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Sample records for accurate treatment delivery

  1. SU-E-T-273: Do Task Group External Beam QA Recommendations Guarantee Accurate Treatment Plan Dose Delivery?

    SciTech Connect

    Templeton, A; Liao, Y; Redler, G; Zhen, H

    2015-06-15

    Purpose: AAPM task groups 40/142 have provided an invaluable set of goals for physicists designing QA programs, attempting to standardize what would otherwise likely be a highly variable phenomenon across institutions. However, with the complexity of modalities such as VMAT, we hypothesize that following these guidelines to the letter might still allow unacceptable dose discrepancies. To explore this hypothesis we simulated machines bordering on QA acceptability, and calculated the effect on patient plans. Methods: Two errant machines were simulated in Aria/Eclipse, each just within task group criteria for output, percent depth dose, beam profile, gantry and collimator rotations, and jaw and MLC positions. One machine minimized dose to the PTV (machine A) and the other maximized dose to the OARs (machine B). Clinical treatment plans (3-phase prostate, n=3; hypofractionated lung, n=1) were calculated on these machines and the dose distributions compared. A prostate case was examined for contribution of error sources and evaluated using delivery QA data. Results: The prostate plans showed mean decreases in target D95 of 9.9% of prescription dose on machine A. On machine B, The rectal and bladder V70Gy each increased by 7.1 percentage points, while their V45Gy increased by 16.2% and 15.0% respectively. In the lung plan, the target D95 decreased by 12.8% and the bronchial tree Dmax increased by 21% of prescription dose, on machines A and B. One prostate plan showed target dose errors of 3.8% from MLC changes, 2% from output, ∼3% from energy and ∼0.5% from other factors. This plan achieved an 88.4% gamma passing rate using 3%/3mm using ArcCHECK. Conclusion: In the unlikely event that a machine exhibits all maximum errors allowed by TG 40/142, unacceptably large changes in dose delivered are possible especially in highly modulated VMAT plans, despite the machine passing routine QA.

  2. Image-guided radiation therapy for treatment delivery and verification

    NASA Astrophysics Data System (ADS)

    Schubert, Leah Kayomi

    Target conformity and normal tissue sparing provided by modern radiation therapy techniques often result in steep dose gradients, which increase the need for more accurate patient setup and treatment delivery. Image guidance is starting to play a major role in determining the accuracy of treatment setup. A typical objective of image-guided radiation therapy (IGRT) is to minimize differences between planned and delivered treatment by imaging the patient prior to delivery. This step verifies and corrects for patient setup and is referred to as setup verification. This dissertation evaluates the efficacy of daily imaging for setup verification and investigