparticulate drug carriers to improve the cure efficacy. Nanoparticle based drug carriers are capable of improving the therapeutic effectiveness of the drugs by using active targeting for the site-specific delivery, passive targeting mechanisms such as enhanced permeability and retention (EPR), de novo synthesis and uptake of low density liposome in cancer cells or by being water-soluble to improve the suboptimal pharmacokinetics in limited water-soluble delivery methods. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Enzyme-Responsive Nanomaterials for Controlled Drug Delivery

PubMed Central

Hu, Quanyin; Katti, Prateek S.; Gu, Zhen

2015-01-01

Enzymes underpin physiological function and exhibit dysregulation in many disease-associated microenvironments and aberrant cell processes. Exploiting altered enzyme activity and expression for diagnostics, drug targeting, and drug release is tremendously promising. When combined with booming research in nanobiotechnology, enzyme-responsive nanomaterials for controlled drug release have achieved significant development and been studied as an important class of drug delivery devices in nanomedicine. In this review, we describe enzymes such as proteases, phospholipase and oxidoreductases that serve as delivery triggers. Subsequently, we explore recently developed enzyme-responsive nanomaterials with versatile applications for extracellular and intracellular drug delivery. We conclude by discussing future opportunities and challenges in this area. PMID:25251024

Enzyme-responsive nanomaterials for controlled drug delivery

NASA Astrophysics Data System (ADS)

Hu, Quanyin; Katti, Prateek S.; Gu, Zhen

2014-10-01

Enzymes underpin physiological function and exhibit dysregulation in many disease-associated microenvironments and aberrant cell processes. Exploiting altered enzyme activity and expression for diagnostics, drug targeting, and drug release is tremendously promising. When combined with booming research in nanobiotechnology, enzyme-responsive nanomaterials used for controlled drug release have achieved significant development and have been studied as an important class of drug delivery strategies in nanomedicine. In this review, we describe enzymes such as proteases, phospholipases and oxidoreductases that serve as delivery triggers. Subsequently, we explore recently developed enzyme-responsive nanomaterials with versatile applications for extracellular and intracellular drug delivery. We conclude by discussing future opportunities and challenges in this area.

Chitosan Microspheres in Novel Drug Delivery Systems

PubMed Central

Mitra, Analava; Dey, Baishakhi

2011-01-01

The main aim in the drug therapy of any disease is to attain the desired therapeutic concentration of the drug in plasma or at the site of action and maintain it for the entire duration of treatment. A drug on being used in conventional dosage forms leads to unavoidable fluctuations in the drug concentration leading to under medication or overmedication and increased frequency of dose administration as well as poor patient compliance. To minimize drug degradation and loss, to prevent harmful side effects and to increase drug bioavailability various drug delivery and drug targeting systems are currently under development. Handling the treatment of severe disease conditions has necessitated the development of innovative ideas to modify drug delivery techniques. Drug targeting means delivery of the drug-loaded system to the site of interest. Drug carrier systems include polymers, micelles, microcapsules, liposomes and lipoproteins to name some. Different polymer carriers exert different effects on drug delivery. Synthetic polymers are usually non-biocompatible, non-biodegradable and expensive. Natural polymers such as chitin and chitosan are devoid of such problems. Chitosan comes from the deacetylation of chitin, a natural biopolymer originating from crustacean shells. Chitosan is a biocompatible, biodegradable, and nontoxic natural polymer with excellent film-forming ability. Being of cationic character, chitosan is able to react with polyanions giving rise to polyelectrolyte complexes. Hence chitosan has become a promising natural polymer for the preparation of microspheres/nanospheres and microcapsules. The techniques employed to microencapsulate with chitosan include ionotropic gelation, spray drying, emulsion phase separation, simple and complex coacervation. This review focuses on the preparation, characterization of chitosan microspheres and their role in novel drug delivery systems. PMID:22707817

Nanocarriers in ocular drug delivery: an update review.

PubMed

Wadhwa, Sheetu; Paliwal, Rishi; Paliwal, Shivani Rai; Vyas, S P

2009-01-01

Controlled drug delivery to eye is one of the most challenging fields of pharmaceutical research. Low drug-contact time and poor ocular bioavailability due to drainage of solution, tear turnover and its dilution or lacrimation are the problems associated with conventional systems. In addition, anatomical barriers and physiological conditions of eye are also important parameters which control designing of drug delivery systems. Nanosized carriers like micro/nano-suspensions, liposome, niosome, dendrimer, nanoparticles, ocular inserts, implants, hydrogels and prodrug approaches have been developed for this purpose. These novel systems offer manifold advantages over conventional systems as they increase the efficiency of drug delivery by improving the release profile and also reduce drug toxicity. Conventional delivery systems get diluted with tear, washed away through the lacrimal gland and usually require administering at regular time intervals whereas nanocarriers release drug at constant rate for a prolonged period of time and thus enhance its absorption and site specific delivery. This review presents an overview of the various aspects of the ocular drug delivery, with special emphasis on nanocarrier based strategies, including structure of eye, its barriers, delivery routes and the challenges/limitations associated with development of novel nanocarriers. The recent progresses in therapy of ocular disease like gene therapy have also been included so that future options should also be considered from the delivery point of view. Recent progress in the delivery of proteins and peptides via ocular route has also been incorporated for reader benefit.

Nanoparticle-Hydrogel: A Hybrid Biomaterial System for Localized Drug Delivery

PubMed Central

Gao, Weiwei; Zhang, Yue; Zhang, Qiangzhe; Zhang, Liangfang

2016-01-01

Nanoparticles have offered a unique set of properties for drug delivery including high drug loading capacity, combinatorial delivery, controlled and sustained drug release, prolonged stability and lifetime, and targeted delivery. To further enhance therapeutic index, especially for localized application, nanoparticles have been increasingly combined with hydrogels to form a hybrid biomaterial system for controlled drug delivery. Herein, we review recent progresses in engineering such nanoparticle-hydrogel hybrid system (namely ‘NP-gel’) with a particular focus on its application for localized drug delivery. Specifically, we highlight four research areas where NP-gel has shown great promises, including (1) passively controlled drug release, (2) stimuli-responsive drug delivery, (3) site-specific drug delivery, and (4) detoxification. Overall, integrating therapeutic nanoparticles with hydrogel technologies creates a unique and robust hybrid biomaterial system that enables effective localized drug delivery. PMID:26951462

Abuse-resistant drug delivery.

PubMed

DuPont, Robert L; Bensinger, Peter B

2006-08-01

In attempting to reduce the nonmedical use of controlled substances, a reasonable step is to educate the physicians prescribing controlled substances, including the prescription stimulants used to treat ADHD, as well as patients and family members, about the risks of nonmedical use and the dangers of giving or selling these medicines to persons for whom they were not prescribed. Patients who find benefits in the use of such medicines have a significant interest in protecting their continued access to them. Such access is potentially threatened by concerns about widespread nonmedical use. Physicians can help protect the appropriate medical use of prescription stimulants by considering the abuse potential of various medicines used to treat patients with ADHD, especially when these patients also have a history of nonmedical substance use. In addition, we suggest that today there is an opportunity to add a new and perhaps more hopeful paradigm: the wider use of drug delivery systems that make products less attractive to drug abusers. This new drug abuse prevention paradigm holds great promise for efforts to reduce the nonmedical use of prescription controlled substances, including the prescription stimulants used to treat ADHD. To achieve the full potential of this new paradigm to reduce prescription drug abuse, it will be necessary to develop standards to assess the relative abuse resistance of various drug formulations and delivery systems, as well as meaningful incentives to foster the development of these abuse-resistant delivery systems for controlled substances.

Elastin-Like Recombinamers As Smart Drug Delivery Systems.

PubMed

Arias, F Javier; Santos, Mercedes; Ibanez-Fonseca, Arturo; Pina, Maria Jesus; Serrano, Sofía

2018-02-19

Drug delivery systems that are able to control the release of bioactive molecules and designed to carry drugs to target sites are of particular interest for tissue therapy. Moreover, systems comprising materials that can respond to environmental stimuli and promote self-assembly and higher order supramolecular organization are especially useful in the biomedical field. Objetive: This review focuses on biomaterials suitable for this purpose and that include elastin-like recombinamers (ELRs), a class of proteinaceous polymers bioinspired by natural elastin, designed using recombinant technologies. The self-assembly and thermoresponsive behaviour of these systems, along with their biodegradability, biocompatibility and well-defined composition as a result of their tailormade design, make them particularly attractive for controlled drug delivery. ELR-based delivery systems that allow targeted delivery are reviewed, especially ELR-drug recombinant fusion constructs, ELR-drug systems chemically bioconjugated in their monomeric and soluble forms, and drug encapsulation by nanoparticle-forming ELRs. Subsequently, the review focuses on those drug carriers in which smart release is triggered by pH or temperature with a particular focus on cancer treatments. Systems for controlled drug release based on depots and hydrogels that act as both a support and reservoir in which drugs can be stored will be described, and their applications in drug delivery discussed. Finally, smart drug-delivery systems not based on ELRs, including those comprising proteins, synthetic polymers and non-polymeric systems, will also be briefly discussed. Several different constructions based on ELRs are potential candidates for controlled drug delivery to be applied in advanced biomedical treatments. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Synergistic effects of plasma-activated medium and chemotherapeutic drugs in cancer treatment

NASA Astrophysics Data System (ADS)

Chen, Chao-Yu; Cheng, Yun-Chien; Cheng, Yi-Jing

2018-04-01

Chemotherapy is an important treatment method for metastatic cancer, but the drug-uptake efficiency of cancer cells needs to be enhanced in order to diminish the side effects of chemotherapeutic drugs and improve survival. The use of a nonequilibrium low-temperature atmospheric-pressure plasma jet (APPJ) has been demonstrated to exert selective effects in cancer therapy and to be able to enhance the uptake of molecules by cells, which makes an APPJ a good candidate adjuvant in combination chemotherapy. This study estimated the effects of direct helium-based APPJ (He-APPJ) exposure (DE) and He-APPJ-activated RPMI medium (PAM) on cell viability and migration. Both of these treatments decreased cell viability and inhibited cell migration, but to different degrees in different cell types. The use of PAM as a culture medium resulted in the dialkylcarbocyanine (DiI) fluorescent dye entering the cells more efficiently. PAM was combined with the anticancer drug doxorubicin (Doxo) to treat human heptocellular carcinoma HepG2 cells and human adenocarcinomic alveolar basal epithelial A549 cells. The results showed that the synergistic effects of combined PAM and Doxo treatment resulted in stronger lethality in cancer cells than did PAM or Doxo treatment alone. To sum up, PAM has potential as an adjuvant in combination with other drugs to improve curative cancer therapies.

Local Drug Delivery to Prevent Restenosis

PubMed Central

Seedial, Stephen M.; Ghosh, Soumojit; Saunders, R. Scott; Suwanabol, Pasithorn A.; Shi, Xudong; Liu, Bo; Kent, K. Craig

2013-01-01

Introduction Despite significant advances in vascular biology, bioengineering and pharmacology, restenosis remains a limitation to the overall efficacy of vascular reconstructions, both percutaneous and open. Although the pathophysiology of intimal hyperplasia is complex, a number of drugs and/or molecular tools have been identified that can prevent restenosis. Moreover, the focal nature of this process lends itself to treatment with local drug administration. In this article we provide a broad overview of current and future techniques for local drug delivery that have been developed to prevent restenosis following vascular intervention. Methods A systematic electronic literature search using PubMed was performed for all accessible published articles through September 2012. In an effort to remain current, additional searches were performed for abstracts presented at relevant societal meetings, filed patents, clinical trials and funded NIH awards. Results The efficacy of local drug delivery has been demonstrated in the coronary circulation with the current clinical use of drug-eluting stents (DES). Until recently, however, DES were not found to be efficacious in the peripheral circulation. Further pursuit of intraluminal devices has led to the development of balloon-based technologies with a recent surge in trials involving drug-eluting balloons. Early data appears encouraging, particularly for treatment of lesions in the superficial femoral artery, with several devices having recently received the CE mark in Europe. Investigators have also explored periadventitial application of biomaterials containing anti-restenotic drugs, an approach that could be particularly useful for surgical bypass or endarterectomy. In the past systemic drug delivery has been unsuccessful, however, there has been recent exploration of intravenous delivery of drugs designed specifically to target injured or reconstructed arteries. Our review revealed a multitude of additional interesting

Photoacoustic microscopy imaging for microneedle drug delivery

NASA Astrophysics Data System (ADS)

Moothanchery, Mohesh; Seeni, Razina Z.; Xu, Chenjie; Pramanik, Manojit

2018-02-01

The recent development of novel transdermal drug delivery systems (TDDS) using microneedle technology allows micron-sized conduits to be formed within the outermost skin layers attracting keen interest in skin as an interface for localized and systemic delivery of therapeutics. In light of this, researchers are using microneedles as tools to deliver nanoparticle formulations to targeted sites for effective therapy. However, in such studies the use of traditional histological methods are employed for characterization and do not allow for the in vivo visualization of drug delivery mechanism. Hence, this study presents a novel imaging technology to characterize microneedle based nanoparticle delivery systems using optical resolution-photoacoustic microscopy (OR-PAM). In this study in vivo transdermal delivery of gold nanoparticles using microneedles in mice ear and the spatial distribution of the nanoparticles in the tissue was successfully illustrated. Characterization of parameters that are relevant in drug delivery studies such as penetration depth, efficiency of delivered gold nanoparticles were monitored using the system. Photoacoustic microscopy proves an ideal tool for the characterization studies of microneedle properties and the studies shows microneedles as an ideal tool for precise and controlled drug delivery.

Mucoadhesive drug delivery systems

PubMed Central

Shaikh, Rahamatullah; Raj Singh, Thakur Raghu; Garland, Martin James; Woolfson, A David; Donnelly, Ryan F.

2011-01-01

Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. Over the past few decades, mucosal drug delivery has received a great deal of attention. Mucoadhesive dosage forms may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome. Application of dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. The mucoadhesive ability of a dosage form is dependent upon a variety of factors, including the nature of the mucosal tissue and the physicochemical properties of the polymeric formulation. This review article aims to provide an overview of the various aspects of mucoadhesion, mucoadhesive materials, factors affecting mucoadhesion, evaluating methods, and finally various mucoadhesive drug delivery systems (buccal, nasal, ocular, gastro, vaginal, and rectal). PMID:21430958

Synthesis and characterization of a multifunctional gold-doxorubicin nanoparticle system for pH triggered intracellular anticancer drug release.

PubMed

Khutale, Ganesh V; Casey, Alan

2017-10-01

A nanoparticle drug carrier system has been developed to alter the cellular uptake and chemotherapeutic performance of an available chemotherapeutic drug. The system comprises of a multifunctional gold nanoparticle based drug delivery system (Au-PEG-PAMAM-DOX) as a novel platform for intracellular delivery of doxorubicin (DOX). Spherical gold nanoparticles were synthesized by a gold chloride reduction, stabilized with thiolated polyethylene glycol (PEG) and then covalently coupled with a polyamidoamine (PAMAM) G4 dendrimer. Further, conjugation of an anti-cancer drug doxorubicin to the dendrimer via amide bond resulted in Au-PEG-PAMAM-DOX drug delivery system. Acellular drug release studies proved that DOX released from Au-PEG-PAMAM-DOX at physiological pH was negligible but it was significantly increased at a weak acidic milieu. The intracellular drug release was monitored with confocal laser scanning microscopy analysis. In vitro viability studies showed an increase in the associated doxorubicin cytotoxicity not attributed to carrier components indicating the efficiency of the doxorubicin was improved, upon conjugation to the nano system. As such it is postulated that the developed pH triggered multifunctional doxorubicin-gold nanoparticle system, could lead to a promising platform for intracellular delivery of variety of anticancer drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Thermo/pH dual-stimuli-responsive drug delivery for chemo-/photothermal therapy monitored by cell imaging.

PubMed

Shu, Yang; Song, Rusheng; Zheng, Anqi; Huang, Jingli; Chen, Mingli; Wang, Jianhua

2018-05-01

A thermo/pH dual-stimuli-responsive drug delivery system (DDS) based on polymer coated mesoporous silica nanostructures (MSNs) is developed for facilitating chemotherapy and photothermal therapy. Thermo/pH-responsive polymer, poly((N-isopropylacrylamide, NIPAM)-co-methacrylic acid, MA), is grafted onto MSNs by in situ polymerization, followed by loading a chemotherapeutic drug (doxorubicin hydrochloride, DOX) and a near-infrared-absorbing phototherapeutic agent (indocyanine green, ICG) to construct the intelligent drug delivery system, shortly as DOX-ICG-MSN@p(NIPAM-co-MA). At NIR irradiation, the photothermal conversion capability of ICG raises the temperature of the DDS and opens the gatekeeper by shrinkage of the copolymer p(NIPAM-co-MA), which triggers controlled release of DOX at an elevated temperature. On the other hand, drug release is also realized at pH 5.3, a characteristic pH value in cancer cell microenvironment, at which it not only causes the shrinkage of the pH-sensitive polymeric moiety of methacrylic acid in MSN@p(NIPAM-co-MA) but also deteriorates electrostatic interaction of DOX molecules in the mesoporous channel by protonation of silanols. In addition, ICG further ensures photothermal therapy (PTT) and photodynamic therapy (PDT). The cytotoxicity assay of HeLa cells shows obvious synergistic effect by demonstrating that the combined use of DOX and ICG is more effective in killing HeLa cells than free DOX and ICG. The endocytosis of the drug is monitored by cell imaging. Copyright © 2018 Elsevier B.V. All rights reserved.

Polymer nanogels: a versatile nanoscopic drug delivery platform

PubMed Central

Chacko, Reuben T.; Ventura, Judy; Zhuang, Jiaming; Thayumanavan, S.

2012-01-01

In this review we put the spotlight on crosslinked polymer nanogels, a promising platform that has the characteristics of an “ideal” drug delivery vehicle. Some of the key aspects of drug delivery vehicle design like stability, response to biologically relevant stimuli, passive targeting, active targeting, toxicity and ease of synthesis are discussed. We discuss several delivery systems in this light and highlight some examples of systems, which satisfy some or all of these design requirements. In particular, we point to the advantages that crosslinked polymeric systems bring to drug delivery. We review some of the synthetic methods of nanogel synthesis and conclude with the diverse applications in drug delivery where nanogels have been fruitfully employed. PMID:22342438

Porous Carriers for Controlled/Modulated Drug Delivery

PubMed Central

Ahuja, G.; Pathak, K.

2009-01-01

Considerable research efforts have been directed in recent years towards the development of porous carriers as controlled drug delivery matrices because of possessing several features such as stable uniform porous structure, high surface area, tunable pore size and well-defined surface properties. Owing to wide range of useful properties porous carriers have been used in pharmaceuticals for many purposes including development of floating drug delivery systems, sustained drug delivery systems. Various types of pores like open, closed, transport and blind pores in the porous solid allow them to adsorb drugs and release them in a more reproducible and predictable manner. Pharmaceutically exploited porous adsorbents includes, silica (mesoporous), ethylene vinyl acetate (macroporous), polypropylene foam powder (microporous), titanium dioxide (nanoporous). When porous polymeric drug delivery system is placed in contact with appropriate dissolution medium, release of drug to medium must be preceded by the drug dissolution in the water filled pores or from surface and by diffusion through the water filled channels. The porous carriers are used to improve the oral bioavailability of poorly water soluble drugs, to increase the dissolution of relatively insoluble powders and conversion of crystalline state to amorphous state. PMID:20376211

Microneedles for drug and vaccine delivery

PubMed Central

Kim, Yeu-Chun; Park, Jung-Hwan; Prausnitz, Mark R.

2012-01-01

Microneedles were first conceptualized for drug delivery many decades ago, but only became the subject of significant research starting in the mid-1990’s when microfabrication technology enabled their manufacture as (i) solid microneedles for skin pretreatment to increase skin permeability, (ii) microneedles coated with drug that dissolves off in the skin, (iii) polymer microneedles that encapsulate drug and fully dissolve in the skin and (iv) hollow microneedles for drug infusion into the skin. As shown in more than 350 papers now published in the field, microneedles have been used to deliver a broad range of different low molecular weight drugs, biotherapeutics and vaccines, including published human studies with a number of small-molecule and protein drugs and vaccines. Influenza vaccination using a hollow microneedle is in widespread clinical use and a number of solid microneedle products are sold for cosmetic purposes. In addition to applications in the skin, microneedles have also been adapted for delivery of bioactives into the eye and into cells. Successful application of microneedles depends on device function that facilitates microneedle insertion and possible infusion into skin, skin recovery after microneedle removal, and drug stability during manufacturing, storage and delivery, and on patient outcomes, including lack of pain, skin irritation and skin infection, in addition to drug efficacy and safety. Building off a strong technology base and multiple demonstrations of successful drug delivery, microneedles are poised to advance further into clinical practice to enable better pharmaceutical therapies, vaccination and other applications. PMID:22575858

Inorganic Nanomaterials as Carriers for Drug Delivery.

PubMed

Chen, Shizhu; Hao, Xiaohong; Liang, Xingjie; Zhang, Qun; Zhang, Cuimiao; Zhou, Guoqiang; Shen, Shigang; Jia, Guang; Zhang, Jinchao

2016-01-01

For safe and effective therapy, drugs must be delivered efficiently and with minimal systemic side effects. Nanostructured drug carriers enable the delivery of small-molecule drugs as well as nucleic acids and proteins. Inorganic nanomaterials are ideal for drug delivery platforms due to their unique physicochemical properties, such as facile preparation, good storage stability and biocompatibility. Many inorganic nanostructure-based drug delivery platforms have been prepared. Although there are still many obstacles to overcome, significant advances have been made in recent years. This review focuses on the status and development of inorganic nanostructures, including silica, quantum dots, gold, carbon-based and magnetic iron oxide-based nanostructures, as carriers for chemical and biological drugs. We specifically highlight the extensive use of these inorganic drug carriers for cancer therapy. Finally, we discuss the most important areas in the field that urgently require further study.

Biomaterial-based regional chemotherapy: Local anticancer drug delivery to enhance chemotherapy and minimize its side-effects.

PubMed

Krukiewicz, Katarzyna; Zak, Jerzy K

2016-05-01

Since the majority of anticancer pharmacological agents affect not only cancer tissue but also normal cells, chemotherapy is usually accompanied with severe side effects. Regional chemotherapy, as the alternative version of conventional treatment, leads to the enhancement of the therapeutic efficiency of anticancer drugs and, simultaneously, reduction of toxic effects to healthy tissues. This paper provides an insight into different approaches of local delivery of chemotherapeutics, such as the injection of anticancer agents directly into tumor tissue, the use of injectable in situ forming drug carriers or injectable platforms in a form of implants. The wide range of biomaterials used as reservoirs of anticancer drugs is described, i.e. poly(ethylene glycol) and its copolymers, polyurethanes, poly(lactic acid) and its copolymers, poly(ɛ-caprolactone), polyanhydrides, chitosan, cellulose, cyclodextrins, silk, conducting polymers, modified titanium surfaces, calcium phosphate based biomaterials, silicone and silica implants, as well as carbon nanotubes and graphene. To emphasize the applicability of regional chemotherapy in cancer treatment, the commercially available products approved by the relevant health agencies are presented. Copyright © 2016 Elsevier B.V. All rights reserved.

Drug delivery with microsecond laser pulses into gelatin.

PubMed

Shangguan, H; Casperson, L W; Shearin, A; Gregory, K W; Prahl, S A

1996-07-01

Photo acoustic drug delivery is a technique for localized drug delivery by laser-induced hydrodynamic pressure following cavitation bubble expansion and collapse. Photoacoustic drug delivery was investigated on gelatin-based thrombus models with planar and cylindrical geometries by use of one microsecond laser pulses. Solutions of a hydrophobic dye in mineral oil permitted monitoring of delivered colored oil into clear gelatin-based thrombus models. Cavitation bubble development and photoacoustic drug delivery were visualized with flash photography. This study demonstrated that cavitation is the governing mechanism for photoacoustic drug delivery, and the deepest penetration of colored oil in gels followed the bubble collapse. Spatial distribution measurements revealed that colored oil could be driven a few millimeters into the gels in both axial and radial directions, and the penetration was less than 500 µm when the gelatin structure was not fractured.

Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery.

PubMed

Pan, Dipanjan; Pham, Christine T N; Weilbaecher, Katherine N; Tomasson, Michael H; Wickline, Samuel A; Lanza, Gregory M

2016-01-01

Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a 'magic bullet' to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies equally well for vascular constrained lipid-encapsulated particles and micelles the size of proteins that penetrate through naturally fenestrated endothelium in the bone marrow or thin-walled venules of an inflamed microcirculation. At one time Nanomedicine was considered a 'Grail Quest' by its loyal opposition and even many in the field adsorbing the pains of a long-learning curve about human biology and particles. However, Nanomedicine with innovations like Sn2 phospholipid prodrugs has finally made 'made the turn' toward meaningful translational success. © 2015 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals, Inc.

Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery

PubMed Central

Pan, Dipanjan; Pham, Christine TN; Weilbaecher, Katherine N; Tomasson, Michael H; Wickline, Samuel A; Lanza, Gregory M

2016-01-01

Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a ‘magic bullet’ to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies equally well for vascular constrained lipid-encapsulated particles and micelles the size of proteins that penetrate through naturally fenestrated endothelium in the bone marrow or thin-walled venules of an inflamed microcirculation. At one time Nanomedicine was considered a ‘Grail Quest’ by its loyal opposition and even many in the field adsorbing the pains of a long-learning curve about human biology and particles. However, Nanomedicine with innovations like Sn2 phospholipid prodrugs has finally made ‘made the turn’ toward meaningful translational success. PMID:26296541

STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs.

PubMed

Walch-Rückheim, Barbara; Pahne-Zeppenfeld, Jennifer; Fischbach, Jil; Wickenhauser, Claudia; Horn, Lars Christian; Tharun, Lars; Büttner, Reinhard; Mallmann, Peter; Stern, Peter; Kim, Yoo-Jin; Bohle, Rainer Maria; Rübe, Christian; Ströder, Russalina; Juhasz-Böss, Ingolf; Solomayer, Erich-Franz; Smola, Sigrun

2016-07-01

Neoadjuvant radio/chemotherapy regimens can markedly improve cervical cancer outcome in a subset of patients, while other patients show poor responses, but may encounter severe adverse effects. Thus, there is a strong need for predictive biomarkers to improve clinical management of cervical cancer patients. STAT3 is considered as a critical antiapoptotic factor in various malignancies. We therefore investigated STAT3 activation during cervical carcinogenesis and its impact on the response of cervical cancer cells to chemotherapeutic drugs. Tyr705-phosphorylated STAT3 increased from low-grade cervical intraepithelial neoplasia (CIN1) to precancerous CIN3 lesions. Notably, pTyr705-STAT3 activation significantly declined from CIN3 to invasive cancer, also when compared in the same clinical biopsy. pTyr705-STAT3 was also low or absent in cultured human cervical cancer cell lines, consistent with the in vivo expression data. Unexpectedly, IL6-type cytokine signaling inducing STAT3 activation rendered cervical cancer cells significantly more susceptible to chemotherapeutic drugs, that is, cisplatin or etoposide. This chemosensitization was STAT3-dependent and we identified IFN regulatory factor-1 (IRF1) as the STAT3-inducible mediator required for cell death enhancement. In line with these data, pTyr705-STAT3 significantly correlated with nuclear IRF1 expression in cervical cancer in vivo Importantly, high IRF1 expression in pretreatment cervical cancer biopsy cells was associated with a significantly better response to neoadjuvant radio/chemotherapy of the patients. In summary, our study has identified a key role of the STAT3/IRF1 pathway for chemosensitization in cervical cancer. Our results suggest that pretherapeutic IRF1 expression should be evaluated as a novel predictive biomarker for neoadjuvant radio/chemotherapy responses. Cancer Res; 76(13); 3872-83. ©2016 AACR. ©2016 American Association for Cancer Research.

A pulsed mode electrolytic drug delivery device

NASA Astrophysics Data System (ADS)

Yi, Ying; Buttner, Ulrich; Carreno, Armando A. A.; Conchouso, David; Foulds, Ian G.

2015-10-01

This paper reports the design of a proof-of-concept drug delivery device that is actuated using the bubbles formed during electrolysis. The device uses a platinum (Pt) coated nickel (Ni) metal foam and a solid drug in reservoir (SDR) approach to improve the device’s performance. This electrochemically-driven pump has many features that are unlike conventional drug delivery devices: it is capable of pumping periodically and being refilled automatically; it features drug release control; and it enables targeted delivery. Pt-coated metal foam is used as a catalytic reforming element, which reduces the period of each delivery cycle. Two methods were used for fabricating the Pt-coated metal: sputtering and electroplating. Of these two methods, the sputtered Pt-coated metal foam has a higher pumping rate; it also has a comparable recombination rate when compared to the electroplated Pt-coated metal foam. The only drawback of this catalytic reformer is that it consumes nickel scaffold. Considering long-term applications, the electroplated Pt metal foam was selected for drug delivery, where a controlled drug release rate of 2.2 μg  ±  0.3 μg per actuation pulse was achieved using 4 mW of power.

Drug self-delivery systems for cancer therapy.

PubMed

Qin, Si-Yong; Zhang, Ai-Qing; Cheng, Si-Xue; Rong, Lei; Zhang, Xian-Zheng

2017-01-01

Carrier-assistant drug delivery systems (DDSs) have been rapidly established for cancer therapy and great strides have been made in recent years. However, further development of DDSs is retarded by the aspects such as the low drug carrying capacity, carrier-induced toxicity and immunogenicity, complex synthesis manipulation. Drug self-delivery systems (DSDSs), in which active drugs exhibit nanoscale characteristic to realize intracellular delivery by themselves without the help of nanocarriers, have been rapidly developed to address these issues. In this review, we present a comprehensive summary of the recent advances in DSDSs for cancer therapy. After a brief introduction to the major types of DSDSs and their fabrication strategies, we emphatically discuss some representative achievements of these DSDSs for passive or/and positive targeting therapy, combinational therapy as well as theranostics. The design principle is explained and justified, which can cast a new light on developing drug delivery systems for cancer treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

Current Strategies for Brain Drug Delivery

PubMed Central

Dong, Xiaowei

2018-01-01

The blood-brain barrier (BBB) has been a great hurdle for brain drug delivery. The BBB in healthy brain is a diffusion barrier essential for protecting normal brain function by impeding most compounds from transiting from the blood to the brain; only small molecules can cross the BBB. Under certain pathological conditions of diseases such as stroke, diabetes, seizures, multiple sclerosis, Parkinson's disease and Alzheimer disease, the BBB is disrupted. The objective of this review is to provide a broad overview on current strategies for brain drug delivery and related subjects from the past five years. It is hoped that this review could inspire readers to discover possible approaches to deliver drugs into the brain. After an initial overview of the BBB structure and function in both healthy and pathological conditions, this review re-visits, according to recent publications, some questions that are controversial, such as whether nanoparticles by themselves could cross the BBB and whether drugs are specifically transferred to the brain by actively targeted nanoparticles. Current non-nanoparticle strategies are also reviewed, such as delivery of drugs through the permeable BBB under pathological conditions and using non-invasive techniques to enhance brain drug uptake. Finally, one particular area that is often neglected in brain drug delivery is the influence of aging on the BBB, which is captured in this review based on the limited studies in the literature. PMID:29556336

Drug Delivery of the Future: Chasing the Invisible Gorilla

PubMed Central

Park, Kinam

2015-01-01

For more than 60 years drug delivery systems have produced numerous controlled release formulations helping patients improve compliance and maximize the drug efficacy. Development of new controlled drug delivery systems was very productive during the period 1950-1980. The productivity, as measured by the number of clinically used formulations, dropped significantly during 1980-2010. This reduced productivity needs to be understood so that the future development of drug delivery systems can be accelerated and prolific again. This requires critical evaluation of the current drug delivery field, so that the factors inhibiting rapid progress can be identified and resolved. The current drug delivery field is faced with an invisible gorilla syndrome, i.e., seeing a gorilla when it is not present and missing a gorilla when it actually exists. Overcoming this syndrome requires a new way of thinking, questioning the status quo. Advances in drug delivery technologies occur by an evolutionary process, and thus, the more trials and errors lead to faster advances. The drug delivery area needs to nurture the environment where vastly different ideas can be tested, and all data, positive or negative, need to be exchanged freely as they have equal importance. PMID:26519857

Inhaled nano- and microparticles for drug delivery

PubMed Central

El-Sherbiny, Ibrahim M.; El-Baz, Nancy M.; Yacoub, Magdi H.

2015-01-01

The 21st century has seen a paradigm shift to inhaled therapy, for both systemic and local drug delivery, due to the lung's favourable properties of a large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including non-invasive route of administration, low metabolic activity, control environment for systemic absorption and avoids first bypass metabolism. However, because the lung is one of the major ports of entry, it has multiple clearance mechanisms, which prevent foreign particles from entering the body. Although these clearance mechanisms maintain the sterility of the lung, clearance mechanisms can also act as barriers to the therapeutic effectiveness of inhaled drugs. This effectiveness is also influenced by the deposition site and delivered dose. Particulate-based drug delivery systems have emerged as an innovative and promising alternative to conventional inhaled drugs to circumvent pulmonary clearance mechanisms and provide enhanced therapeutic efficiency and controlled drug release. The principle of multiple pulmonary clearance mechanisms is reviewed, including mucociliary, alveolar macrophages, absorptive, and metabolic degradation. This review also discusses the current approaches and formulations developed to achieve optimal pulmonary drug delivery systems. PMID:26779496

Inner Ear Drug Delivery for Auditory Applications

PubMed Central

Swan, Erin E. Leary; Mescher, Mark J.; Sewell, William F.; Tao, Sarah L.; Borenstein, Jeffrey T.

2008-01-01

Many inner ear disorders cannot be adequately treated by systemic drug delivery. A blood-cochlear barrier exists, similar physiologically to the blood-brain barrier, which limits the concentration and size of molecules able to leave the circulation and gain access to the cells of the inner ear. However, research in novel therapeutics and delivery systems has led to significant progress in the development of local methods of drug delivery to the inner ear. Intratympanic approaches, which deliver therapeutics to the middle ear, rely on permeation through tissue for access to the structures of the inner ear, whereas intracochlear methods are able to directly insert drugs into the inner ear. Innovative drug delivery systems to treat various inner ear ailments such as ototoxicity, sudden sensorineural hearing loss, autoimmune inner ear disease, and for preserving neurons and regenerating sensory cells are being explored. PMID:18848590

Development of a gastroretentive pulsatile drug delivery platform.

PubMed

Thitinan, Sumalee; McConville, Jason T

2012-04-01

To develop a novel gastroretentive pulsatile drug delivery platform by combining the advantages of floating dosage forms for the stomach and pulsatile drug delivery systems. A gastric fluid impermeable capsule body was used as a vessel to contain one or more drug layer(s) as well as one or more lag-time controlling layer(s). A controlled amount of air was sealed in the innermost portion of the capsule body to reduce the overall density of the drug delivery platform, enabling gastric floatation. An optimal mass fill inside the gastric fluid impermeable capsule body enabled buoyancy in a vertical orientation to provide a constant surface area for controlled erosion of the lag-time controlling layer. The lag-time controlling layer consisted of a swellable polymer, which rapidly formed a gel to seal the mouth of capsule body and act as a barrier to gastric fluid ingress. By varying the composition of the lag-time controlling layer, it was possible to selectively program the onset of the pulsatile delivery of a drug. This new delivery platform offers a new method of delivery for a variety of suitable drugs targeted in chronopharmaceutical therapy. This strategy could ultimately improve drug efficacy and patient compliance, and reduce harmful side effects by scaling back doses of drug administered. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Development In Drug Targeting And Delivery In Cervical Cancer.

PubMed

Aggarwal, Urvashi; Goyal, Amit Kumar; Rath, Goutam

2017-10-09

Cervical cancer is the second most common cancer in women. Standard treatment options available for cervical cancer including chemotherapy, surgery and radiation therapy associated with their own side effects and toxicities. Tumor-targeted delivery of anticancer drugs is perhaps one of the most appropriate strategies to achieve optimal outcomes from treatment and improve quality of life. Recently nanocarriers based drug delivery systems owing to their unique properties have been extensively investigated for anticancer drug delivery. In addition to that addressing the anatomical significance of cervical cancer, various local drug delivery strategies for the cancer treatment are introduced like: gels, nanoparticles, polymeric films, rods and wafers, lipid based nanocarrier. Localized drug delivery systems allows passive drug targeting results in high drug concentration at the target site. Further they can be tailor made to achieve both sustained and controlled release behavior, substantially improving therapeutic outcomes and minimizing side effects. This review summarizes the meaningful advances in drug delivery strategies to treat cervical cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Preparation and characterization of silk fibroin as a biomaterial with potential for drug delivery

PubMed Central

2012-01-01

Background Degummed silk fibroin from Bombyx mori (silkworm) has potential carrier capabilities for drug delivery in humans; however, the processing methods have yet to be comparatively analyzed to determine the differential effects on the silk protein properties, including crystalline structure and activity. Methods In this study, we treated degummed silk with four kinds of calcium-alcohol solutions, and performed secondary structure measurements and enzyme activity test to distinguish the differences between the regenerated fibroins and degummed silk fibroin. Results Gel electrophoresis analysis revealed that Ca(NO3)2-methanol, Ca(NO3)2-ethanol, or CaCl2-methanol treatments produced more lower molecular weights of silk fibroin than CaCl2-ethanol. X-ray diffraction and Fourier-transform infrared spectroscopy showed that CaCl2-ethanol produced a crystalline structure with more silk I (α-form, type II β-turn), while the other treatments produced more silk II (β-form, anti-parallel β-pleated sheet). Solid-State 13C cross polarization and magic angle spinning-nuclear magnetic resonance measurements suggested that regenerated fibroins from CaCl2-ethanol were nearly identical to degummed silk fibroin, while the other treatments produced fibroins with significantly different chemical shifts. Finally, enzyme activity test indicated that silk fibroins from CaCl2-ethanol had higher activity when linked to a known chemotherapeutic drug, L-asparaginase, than the fibroins from other treatments. Conclusions Collectively, these results suggest that the CaCl2-ethanol processing method produces silk fibroin with biomaterial properties that are appropriate for drug delivery. PMID:22676291

Rapidly separating microneedles for transdermal drug delivery.

PubMed

Zhu, Dan Dan; Wang, Qi Lei; Liu, Xu Bo; Guo, Xin Dong

2016-09-01

The applications of polymer microneedles (MNs) into human skin emerged as an alternative of the conventional hypodermic needles. However, dissolving MNs require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin, which may lead to the low drug delivery efficiency. To address these issues, we introduce rapidly separating MNs that can rapidly deliver drugs into the skin in a minimally invasive way. For the rapidly separating MNs, drug loaded dissolving MNs are mounted on the top of solid MNs, which are made of biodegradable polylactic acid which eliminate the biohazardous waste. These MNs have sufficient mechanical strength to be inserted into the skin with the drug loaded tips fully embedded for subsequent dissolution. Compared with the traditional MNs, rapidly separating MNs achieve over 90% of drug delivery efficiency in 30s while the traditional MNs needs 2min to achieve the same efficiency. With the in vivo test in mice, the micro-holes caused by rapidly separating MNs can heal in 1h, indicating that the rapidly separating MNs are safe for future applications. These results indicate that the design of rapidly separating dissolvable MNs can offer a quick, high efficient, convenient, safe and potentially self-administered method of drug delivery. Polymer microneedles offer an attractive, painless and minimally invasive approach for transdermal drug delivery. However, dissolving microneedles require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin due to the skin deformation, which may lead to the low drug delivery efficiency. In this work we proposed rapidly separating microneedles which can deliver over 90% of drug into the skin in 30s. The in vitro and in vivo results indicate that the new design of these microneedles can offer a quick, high efficient, convenient and safe method for transdermal drug delivery. Copyright © 2016 Acta Materialia Inc

The effect of nanoparticle size on theranostic systems: the optimal particle size for imaging is not necessarily optimal for drug delivery

NASA Astrophysics Data System (ADS)

Dreifuss, Tamar; Betzer, Oshra; Barnoy, Eran; Motiei, Menachem; Popovtzer, Rachela

2018-02-01

Theranostics is an emerging field, defined as combination of therapeutic and diagnostic capabilities in the same material. Nanoparticles are considered as an efficient platform for theranostics, particularly in cancer treatment, as they offer substantial advantages over both common imaging contrast agents and chemotherapeutic drugs. However, the development of theranostic nanoplatforms raises an important question: Is the optimal particle for imaging also optimal for therapy? Are the specific parameters required for maximal drug delivery, similar to those required for imaging applications? Herein, we examined this issue by investigating the effect of nanoparticle size on tumor uptake and imaging. Anti-epidermal growth factor receptor (EGFR)-conjugated gold nanoparticles (GNPs) in different sizes (diameter range: 20-120 nm) were injected to tumor bearing mice and their uptake by tumors was measured, as well as their tumor visualization capabilities as tumor-targeted CT contrast agent. Interestingly, the results showed that different particles led to highest tumor uptake or highest contrast enhancement, meaning that the optimal particle size for drug delivery is not necessarily optimal for tumor imaging. These results have important implications on the design of theranostic nanoplatforms.

Engineered Polymers for Advanced Drug Delivery

PubMed Central

Kim, Sungwon; Kim, Jong-Ho; Jeon, Oju; Kwon, Ick Chan; Park, Kinam

2009-01-01

Engineered polymers have been utilized for developing advanced drug delivery systems. The development of such polymers has caused advances in polymer chemistry, which, in turn, has resulted in smart polymers that can respond to changes in environmental condition, such as temperature, pH, and biomolecules. The responses vary widely from swelling/deswelling to degradation. Drug-polymer conjugates and drug-containing nano/micro-particles have been used for drug targeting. Engineered polymers and polymeric systems have also been used in new areas, such as molecular imaging as well as in nanotechnology. This review examines the engineered polymers that have been used as traditional drug delivery and as more recent applications in nanotechnology. PMID:18977434

Infrared free electron laser enhanced transdermal drug delivery

NASA Astrophysics Data System (ADS)

Awazu, Kunio; Uchizono, Takeyuki; Suzuki, Sachiko; Yoshikawa, Kazushi

2005-08-01

It is necessary to control enhancement of transdermal drug delivery with non-invasive. The present study was investigated to assess the effectivity of enhancing the drug delivery by irradiating 6-μm region mid infrared free electron laser (MIR-FEL). The enhancement of transdermal drug (lidocaine) delivery of the samples (hairless mouse skin) irradiated with lasers was examined for flux (μg/cm2/h) and total penetration amount (μg/cm2) of lidocaine by High performance Liquid Chromatography (HPLC). The flux and total amount penatration date was enhanced 200-300 fold faster than the control date by the laser irradiation. FEL irradiating had the stratum corneum, and had the less thermal damage in epidermis. The effect of 6-μm region MIR-FEL has the enhancement of transdermal drug delivery without removing the stratum corneum because it has the less thermal damage. It leads to enhancement drug delivery system with non-invasive laser treatment.

Novel Strategies for Anterior Segment Ocular Drug Delivery

PubMed Central

Cholkar, Kishore; Patel, Sulabh P.; Vadlapudi, Aswani Dutt

2013-01-01

Abstract Research advancements in pharmaceutical sciences have led to the development of new strategies in drug delivery to anterior segment. Designing a new delivery system that can efficiently target the diseased anterior ocular tissue, generate high drug levels, and maintain prolonged and effective concentrations with no or minimal side effects is the major focus of current research. Drug delivery by traditional method of administration via topical dosing is impeded by ocular static and dynamic barriers. Various products have been introduced into the market that prolong drug retention in the precorneal pocket and to improve bioavailability. However, there is a need of a delivery system that can provide controlled release to treat chronic ocular diseases with a reduced dosing frequency without causing any visual disturbances. This review provides an overview of anterior ocular barriers along with strategies to overcome these ocular barriers and deliver therapeutic agents to the affected anterior ocular tissue with a special emphasis on nanotechnology-based drug delivery approaches. PMID:23215539

Thiolated polymers as mucoadhesive drug delivery systems.

PubMed

Duggan, Sarah; Cummins, Wayne; O' Donovan, Orla; Hughes, Helen; Owens, Eleanor

2017-03-30

Mucoadhesion is the process of binding a material to the mucosal layer of the body. Utilising both natural and synthetic polymers, mucoadhesive drug delivery is a method of controlled drug release which allows for intimate contact between the polymer and a target tissue. It has the potential to increase bioavailability, decrease potential side effects and offer protection to more sensitive drugs such as proteins and peptide based drugs. The thiolation of polymers has, in the last number of years, come to the fore of mucoadhesive drug delivery, markedly improving mucoadhesion due to the introduction of free thiol groups onto the polymer backbone while also offering a more cohesive polymeric matrix for the slower and more controlled release of drug. This review explores the concept of mucoadhesion and the recent advances in both the polymers and the methods of thiolation used in the synthesis of mucoadhesive drug delivery devices. Copyright © 2017 Elsevier B.V. All rights reserved.

Role of Nanodiamonds in Drug Delivery and Stem Cell Therapy.

PubMed

Ansari, Shakeel Ahmed; Satar, Rukhsana; Jafri, Mohammad Alam; Rasool, Mahmood; Ahmad, Waseem; Kashif Zaidi, Syed

2016-09-01

The use of nanotechnology in medicine and more specifically drug delivery is set to spread rapidly. Currently many substances are under investigation for drug delivery and more specifically for cancer therapy. Nanodiamonds (NDs) have contributed significantly in the development of highly efficient and successful drug delivery systems, and in stem cell therapy. Drug delivery through NDs is an intricate and complex process that deserves special attention to unravel underlying molecular mechanisms in order to overcome certain bottlenecks associated with it. It has already been established that NDs based drug delivery systems have excellent biocompatibility, nontoxicity, photostability and facile surface functionalization properties. There is mounting evidence that suggests that such conjugated delivery systems well retain the properties of nanoparticles like small size, large surface area to volume ratio that provide greater biocatalytic activity to the attached drug in terms of selectivity, loading and stability. NDs based drug delivery systems may form the basis for the development of effective novel drug delivery vehicles with salient features that may facilitate their utility in fluorescence imaging, target specificity and sustainedrelease.

Micro-scale Devices for Transdermal Drug Delivery

PubMed Central

Arora, Anubhav; Prausnitz, Mark; Mitragotri, Samir

2009-01-01

Skin makes an excellent site for drug and vaccine delivery due to easy accessibility, immuno-surveillance functions, avoidance of macromolecular degradation in the gastrointestinal tract and possibility of self-administration. However, macromolecular drug delivery across the skin is primarily accomplished using hypodermic needles, which have several disadvantages including accidental needle-sticks, pain and needle phobia. These limitations have led to extensive research and development of alternative methods for drug and vaccine delivery across the skin. This review focuses on the recent trends and developments in this field of micro-scale devices for transdermal macromolecular delivery. These include liquid jet injectors, powder injectors, microneedles and thermal microablation. The historical perspective, mechanisms of action, important design parameters, applications and challenges are discussed for each method. PMID:18805472

Facilitation of transscleral drug delivery by drug loaded magnetic polymeric particles.

PubMed

Mousavikhamene, Zeynab; Abdekhodaie, Mohammad J; Ahmadieh, Hamid

2017-10-01

A unique method was used to facilitate ocular drug delivery from periocular route by drug loaded magnetic sensitive particles. Injection of particles in periocular space along the eye axis followed by application of magnetic field in front of the eye would trigger the magnetic polymeric particles to move along the direction of magnetic force and reside against the outer surface of the sclera. This technique prevents removal of drug in the periocular space, observed in conventional transscleral drug delivery systems and hence higher amount of drug can enter the eye in a longer period of time. The experiments were performed by fresh human sclera and an experimental setup. Experimental setup was designed by side by side diffusion cell and hydrodynamic and thermal simulation of the posterior segment of the eye were applied. Magnetic polymeric particles were synthesized by alginate as a model polymer, iron oxide nanoparticles as a magnetic agent and diclofenac sodium as a model drug and characterized by SEM, TEM, DLS and FT-IR techniques. According to the SEM images, the size range of particles is around 60 to 800nm. The results revealed that the cumulative drug transfer from magnetic sensitive particles across the sclera improves by 70% in the presence of magnetic field. The results of this research show promising method of drug delivery to use magnetic properties to facilitate drug delivery to the back of the eye. Copyright © 2017. Published by Elsevier B.V.

[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 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

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.

Ophthalmic Drug Delivery Systems for Antibiotherapy—A Review

PubMed Central

Dubald, Marion; Bourgeois, Sandrine; Andrieu, Véronique; Fessi, Hatem

2018-01-01

The last fifty years, ophthalmic drug delivery research has made much progress, challenging scientists about the advantages and limitations of this drug delivery approach. Topical eye drops are the most commonly used formulation in ocular drug delivery. Despite the good tolerance for patients, this topical administration is only focus on the anterior ocular diseases and had a high precorneal loss of drugs due to the tears production and ocular barriers. Antibiotics are popularly used in solution or in ointment for the ophthalmic route. However, their local bioavailability needs to be improved in order to decrease the frequency of administrations and the side effects and to increase their therapeutic efficiency. For this purpose, sustained release forms for ophthalmic delivery of antibiotics were developed. This review briefly describes the ocular administration with the ocular barriers and the currently topical forms. It focuses on experimental results to bypass the limitations of ocular antibiotic delivery with new ocular technology as colloidal and in situ gelling systems or with the improvement of existing forms as implants and contact lenses. Nanotechnology is presently a promising drug delivery way to provide protection of antibiotics and improve pathway through ocular barriers and deliver drugs to specific target sites. PMID:29342879

Drug Delivery Research: The Invention Cycle.

PubMed

Park, Kinam

2016-07-05

Controlled drug delivery systems have been successful in introducing improved formulations for better use of existing drugs and novel delivery of biologicals. The initial success of producing many oral products and some injectable depot formulations, however, reached a plateau, and the progress over the past three decades has been slow. This is likely due to the difficulties of formulating hydrophilic, high molecular weight drugs, such as proteins and nucleic acids, for targeting specific cells, month-long sustained delivery, and pulsatile release. Since the approaches that have served well for delivery of small molecules are not applicable to large molecules, it is time to develop new methods for biologicals. The process of developing future drug delivery systems, termed as the invention cycle, is proposed, and it starts with clearly defining the problems for developing certain formulations. Once the problems are well-defined, creative imagination examines all potential options and selects the best answer and alternatives. Then, innovation takes over to generate unique solutions for developing new formulations that resolve the previously identified problems. Ultimately, the new delivery systems will have to go through a translational process to produce the final formulations for clinical use. The invention cycle also emphasizes examining the reasons for success of certain formulations, not just the reasons for failure of many systems. Implementation of the new invention cycle requires new mechanisms of funding the younger generation of scientists and a new way of identifying their achievements, thereby releasing them from the burden of short-termism.

Convection-enhanced Delivery of Therapeutics for Malignant Gliomas.

PubMed

Saito, Ryuta; Tominaga, Teiji

2017-01-15

Convection-enhanced delivery (CED) circumvents the blood-brain barrier by delivering agents directly into the tumor and surrounding parenchyma. CED can achieve large volumes of distribution by continuous positive-pressure infusion. Although promising as an effective drug delivery method in concept, the administration of therapeutic agents via CED is not without challenges. Limitations of distribution remain a problem in large brains, such as those of humans. Accurate and consistent delivery of an agent is another challenge associated with CED. Similar to the difficulties caused by immunosuppressive environments associated with gliomas, there are several mechanisms that make effective local drug distribution difficult in malignant gliomas. In this review, methods for local drug application targeting gliomas are discussed with special emphasis on CED. Although early clinical trials have failed to demonstrate the efficacy of CED against gliomas, CED potentially can be a platform for translating the molecular understanding of glioblastomas achieved in the laboratory into effective clinical treatments. Several clinical studies using CED of chemotherapeutic agents are ongoing. Successful delivery of effective agents should prove the efficacy of CED in the near future.

Convection-enhanced Delivery of Therapeutics for Malignant Gliomas

PubMed Central

SAITO, Ryuta; TOMINAGA, Teiji

2017-01-01

Convection-enhanced delivery (CED) circumvents the blood–brain barrier by delivering agents directly into the tumor and surrounding parenchyma. CED can achieve large volumes of distribution by continuous positive-pressure infusion. Although promising as an effective drug delivery method in concept, the administration of therapeutic agents via CED is not without challenges. Limitations of distribution remain a problem in large brains, such as those of humans. Accurate and consistent delivery of an agent is another challenge associated with CED. Similar to the difficulties caused by immunosuppressive environments associated with gliomas, there are several mechanisms that make effective local drug distribution difficult in malignant gliomas. In this review, methods for local drug application targeting gliomas are discussed with special emphasis on CED. Although early clinical trials have failed to demonstrate the efficacy of CED against gliomas, CED potentially can be a platform for translating the molecular understanding of glioblastomas achieved in the laboratory into effective clinical treatments. Several clinical studies using CED of chemotherapeutic agents are ongoing. Successful delivery of effective agents should prove the efficacy of CED in the near future. PMID:27980285

Bioactivity of Hybrid Polymeric Magnetic Nanoparticles and Their Applications in Drug Delivery.

PubMed

Mohammed, Leena; Ragab, Doaa; Gomaa, Hassan

2016-01-01

Engineered magnetic nanoparticles (MNPs) possess unique properties and hold great potential in biomedicine and clinical applications. With their magnetic properties and their ability to work at cellular and molecular level, MNP have been applied both in-vitro and in-vivo in targeted drug delivery and imaging. Focusing on Iron Oxide Superparamagnetic nanoparticles (SPIONs), this paper elaborates on the recent advances in development of hybrid polymeric-magnetic nanoparticles. Their main applications in drug delivery include Chemotherapeutics, Hyperthermia treatment, Radio-therapeutics, Gene delivary, and Biotheraputics. Physiochemical properties such as size, shape, surface and magnetic properties are key factors in determining their behavior. Additionally tailoring SPIONs surface is often vital for desired cell targetting and improved efficiency. Polymer coating is specifically reviewed with brief discussion of SPIONs administration routes. Commonly used drug release models for describing release mechanisms and the nanotoxicity aspects are also discussed. This review focus on superparamagnetic nanoparticles coated with different types of polymers starting with the key physiochemical features that dominate their behavior. The importance of surface modification is addressed. Subsequently, the major classes of polymer modified iron oxide nanoparticles is demonstrated according to their clinical use and application. Clinically approved nanoparticles are then addressed and the different routes of administration are mentioned. Lastly, mathematical models of drug release profile of the common used nanoparticles are addressed. MNPs emerging in recent medicine are remarkable for both imaging and therapeutics, particularly, as drug carriers for their great potential in targeted delivery and cancer treatment. Targeting ability and biocompatibility can be improved though surface coating which provides a mean to alter the surface features including physical characteristics and

Design, Characterization, and Optimization of Controlled Drug Delivery System Containing Antibiotic Drug/s

PubMed Central

Shelate, Pragna; Dave, Divyang

2016-01-01

The objective of this work was design, characterization, and optimization of controlled drug delivery system containing antibiotic drug/s. Osmotic drug delivery system was chosen as controlled drug delivery system. The porous osmotic pump tablets were designed using Plackett-Burman and Box-Behnken factorial design to find out the best formulation. For screening of three categories of polymers, six independent variables were chosen for Plackett-Burman design. Osmotic agent sodium chloride and microcrystalline cellulose, pore forming agent sodium lauryl sulphate and sucrose, and coating agent ethyl cellulose and cellulose acetate were chosen as independent variables. Optimization of osmotic tablets was done by Box-Behnken design by selecting three independent variables. Osmotic agent sodium chloride, pore forming agent sodium lauryl sulphate, and coating agent cellulose acetate were chosen as independent variables. The result of Plackett-Burman and Box-Behnken design and ANOVA studies revealed that osmotic agent and pore former had significant effect on the drug release up to 12 hr. The observed independent variables were found to be very close to predicted values of most satisfactory formulation which demonstrates the feasibility of the optimization procedure in successful development of porous osmotic pump tablets containing antibiotic drug/s by using sodium chloride, sodium lauryl sulphate, and cellulose acetate as key excipients. PMID:27610247

Fundamentals of pulmonary drug delivery.

PubMed

Groneberg, D A; Witt, C; Wagner, U; Chung, K F; Fischer, A

2003-04-01

Aerosol administration of peptide-based drugs plays an important role in the treatment of pulmonary and systemic diseases and the unique cellular properties of airway epithelium offers a great potential to deliver new compounds. As the relative contributions from the large airways to the alveolar space are important to the local and systemic availability, the sites and mechanism of uptake and transport of different target compounds have to be characterized. Among the different respiratory cells, the ciliated epithelial cells of the larger and smaller airways and the type I and type II pneumocytes are the key players in pulmonary drug transport. With their diverse cellular characteristics, each of these cell types displays a unique uptake possibility. Next to the knowledge of these cellular aspects, the nature of aerosolized drugs, characteristics of delivery systems and the depositional and pulmonary clearance mechanisms display major targets to optimize pulmonary drug delivery. Based on the growing knowledge on pulmonary cell biology and pathophysiology due to modern methods of molecular biology, the future characterization of pulmonary drug transport pathways can lead to new strategies in aerosol drug therapy.

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.

Synthesis and Applications of Multimodal Hybrid Albumin Nanoparticles for Chemotherapeutic Drug Delivery and Photothermal Therapy Platforms

NASA Astrophysics Data System (ADS)

Peralta, Donna V.

cellular uptake of AuNR-HSAPs via fluorescence microscopy. Finally, camptothecin (CPT) an antineoplastic agent and BACPT (7-butyl-10-aminocamptothecin) were loaded into HSAPs to combat their aqueous insolubility. BACPT-HSAPs loaded up to 5.25 micrograms BACPT/ mg of HSA. CPT encapsulation could not be determined. BACPT-HSAPs and CPT-HSAPs showed cytotoxicity to human sarcoma cells in vitro. Key words: Hybrid Nanoparticles, Photothermal Therapy, Gold Nanomaterials, Drug Delivery, Combinational Cancer Therapies, Materials, Human Serum Albumin, Colloidal Carriers.

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.

Pharmacosomes: An Emerging Novel Vesicular Drug Delivery System for Poorly Soluble Synthetic and Herbal Drugs

PubMed Central

2013-01-01

In the arena of solubility enhancement, several problems are encountered. A novel approach based on lipid drug delivery system has evolved, pharmacosomes. Pharmacosomes are colloidal, nanometric size micelles, vesicles or may be in the form of hexagonal assembly of colloidal drug dispersions attached covalently to the phospholipid. They act as befitting carrier for delivery of drugs quite precisely owing to their unique properties like small size, amphiphilicity, active drug loading, high entrapment efficiency, and stability. They help in controlled release of drug at the site of action as well as in reduction in cost of therapy, drug leakage and toxicity, increased bioavailability of poorly soluble drugs, and restorative effects. There has been advancement in the scope of this delivery system for a number of drugs used for inflammation, heart diseases, cancer, and protein delivery along with a large number of herbal drugs. Hence, pharmacosomes open new challenges and opportunities for improved novel vesicular drug delivery system. PMID:24106615

APPLICATIONS OF HOT-MELT EXTRUSION FOR DRUG DELIVERY

PubMed Central

Repka, Michael A.; Majumdar, Soumyajit; Battu, Sunil Kumar; Srirangam, Ramesh; Upadhye, Sampada B.

2018-01-01

In today’s pharmaceutical arena, it is estimated that more than 40% of new chemical entities produced during drug discovery efforts exhibit poor solubility characteristics. However, over the last decade hot-melt extrusion (HME) has emerged as a powerful processing technology for drug delivery and has opened the door to a host of such molecules previously considered unviable as drugs. HME is considered to be an efficient technique in developing solid molecular dispersions and has been demonstrated to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. This article reviews the myriad of HME applications for pharmaceutical dosage forms such as tablets, capsules, films and implants for drug delivery through oral, transdermal, transmucosal, transungual, as well as other routes of administration. Interest in HME as a pharmaceutical process continues to grow and the potential of automation and reduction of capital investment and labor costs have made this technique worthy of consideration as a drug delivery solution. PMID:19040397

Recent trends in drug delivery system using protein nanoparticles.

PubMed

Sripriyalakshmi, S; Jose, Pinkybel; Ravindran, Aswathy; Anjali, C H

2014-09-01

Engineered nanoparticles that can facilitate drug formulation and passively target tumours have been under extensive research in recent years. These successes have driven a new wave of significant innovation in the generation of advanced particles. The fate and transport of diagnostic nanoparticles would significantly depend on nonselective drug delivery, and hence the use of high drug dosage is implemented. In this perspective, nanocarrier-based drug targeting strategies can be used which improve the selective delivery of drugs to the site of action, i.e. drug targeting. Pharmaceutical industries majorly focus on reducing the toxicity and side effects of drugs but only recently it has been realised that carrier systems themselves may pose risks to the patient. Proteins are compatible with biological systems and they are biodegradable. They offer a multitude of moieties for modifications to tailor drug binding, imaging or targeting entities. Thus, protein nanoparticles provide outstanding contributions as a carrier for drug delivery systems. This review summarises recent progress in particle-based therapeutic delivery and discusses important concepts in particle design and biological barriers for developing the next generation of particles drug delivery systems.

Drug delivery.

PubMed

Le Souëf, Peter N

2002-09-16

What we know: In preschool children, small-volume spacers perform better than large-volume spacers. Detergent is the best antistatic agent for spacers, increasing lung delivery two- to threefold, but it must not be rinsed off. A mouthpiece should be used in children aged 2-3 years or older, as lung delivery is two- to threefold higher for oral inhalation than nasal inhalation (ie, by mask). Inhaled drug doses do not generally need to be reduced in infants and young children owing to inefficiencies of delivery in younger patients. Nebulisers are "dinosaurs" and not needed for most children with asthma. What we need to know: What is the best inhalation technique for spacers? How long should children breathe, how many breaths should they take, and at what age should they breath-hold? How should children, parents and doctors be instructed to achieve optimal levels of electrostatic charge reduction for spacers? How much should inhaled steroid dose be reduced when a spacer is used optimally? What dosing instructions should be given for beta(2)-agonists delivered by spacer?

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.

Nano drug delivery systems and gamma radiation sterilization.

PubMed

Sakar, F; Özer, A Y; Erdogan, S; Ekizoglu, M; Kart, D; Özalp, M; Colak, S; Zencir, Y

2017-09-01

In recent years, drug delivery systems such as liposomes and microparticles have been used in clinic for the treatment of different diseases and from a regulatory point of view, a parenterally applied drug and drug delivery systems must be sterile and pyrogen free. Radiation sterilization is a method recognized by pharmacopoeias to achieve sterility criteria of parenterals. It has the ability to kill microorganisms in therapeutic products. The ability of, however, irradiation might also affect the performance of drug delivery systems. One of the most critical points is irradiation dose, because certain undesirable chemical and physical changes may accompany with the irradiation, especially with the traditionally applied dose of 25 kGy. Its ionizing property may cause fragmentation of covalent bond. The care must be paid to the applied dose. In this research, the effects of gamma irradiation on different drug delivery systems such as chitosan microparticles, liposomes, niosomes and sphingosomes were investigated. According to the experimental data, it can be concluded that gamma irradiation can be a suitable sterilization technique for liposome, niosome and sphingosome dispersions. When all irradiated drug carrier systems were taken into consideration, chitosan glutamate microparticles were found as the most radioresistant drug delivery system among the others.

Novel Approaches in Formulation and Drug Delivery using Contact Lenses

PubMed Central

Singh, Kishan; Nair, Anroop B; Kumar, Ashok; Kumria, Rachna

2011-01-01

The success of ocular delivery relies on the potential to enhance the drug bioavailability by controlled and extended release of drug on the eye surface. Several new approaches have been attempted to augment the competence and diminish the intrinsic side effects of existing ocular drug delivery systems. In this contest, progress has been made to develop drug-eluting contact lens using different techniques, which have the potential to control and sustain the delivery of drug. Further, the availability of novel polymers have facilitated and promoted the utility of contact lenses in ocular drug delivery. Several research groups have already explored the feasibility and potential of contact lens using conventional drugs for the treatment of periocular and intraocular diseases. Contact lenses formulated using modern technology exhibits high loading, controlled drug release, apposite thickness, water content, superior mechanical and optical properties as compared to commercial lenses. In general, this review discus various factors and approaches designed and explored for the successful delivery of ophthalmic drugs using contact lenses as drug delivery device PMID:24826007

Approaches to Neural Tissue Engineering Using Scaffolds for Drug Delivery

PubMed Central

Willerth, Stephanie M.; Sakiyama-Elbert, Shelly E.

2007-01-01

This review seeks to give an overview of the current approaches to drug delivery from scaffolds for neural tissue engineering applications. The challenges presented by attempting to replicate the three types of nervous tissue (brain, spinal cord, and peripheral nerve) are summarized. Potential scaffold materials (both synthetic and natural) and target drugs are discussed with the benefits and drawbacks given. Finally, common methods of drug delivery, including degradable/diffusion-based delivery systems, affinity-based delivery systems, immobilized drug delivery systems, and electrically controlled drug delivery systems, are examined and critiqued. Based on the current body of work, suggestions for future directions of research in the field of neural tissue engineering are presented. PMID:17482308

Nature engineered diatom biosilica as drug delivery systems.

PubMed

Uthappa, U T; Brahmkhatri, Varsha; Sriram, G; Jung, Ho-Young; Yu, Jingxian; Kurkuri, Nikita; Aminabhavi, Tejraj M; Altalhi, Tariq; Neelgund, Gururaj M; Kurkuri, Mahaveer D

2018-05-14

Diatoms, unicellular photosynthetic algae covered with siliceous cell wall, are also called frustule. These are the most potential naturally available materials for the development of cost-effective drug delivery systems because of their excellent biocompatibility, high surface area, low cost and ease of surface modification. Mesoporous silica materials such as MCM-41 and SBA-15 have been extensively used in drug delivery area. Their synthesis is challenging, time consuming, requires toxic chemicals and are energy intensive, making the entire process expensive and non-viable. Therefore, it is necessary to explore alternative materials. Surprisingly, nature has provided some exciting materials called diatoms; biosilica is one such a material that can be potentially used as a drug delivery vehicle. The present review focuses on different types of diatom species used in drug delivery with respect to their structural properties, morphology, purification process and surface functionalization. In this review, recent advances along with their limitations as well as the future scope to develop them as potential drug delivery vehicles are discussed. Copyright © 2018. Published by Elsevier B.V.

Buccoadhesive drug delivery systems--extensive review on recent patents.

PubMed

Pathan, Shadab A; Iqbal, Zeenat; Sahani, Jasjeet K; Talegaonkar, Sushma; Khar, Roop K; Ahmad, Farhan J

2008-01-01

Peroral administration of drugs, although most preferred by both clinicians and patients has several disadvantages such as hepatic first pass metabolism and enzymatic degradation within the GI tract, that prohibit oral administration of certain classes of drugs especially peptides and proteins. Consequently, other absorptive mucosae are considered as potential sites for administration of these drugs. Among the various transmucosal routes studied the buccal mucosa offers several advantages for controlled drug delivery for extended period of time. The mucosa is well supplied with both vascular and lymphatic drainage and first-pass metabolism in the liver and pre-systemic elimination in the gastrointestinal tract is avoided. The area is well suited for a retentive device and appears to be acceptable to the patient. With the right dosage form, design and formulation, the permeability and the local environment of the mucosa can be controlled and manipulated in order to accommodate drug permeation. Buccal drug delivery is thus a promising area for continued research with the aim of systemic and local delivery of orally inefficient drugs as well as feasible and attractive alternative for non-invasive delivery of potent protein and peptide drug molecules. Extensive review pertaining specifically to the patents relating to buccal drug delivery is currently available. However, many patents e.g. US patents 6, 585,997; US20030059376A1 etc. have been mentioned in few articles. It is the objective of this article to extensively review buccal drug delivery by discussing the recent patents available. Buccal dosage forms will also be reviewed with an emphasis on bioadhesive polymeric based delivery systems.

Nanomedicine to Deal With Cancer Cell Biology in Multi-Drug Resistance.

PubMed

Tekchandani, Pawan; Kurmi, Balak Das; Paliwal, Shivani Rai

2017-01-01

Today Cancer still remains a major cause of mortality and death worldwide, in humans. Chemotherapy, a key treatment strategy in cancer, has significant hurdles such as the occurrence of chemoresistance in cancer, which is inherent unresponsiveness or acquired upon exposure to chemotherapeutics. The resistance of cancer cells to an antineoplastic agent accompanied to other chemotherapeutic drugs with different structures and mechanisms of action called multi-drug resistance (MDR) plays an important role in the failure of chemo- therapeutics. MDR is primarily based on the overexpression of drug efflux pumps in the cellular membrane, which belongs to the ATP-binding cassette (ABC) superfamily of proteins, are P-gp (P-glycoprotein) and multidrug resistance-associated protein (MRP). Over the years, various strategies have been evaluated to overcome MDR, based not only on the use of MDR modulators but also on the implementation an innovative approach and advanced nanosized drug delivery systems. Nanomedicine is an emerging tool of chemotherapy that focuses on alternative drug delivery for improvement of the treatment efficacy and reducing side effects to normal tissues. This review aims to focus on the details biology, reversal strategies option with the limitation of MDR and various advantages of the present medical science nanotechnology with intracellular delivery aspects for overcoming the significant potential for improving the treatment of MDR malignancies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Intracranial drug delivery for subarachnoid hemorrhage.

PubMed

Macdonald, Robert Loch; Leung, Ming; Tice, Tom

2012-01-01

Tice and colleagues pioneered site-specific, sustained-release drug delivery to the brain almost 30 years ago. Currently there is one drug approved for use in this manner. Clinical trials in subarachnoid hemorrhage have led to approval of nimodipine for oral and intravenous use, but other drugs, such as clazosentan, hydroxymethylglutaryl CoA reductase inhibitors (statins) and magnesium, have not shown consistent clinical efficacy. We propose that intracranial delivery of drugs such as nimodipine, formulated in sustained-release preparations, are good candidates for improving outcome after subarachnoid hemorrhage because they can be administered to patients that are already undergoing surgery and who have a self-limited condition from which full recovery is possible.

Recent Perspectives in Ocular Drug Delivery

PubMed Central

Gaudana, Ripal; Jwala, J.; Boddu, Sai H. S.; Mitra, Ashim K.

2015-01-01

Anatomy and physiology of the eye makes it a highly protected organ. Designing an effective therapy for ocular diseases, especially for the posterior segment, has been considered as a formidable task. Limitations of topical and intravitreal route of administration have challenged scientists to find alternative mode of administration like periocular routes. Transporter targeted drug delivery has generated a great deal of interest in the field because of its potential to overcome many barriers associated with current therapy. Application of nanotechnology has been very promising in the treatment of a gamut of diseases. In this review, we have briefly discussed several ocular drug delivery systems such as microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers, implants, and hydrogels. Potential for ocular gene therapy has also been described in this article. In near future, a great deal of attention will be paid to develop non-invasive sustained drug release for both anterior and posterior segment eye disorders. A better understanding of nature of ocular diseases, barriers and factors affecting in vivo performance, would greatly drive the development of new delivery systems. Current momentum in the invention of new drug delivery systems hold a promise towards much improved therapies for the treatment of vision threatening disorders. PMID:18758924

Dendrimeric Systems and Their Applications in Ocular Drug Delivery

PubMed Central

Yavuz, Burçin; Bozdağ Pehlivan, Sibel; Ünlü, Nurşen

2013-01-01

Ophthalmic drug delivery is one of the most attractive and challenging research area for pharmaceutical scientists and ophthalmologists. Absorption of an ophthalmic drug in conventional dosage forms is seriously limited by physiological conditions. The use of nonionic or ionic biodegradable polymers in aqueous solutions and colloidal dosage forms such as liposomes, nanoparticles, nanocapsules, microspheres, microcapsules, microemulsions, and dendrimers has been studied to overcome the problems mentioned above. Dendrimers are a new class of polymeric materials. The unique nanostructured architecture of dendrimers has been studied to examine their role in delivery of therapeutics and imaging agents. Dendrimers can enhance drug's water solubility, bioavailability, and biocompatibility and can be applied for different routes of drug administration successfully. Permeability enhancer properties of dendrimers were also reported. The use of dendrimers can also reduce toxicity versus activity and following an appropriate application route they allow the delivery of the drug to the targeted site and provide desired pharmacokinetic parameters. Therefore, dendrimeric drug delivery systems are of interest in ocular drug delivery. In this review, the limitations related to eye's unique structure, the advantages of dendrimers, and the potential applications of dendrimeric systems to ophthalmology including imaging, drug, peptide, and gene delivery will be discussed. PMID:24396306

Drug delivery strategies for Alzheimer's disease treatment.

PubMed

Di Stefano, Antonio; Iannitelli, Antonio; Laserra, Sara; Sozio, Piera

2011-05-01

Current Alzheimer's disease (AD) therapy is based on the administration of the drugs donepezil, galantamine, rivastigmine and memantine. Until disease-modifying therapies become available, further research is needed to develop new drug delivery strategies to ensure ease of administration and treatment persistence. In addition to the conventional oral formulations, a variety of drug delivery strategies applied to the treatment of AD are reviewed in this paper, with a focus on strategies leading to simplified dosage regimens and to providing new pharmacological tools. Alternatives include extended release, orally disintegrating or sublingual formulations, intranasal or short- and long-acting intramuscular or transdermal forms, and nanotechnology-based delivery systems. The advent of new research on molecular mechanisms of AD pathogenesis has outlined new strategies for therapeutic intervention; these include the stimulation of α-secretase cleavage, the inhibition of γ-secretase activity, the use of non-steroidal anti-inflammatory drugs, neuroprotection based on antioxidant therapy, the use of estrogens, NO synthetase inhibitors, and natural agents such as polyphenols. Unfortunately, these compounds might not help patients with end stage AD, but might hopefully slow or stop the disease process in its early stage. Nanotechnologies may prove to be a promising contribution in future AD drug delivery strategies, in particular drug carrier nano- or microsystems, which can limit the side effects of anti-Alzheimer drugs.

Development of erythropoietin receptor-targeted drug delivery system against breast cancer using tamoxifen-loaded nanostructured lipid carriers

PubMed Central

Beh, Chaw Yee; How, Chee Wun; Foo, Jhi Biau; Foong, Jia Ning; Selvarajah, Gayathri Thevi; Rasedee, Abdullah

2017-01-01

Tamoxifen (TAM) has been used in the treatment of breast cancers and is supplemented with erythropoietin (EPO) to alleviate the cancer-related anemia. The purported deleterious effects caused by the use of EPO with chemotherapeutic agents in the treatment of cancer-related anemia vary across studies and remain controversial. The use of nanoparticles as a drug delivery system has the potential to improve the specificity of anticancer drugs. In this study, we simultaneously incorporated two pharmacological active ingredients in one nanocarrier to develop EPO-conjugated TAM-loaded lipid nanoparticles (EPO-TAMNLC), a targeted delivery system, to enhance the cytotoxic activity while reducing the side effects of the ingredients. The effect of temperature in modulating the thermodynamic parameters associated with the binding of EPO and TAMNLC was assessed using isothermal titration calorimetry, while the unfolding of EPO structure was determined using fluorescence-quenching approach. The association efficiency of EPO and TAMNLC was 55.43%. Unlike binding of albumin to TAMNLC, the binding of EPO to TAMNLC occurred through endothermic and entropy-driven reaction. The EPO-TAMNLC formulation was stable because of the hydrophobic interaction and the high free energy, suggesting the spontaneity of the interactions between EPO and TAMNLC. The EPO-TAMNLC enhanced the in vitro cytotoxicity of TAM to MCF-7 cells. The EPO surface-functionalized TAMNLC could sequentially deliver EPO and TAM as well as improving site-specific delivery of these therapeutic compounds. PMID:28352153

Kinetics of Reciprocating Drug Delivery to the Inner Ear

PubMed Central

Leary Pararas, Erin E.; Chen, Zhiqiang; Fiering, Jason; Mescher, Mark J.; Kim, Ernest S.; McKenna, Michael J.; Kujawa, Sharon G.; Borenstein, Jeffrey T.; Sewell, William F.

2011-01-01

Reciprocating drug delivery is a means of delivering soluble drugs directly to closed fluid spaces in the body via a single cannula without an accompanying fluid volume change. It is ideally suited for drug delivery into small, sensitive and unique fluid spaces such as the cochlea. We characterized the pharmacokinetics of reciprocating drug delivery to the scala tympani within the cochlea by measuring the effects of changes in flow parameters on the distribution of drug throughout the length of the cochlea. Distribution was assessed by monitoring the effects of DNQX, a reversible glutamate receptor blocker, delivered directly to the inner ear of guinea pigs using reciprocating flow profiles. We then modeled the effects of those parameters on distribution using both an iterative curve-fitting approach and a computational fluid dynamic model. Our findings are consistent with the hypothesis that reciprocating delivery distributes the drug into a volume in the base of the cochlea, and suggest that the primary determinant of distribution throughout more distal regions of the cochlea is diffusion. Increases in flow rate distributed the drug into a larger volume that extended more apically. Over short time courses (less than 2 h), the apical extension, though small, significantly enhanced apically directed delivery of drug. Over longer time courses (>5 h) or greater distances (>3 mm), maintenance of drug concentration in the basal scala tympani may prove more advantageous for extending apical delivery than increases in flow rate. These observations demonstrate that this reciprocating technology is capable of providing controlled delivery kinetics to the closed fluid space in the cochlea, and may be suitable for other applications such as localized brain and retinal delivery. PMID:21385596

Smart linkers in polymer-drug conjugates for tumor-targeted delivery.

PubMed

Chang, Minglu; Zhang, Fang; Wei, Ting; Zuo, Tiantian; Guan, Yuanyuan; Lin, Guimei; Shao, Wei

2016-01-01

To achieve effective chemotherapy, many types of drug delivery systems have been developed for the specific environments in tumor tissues. Polymer-drug conjugates are increasingly used in tumor therapy due to several significant advantages over traditional delivery systems. In the fabrication of polymer-drug conjugates, a smart linker is an important component that joins two fragments or molecules together and can be cleared by a specific stimulus, which results in targeted drug delivery and controlled release. By regulating the conjugation between the drug and the nanocarriers, stimulus-sensitive systems based on smart linkers can offer high payloads, certified stability, controlled release and targeted delivery. In this review, we summarize the current state of smart linkers (e.g. disulfide, hydrazone, peptide, azo) used recently in various polymer-drug conjugate-based delivery systems with a primary focus on their sophisticated design principles and drug delivery mechanisms as well as in vivo processes.

MRI-Guided Focused Ultrasound as a New Method of Drug Delivery

PubMed Central

Thanou, M.; Gedroyc, W.

2013-01-01

Ultrasound-mediated drug delivery under the guidance of an imaging modality can improve drug disposition and achieve site-specific drug delivery. The term focal drug delivery has been introduced to describe the focal targeting of drugs in tissues with the help of imaging and focused ultrasound. Focal drug delivery aims to improve the therapeutic profile of drugs by improving their specificity and their permeation in defined areas. Focused-ultrasound- (FUS-) mediated drug delivery has been applied with various molecules to improve their local distribution in tissues. FUS is applied with the aid of microbubbles to enhance the permeability of bioactive molecules across BBB and improve drug distribution in the brain. Recently, FUS has been utilised in combination with MRI-labelled liposomes that respond to temperature increase. This strategy aims to “activate” nanoparticles to release their cargo locally when triggered by hyperthermia induced by FUS. MRI-guided FUS drug delivery provides the opportunity to improve drug bioavailability locally and therefore improve the therapeutic profiles of drugs. This drug delivery strategy can be directly translated to clinic as MRg FUS is a promising clinically therapeutic approach. However, more basic research is required to understand the physiological mechanism of FUS-enhanced drug delivery. PMID:23738076

Synthesis and applications of titania nanotubes: Drug delivery and ionomer composites

NASA Astrophysics Data System (ADS)

Kulkarni, Harsha Prabhakar

In this dissertation, the potential of a tubular form of titania (titanium dioxide) has been explored for two diverse applications, in the field of targeted drug delivery for medical applications and in the field of composite materials for structural applications. We introduce the tubular form of titania, a material well known for its catalytic properties. The tubes are synthesized by hydrothermal procedure and are nanometers in dimension, with an inside diameter of 5-6 nm, outside diameter of 10-12, and an aspect ratio of ˜100:1 (l:d), structures both chemically and thermally stable. Biocompatible titania nanotubes with large catalytic surface area are used as vehicles for carrying Doxorubicin, an anticancer chemotherapeutic drug, to explore its potential in targeted drug delivery. Optical properties of Doxorubicin are used to study adsorption and release of the drug molecule from the nanotube surface. Pilot experiments show strong adsorption of 4 wt% of doxorubicin on the nanotube surface characterized by the quenching of its absorption centered at 490 nm. Quinone and protonated amino groups on the drug molecule, involved in protonation and deprotonation with the surface hydroxyls and molecular water on the nanotube surface, are responsible for adsorption. Doxorubicin adsorbed on the nanotube surface show pH specific release, with 40% release at a physiological pH of 7.4 as compared to 4% and 10% at pH values of 3.4 and 5.7 respectively under sink conditions. In vitro cytotoxicity experiments, used to characterize the anticancer potential of the nanotube-drug conjugate, shows comparable toxicity for the conjugates as the free drug. Nanotubes with strong adsorption of doxorubicin, large surface area, pH controlled release, and effective toxicity, demonstrate its potential as a vehicle for targeted drug delivery. If nanotube-drug conjugates with reversible bonds between them, and a pH controlled release in an aqueous solution are promising for medical applications

Biophysical interactions with model lipid membranes: applications in drug discovery and drug delivery

PubMed Central

Peetla, Chiranjeevi; Stine, Andrew; Labhasetwar, Vinod

2009-01-01

The transport of drugs or drug delivery systems across the cell membrane is a complex biological process, often difficult to understand because of its dynamic nature. In this regard, model lipid membranes, which mimic many aspects of cell-membrane lipids, have been very useful in helping investigators to discern the roles of lipids in cellular interactions. One can use drug-lipid interactions to predict pharmacokinetic properties of drugs, such as their transport, biodistribution, accumulation, and hence efficacy. These interactions can also be used to study the mechanisms of transport, based on the structure and hydrophilicity/hydrophobicity of drug molecules. In recent years, model lipid membranes have also been explored to understand their mechanisms of interactions with peptides, polymers, and nanocarriers. These interaction studies can be used to design and develop efficient drug delivery systems. Changes in the lipid composition of cells and tissue in certain disease conditions may alter biophysical interactions, which could be explored to develop target-specific drugs and drug delivery systems. In this review, we discuss different model membranes, drug-lipid interactions and their significance, studies of model membrane interactions with nanocarriers, and how biophysical interaction studies with lipid model membranes could play an important role in drug discovery and drug delivery. PMID:19432455

Calcium phosphate ceramics in drug delivery

NASA Astrophysics Data System (ADS)

Bose, Susmita; Tarafder, Solaiman; Edgington, Joe; Bandyopadhyay, Amit

2011-04-01

Calcium phosphate (CaP) particulates, cements and scaffolds have attracted significant interest as drug delivery vehicles. CaP systems, including both hydroxyapaptite and tricalcium phosphates, possess variable stoichiometry, functionality and dissolution properties which make them suitable for cellular delivery. Their chemical similarity to bone and thus biocompatibility, as well as variable surface charge density contribute to their controlled release properties. Among specific research areas, nanoparticle size, morphology, surface area due to porosity, and chemistry controlled release kinetics are the most active. This article discusses CaP systems in their particulate, cements, and scaffold forms for drug, protein, and growth factor delivery toward orthopedic and dental applications.

Recent advancements in nanoparticle based drug delivery for gastrointestinal disorders.

PubMed

Mittal, Rahul; Patel, Amit P; Jhaveri, Vasanti M; Kay, Sae-In S; Debs, Luca H; Parrish, James M; Pan, Debbie R; Nguyen, Desiree; Mittal, Jeenu; Jayant, Rahul Dev

2018-03-01

The emergent field of nanoparticles has presented a wealth of opportunities for improving the treatment of human diseases. Recent advances have allowed for promising developments in drug delivery, diagnostics, and therapeutics. Modified delivery systems allow improved drug delivery over traditional pH, microbe, or receptor dependent models, while antibody association allows for more advanced imaging modalities. Nanoparticles have potential clinical application in the field of gastroenterology as they offer several advantages compared to the conventional treatment systems including target drug delivery, enhanced treatment efficacy, and reduced side effects. Areas covered: The aim of this review article is to summarize the recent advancements in developing nanoparticle technologies to treat gastrointestinal diseases. We have covered the application of nanoparticles in various gastrointestinal disorders including inflammatory bowel disease and colorectal cancer. We also have discussed how the gut microbiota affects the nanoparticle based drug delivery in the gastrointestinal tract. Expert opinion: Nanoparticles based drug delivery offers a great platform for targeted drug delivery for gastrointestinal disorders. However, it is influenced by the presence of microbiota, drug interaction with nanoparticles, and cytotoxicity of nanoparticles. With the advancements in nanoparticle technology, it may be possible to overcome these barriers leading to efficient drug delivery for gastrointestinal disorders based on nanoparticle platform.

Functionalization of protein-based nanocages for drug delivery applications.

PubMed

Schoonen, Lise; van Hest, Jan C M

2014-07-07

Traditional drug delivery strategies involve drugs which are not targeted towards the desired tissue. This can lead to undesired side effects, as normal cells are affected by the drugs as well. Therefore, new systems are now being developed which combine targeting functionalities with encapsulation of drug cargo. Protein nanocages are highly promising drug delivery platforms due to their perfectly defined structures, biocompatibility, biodegradability and low toxicity. A variety of protein nanocages have been modified and functionalized for these types of applications. In this review, we aim to give an overview of different types of modifications of protein-based nanocontainers for drug delivery applications.

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

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.

NanoClusters Enhance Drug Delivery in Mechanical Ventilation

NASA Astrophysics Data System (ADS)

Pornputtapitak, Warangkana

The overall goal of this thesis was to develop a dry powder delivery system for patients on mechanical ventilation. The studies were divided into two parts: the formulation development and the device design. The pulmonary system is an attractive route for drug delivery since the lungs have a large accessible surface area for treatment or drug absorption. For ventilated patients, inhaled drugs have to successfully navigate ventilator tubing and an endotracheal tube. Agglomerates of drug nanoparticles (also known as 'NanoClusters') are fine dry powder aerosols that were hypothesized to enable drug delivery through ventilator circuits. This Thesis systematically investigated formulations of NanoClusters and their aerosol performance in a conventional inhaler and a device designed for use during mechanical ventilation. These engineered powders of budesonide (NC-Bud) were delivered via a MonodoseRTM inhaler or a novel device through commercial endotracheal tubes, and analyzed by cascade impaction. NC-Bud had a higher efficiency of aerosol delivery compared to micronized stock budesonide. The delivery efficiency was independent of ventilator parameters such as inspiration patterns, inspiration volumes, and inspiration flow rates. A novel device designed to fit directly to the ventilator and endotracheal tubing connections and the MonodoseRTM inhaler showed the same efficiency of drug delivery. The new device combined with NanoCluster formulation technology, therefore, allowed convenient and efficient drug delivery through endotracheal tubes. Furthermore, itraconazole (ITZ), a triazole antifungal agent, was formulated as a NanoCluster powder via milling (top-down process) or precipitation (bottom-up process) without using any excipients. ITZ NanoClusters prepared by wet milling showed better aerosol performance compared to micronized stock ITZ and ITZ NanoClusters prepared by precipitation. ITZ NanoClusters prepared by precipitation methods also showed an amorphous state

Concentration rather than dose defines the local brain toxicity of agents that are effectively distributed by convection-enhanced delivery.

PubMed

Zhang, Rong; Saito, Ryuta; Mano, Yui; Kanamori, Masayuki; Sonoda, Yukihiko; Kumabe, Toshihiro; Tominaga, Teiji

2014-01-30

Convection-enhanced delivery (CED) has been developed as a potentially effective drug-delivery strategy into the central nervous system. In contrast to systemic intravenous administration, local delivery achieves high concentration and prolonged retention in the local tissue, with increased chance of local toxicity, especially with toxic agents such as chemotherapeutic agents. Therefore, the factors that affect local toxicity should be extensively studied. With the assumption that concentration-oriented evaluation of toxicity is important for local CED, we evaluated the appearance of local toxicity among different agents after delivery with CED and studied if it is dose dependent or concentration dependent. Local toxicity profile of chemotherapeutic agents delivered via CED indicates BCNU was dose-dependent, whereas that of ACNU was concentration-dependent. On the other hand, local toxicity for doxorubicin, which is not distributed effectively by CED, was dose-dependent. Local toxicity for PLD, which is extensively distributed by CED, was concentration-dependent. Traditional evaluation of drug induced toxicity was dose-oriented. This is true for systemic intravascular delivery. However, with local CED, toxicity of several drugs exacerbated in concentration-dependent manner. From our study, local toxicity of drugs that are likely to distribute effectively tended to be concentration-dependent. Concentration rather than dose may be more important for the toxicity of agents that are effectively distributed by CED. Concentration-oriented evaluation of toxicity is more important for CED. Copyright © 2013 Elsevier B.V. All rights reserved.

3D printing applications for transdermal drug delivery.

PubMed

Economidou, Sophia N; Lamprou, Dimitrios A; Douroumis, Dennis

2018-06-15

The role of two and three-dimensional printing as a fabrication technology for sophisticated transdermal drug delivery systems is explored in literature. 3D printing encompasses a family of distinct technologies that employ a virtual model to produce a physical object through numerically controlled apparatuses. The applicability of several printing technologies has been researched for the direct or indirect printing of microneedle arrays or for the modification of their surface through drug-containing coatings. The findings of the respective studies are presented. The range of printable materials that are currently used or potentially can be employed for 3D printing of transdermal drug delivery (TDD) systems is also reviewed. Moreover, the expected impact and challenges of the adoption of 3D printing as a manufacturing technique for transdermal drug delivery systems, are assessed. Finally, this paper outlines the current regulatory framework associated with 3D printed transdermal drug delivery systems. Copyright © 2018 Elsevier B.V. All rights reserved.

Kinetics of reciprocating drug delivery to the inner ear.

PubMed

Pararas, Erin E Leary; Chen, Zhiqiang; Fiering, Jason; Mescher, Mark J; Kim, Ernest S; McKenna, Michael J; Kujawa, Sharon G; Borenstein, Jeffrey T; Sewell, William F

2011-06-10

Reciprocating drug delivery is a means of delivering soluble drugs directly to closed fluid spaces in the body via a single cannula without an accompanying fluid volume change. It is ideally suited for drug delivery into small, sensitive and unique fluid spaces such as the cochlea. We characterized the pharmacokinetics of reciprocating drug delivery to the scala tympani within the cochlea by measuring the effects of changes in flow parameters on the distribution of drug throughout the length of the cochlea. Distribution was assessed by monitoring the effects of DNQX, a reversible glutamate receptor blocker, delivered directly to the inner ear of guinea pigs using reciprocating flow profiles. We then modeled the effects of those parameters on distribution using both an iterative curve-fitting approach and a computational fluid dynamic model. Our findings are consistent with the hypothesis that reciprocating delivery distributes the drug into a volume in the base of the cochlea, and suggest that the primary determinant of distribution throughout more distal regions of the cochlea is diffusion. Increases in flow rate distributed the drug into a larger volume that extended more apically. Over short time courses (less than 2h), the apical extension, though small, significantly enhanced apically directed delivery of drug. Over longer time courses (>5h) or greater distances (>3mm), maintenance of drug concentration in the basal scala tympani may prove more advantageous for extending apical delivery than increases in flow rate. These observations demonstrate that this reciprocating technology is capable of providing controlled delivery kinetics to the closed fluid space in the cochlea, and may be suitable for other applications such as localized brain and retinal delivery. Copyright © 2011 Elsevier B.V. All rights reserved.

Photomedicine with laser drug delivery technologies

NASA Astrophysics Data System (ADS)

Zharov, Vladimir P.; Latyshev, Alexei S.; Leviev, Dmitry O.

1999-07-01

This paper presents a new technology, which consists in utilizing laser drug delivery methods for the purposes of photodrug therapy. According to this technology, photosensitizer is applied onto the treated surface and then the solution is either impregnated or injected into the medium, with it being suggested to employ laser drug delivery techniques for the impregnation and injection of the photosensitizer. After introducing the photosensitizer, the area is illuminated by a matrix of light-emission diodes.

Calcium carbonate nanoparticles as cancer drug delivery system.

PubMed

Maleki Dizaj, Solmaz; Barzegar-Jalali, Mohammad; Zarrintan, Mohammad Hossein; Adibkia, Khosro; Lotfipour, Farzaneh

2015-01-01

Calcium carbonate (CaCO3) has broad biomedical utilizations owing to its availability, low cost, safety, biocompatibility, pH-sensitivity and slow biodegradability. Recently, there has been widespread interest in their application as drug delivery systems for different groups of drugs. Among them, CaCO3 nanoparticles have exhibited promising potential as drug carriers targeting cancer tissues and cells. The pH-dependent properties, alongside the potential to be functionalized with targeting agents give them the unique property that can be used in targeted delivery systems for anticancer drugs. Also, due to the slow degradation of CaCO3 matrices, these nanoparticles can be used as sustained release systems to retain drugs in cancer tissues for longer times after administration. Development of drug delivery carriers using CaCO3 nanoparticles has been reviewed. The current state of CaCO3 nanoparticles as cancer drug delivery systems with focus on their special properties like pH-sensitivity and biodegradability has also been evaluated. According to our review, CaCO3 nanoparticles, owing to their special characteristics, will have a potential role in safe and efficient cancer treatment in future.

Tissue Bioeffects during Ultrasound-mediated Drug Delivery

NASA Astrophysics Data System (ADS)

Sutton, Jonathan

Ultrasound has been developed as both a valuable diagnostic tool and a potent promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. Vascular effects can be mediated by mechanical oscillations of circulating microbubbles, or ultrasound contrast agents, which may also encapsulate and shield a therapeutic agent in the bloodstream. Oscillating microbubbles can create stresses directly on nearby tissue or induce fluid effects that effect drug penetration into vascular tissue, lyse thrombi, or direct drugs to optimal locations for delivery. These investigations have spurred continued research into alternative therapeutic applications, such as bioactive gas delivery. This dissertation addresses a fundamental hypothesis in biomedical ultrasound: ultrasound-mediated drug delivery is capable of increasing the penetration of drugs across different physiologic barriers within the cardiovascular system, such as the vascular endothelium, blood clots, and smooth muscle cells.

Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

DTIC Science & Technology

2011-09-01

breast-cancer-targeted nuclear drug delivery carriers , but we found that the ability of the PEI to disrupt the endosome/lysosome membrane was not...AD_________________ Award Number: W81XWH-09-1-0502 TITLE: Breast Cancer-Targeted Nuclear Drug ...Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy PRINCIPAL INVESTIGATOR: Youqing Shen, Ph.D

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.

Nanothermite-Based Microsystem for Drug Delivery and Cell Transfection

DTIC Science & Technology

2008-12-01

micropyrotechnic-based system in which a nanothermite energy source is coupled to a biological target for gene transfer and drug delivery ... delivery of particulate vaccines and drugs to human skin with a practical, hand-held shock tube-based system . Shock Waves, 12, 23-30. Kodama, T., M...1 NANOTHERMITE-BASED MICROSYSTEM FOR DRUG DELIVERY AND CELL TRANSFECTION S. Apperson, R. Thiruvengadathan, A. Bezmelnitsyn, K. Gangopadhyay, S

Current and emerging lipid-based systems for transdermal drug delivery.

PubMed

Singla, Sumeet K; Sachdeva, Vishal

2015-01-01

Developing a transdermal drug delivery system is a challenging task considering the selective permeability of the skin and the physicochemical properties the drug must possess to permeate through the skin. Lipid-based drug delivery systems have contributed a great deal in this direction in the last few decades, and thereby have helped to expand the range of therapeutic molecules that can be delivered through the skin in a safe and effective manner. Additionally, vesicular delivery systems such as nanoparticles and emulsions have also played important roles in providing alternative novel approaches for drug delivery. In this article, we will discuss some of the current and future lipid-based systems for transdermal drug delivery along with the associated challenges.

Recent technologies in pulsatile drug delivery systems

PubMed Central

Jain, Deepika; Raturi, Richa; Jain, Vikas; Bansal, Praveen; Singh, Ranjit

2011-01-01

Pulsatile drug delivery systems (PDDS) have attracted attraction because of their multiple benefits over conventional dosage forms. They deliver the drug at the right time, at the right site of action and in the right amount, which provides more benefit than conventional dosages and increased patient compliance. These systems are designed according to the circadian rhythm of the body, and the drug is released rapidly and completely as a pulse after a lag time. These products follow the sigmoid release profile characterized by a time period. These systems are beneficial for drugs with chronopharmacological behavior, where nocturnal dosing is required, and for drugs that show the first-pass effect. This review covers methods and marketed technologies that have been developed to achieve pulsatile delivery. Marketed technologies, such as PulsincapTM, Diffucaps®, CODAS®, OROS® and PULSYSTM, follow the above mechanism to render a sigmoidal drug release profile. Diseases wherein PDDS are promising include asthma, peptic ulcers, cardiovascular ailments, arthritis and attention deficit syndrome in children and hypercholesterolemia. Pulsatile drug delivery systems have the potential to bring new developments in the therapy of many diseases. PMID:23507727

Heat: A Highly Efficient Skin Enhancer for Transdermal Drug Delivery.

PubMed

Szunerits, Sabine; Boukherroub, Rabah

2018-01-01

Advances in materials science and bionanotechnology have allowed the refinements of current drug delivery systems, expected to facilitate the development of personalized medicine. While dermatological topical pharmaceutical formulations such as foams, creams, lotions, gels, etc., have been proposed for decades, these systems target mainly skin-based diseases. To treat systemic medical conditions as well as localized problems such as joint or muscle concerns, transdermal delivery systems (TDDSs), which use the skin as the main route of drug delivery, are very appealing. Over the years, these systems have shown to offer important advantages over oral as well as intravenous drug delivery routes. Besides being non-invasive and painless, TDDSs are able to deliver drugs with a short-half-life time more easily and are well adapted to eliminate frequent administrations to maintain constant drug delivery. The possibility of self-administration of a predetermined drug dose at defined time intervals makes it also the most convenient personalized point-of-care approach. The transdermal market still remains limited to a narrow range of drugs. While small and lipophilic drugs have been successfully delivered using TDDSs, this approach fails to deliver therapeutic macromolecules due to size-limited transport across the stratum corneum , the outermost layer of the epidermis. The low permeability of the stratum corneum to water-soluble drugs as well as macromolecules poses important challenges to transdermal administration. To widen the scope of drugs for transdermal delivery, new procedures to enhance skin permeation to hydrophilic drugs and macromolecules are under development. Next to iontophoresis and microneedle-based concepts, thermal-based approaches have shown great promise to enhance transdermal drug delivery of different therapeutics. In this inaugural article for the section "Frontiers in Bioengineering and Biotechnology," the advances in this field and the handful of

Opportunities and Challenges for Niosomes as Drug Delivery Systems.

PubMed

Thakkar, Miloni; Brijesh, S

2016-01-01

With the increase in drug resistance observed in most infectious diseases as well as some forms of cancer, and with the chances of development of new drug molecules to address this issue looking bleak, one of the most plausible ways to disease treatment is combination therapy. Combination therapy would ensure delay in drug resistance, if utilized rationally. However, the biggest difficulty in employing combination therapy are adverse effects due to potential drug-drug interactions and patient compliance due to multiple routes of administration or multiple dosing that may be required. To overcome these issues, researchers have utilized nanoparticle-based systems that can hold multiple drugs in a single carrier. There are several nanocarrier systems available for such purposes. However, the focus of this review will be non-ionic surfactant-based systems (niosomes) for delivery of multiple therapeutic agents. Niosomes are artificially prepared drug delivery carriers. They are structurally similar to liposomes albeit more stable than them. Literature pertaining to combination drug delivery and various drug delivery systems was reviewed. It was conceptualized that many of the methods used to prepare various types of carriers for combination delivery of drugs may be used for niosomal systems as well. We envisage that niosomes may effectively be utilized to package older drugs in newer ways. The review will thus focus on techniques that may be used for the formulation of niosomes, ways to encapsulate multiple-drug moieties, and challenges associated in preparing and optimizing such systems.

DNA Nanotechnology-Enabled Drug Delivery Systems.

PubMed

Hu, Qinqin; Li, Hua; Wang, Lihua; Gu, Hongzhou; Fan, Chunhai

2018-02-21

Over the past decade, we have seen rapid advances in applying nanotechnology in biomedical areas including bioimaging, biodetection, and drug delivery. As an emerging field, DNA nanotechnology offers simple yet powerful design techniques for self-assembly of nanostructures with unique advantages and high potential in enhancing drug targeting and reducing drug toxicity. Various sequence programming and optimization approaches have been developed to design DNA nanostructures with precisely engineered, controllable size, shape, surface chemistry, and function. Potent anticancer drug molecules, including Doxorubicin and CpG oligonucleotides, have been successfully loaded on DNA nanostructures to increase their cell uptake efficiency. These advances have implicated the bright future of DNA nanotechnology-enabled nanomedicine. In this review, we begin with the origin of DNA nanotechnology, followed by summarizing state-of-the-art strategies for the construction of DNA nanostructures and drug payloads delivered by DNA nanovehicles. Further, we discuss the cellular fates of DNA nanostructures as well as challenges and opportunities for DNA nanostructure-based drug delivery.

Nanoparticle-based drug delivery to the vagina: a review

PubMed Central

Ensign, Laura M.; Cone, Richard; Hanes, Justin

2014-01-01

Vaginal drug administration can improve prophylaxis and treatment of many conditions affecting the female reproductive tract, including sexually transmitted diseases, fungal and bacterial infections, and cancer. However, achieving sustained local drug concentrations in the vagina can be challenging, due to the high permeability of the vaginal epithelium and expulsion of conventional soluble drug dosage forms. Nanoparticle-based drug delivery platforms have received considerable attention for vaginal drug delivery, as nanoparticles can provide sustained release, cellular targeting, and even intrinsic antimicrobial or adjuvant properties that can improve the potency and/or efficacy of prophylactic and therapeutic modalities. Here, we review the use of polymeric nanoparticles, liposomes, dendrimers, and inorganic nanoparticles for vaginal drug delivery. Although most of the work toward nanoparticle-based drug delivery in the vagina has been focused on HIV prevention, strategies for treatment and prevention of other sexually transmitted infections, treatment for reproductive tract cancer, and treatment of fungal and bacterial infections are also highlighted. PMID:24830303

Otic drug delivery systems: formulation principles and recent developments.

PubMed

Liu, Xu; Li, Mingshuang; Smyth, Hugh; Zhang, Feng

2018-04-25

Disorders of the ear severely impact the quality of life of millions of people, but the treatment of these disorders is an ongoing, but often overlooked challenge particularly in terms of formulation design and product development. The prevalence of ear disorders has spurred significant efforts to develop new therapeutic agents, but perhaps less innovation has been applied to new drug delivery systems to improve the efficacy of ear disease treatments. This review provides a brief overview of physiology, major diseases, and current therapies used via the otic route of administration. The primary focuses are on the various administration routes and their formulation principles. The article also presents recent advances in otic drug deliveries as well as potential limitations. Otic drug delivery technology will likely evolve in the next decade and more efficient or specific treatments for ear disease will arise from the development of less invasive drug delivery methods, safe and highly controlled drug delivery systems, and biotechnology targeting therapies.

Systematic screen of chemotherapeutics in Drosophila stem cell tumors

PubMed Central

Markstein, Michele; Dettorre, Samantha; Cho, Julio; Neumüller, Ralph A.; Craig-Müller, Sören; Perrimon, Norbert

2014-01-01

Here we report the development of an in vivo system to study the interaction of stem cells with drugs using a tumor model in the adult Drosophila intestine. Strikingly, we find that some Food and Drug Administration-approved chemotherapeutics that can inhibit the growth of Drosophila tumor stem cells can paradoxically promote the hyperproliferation of their wild-type counterparts. These results reveal an unanticipated side effect on stem cells that may contribute to tumor recurrence. We propose that the same side effect may occur in humans based on our finding that it is driven in Drosophila by the evolutionarily conserved Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway. An immediate implication of our findings is that supplementing traditional chemotherapeutics with anti-inflammatories may reduce tumor recurrence. PMID:24616500

The importance of nanoparticle shape in cancer drug delivery.

PubMed

Truong, Nghia P; Whittaker, Michael R; Mak, Catherine W; Davis, Thomas P

2015-01-01

Nanoparticles have been successfully used for cancer drug delivery since 1995. In the design of commercial nanoparticles, size and surface characteristics have been exploited to achieve efficacious delivery. However, the design of optimized drug delivery platforms for efficient delivery to disease sites with minimal off-target effects remains a major research goal. One crucial element of nanoparticle design influencing both pharmacokinetics and cell uptake is nanoparticle morphology (both size and shape). In this succinct review, the authors collate the recent literature to assess the current state of understanding of the influence of nanoparticle shape on the effectiveness of drug delivery with a special emphasis on cancer therapy. This review draws on studies that have focused on the role of nonspherical nanoparticles used for cancer drug delivery. In particular, the authors summarize the influence of nanoparticle shape on biocirculation, biodistribution, cellular uptake and overall drug efficacy. By comparing spherical and nonspherical nanoparticles, they establish some general design principles to serve as guidelines for developing the next generation of nanocarriers for drug delivery. Pioneering studies on nanoparticles show that nonspherical shapes show great promise as cancer drug delivery vectors. Filamentous or worm-like micelles together with other rare morphologies such as needles or disks may become the norm for next-generation drug carriers, though at present, traditional spherical micelles remain the dominant shape of nanocarriers described in the literature due to synthesis and testing difficulties. The few reports that do exist describing nonspherical nanoparticles show a number of favorable properties that should encourage more efforts to develop facile and versatile nanoparticle synthesis methodologies with the flexibility to create different shapes, tunable sizes and adaptable surface chemistries. In addition, the authors note that there is a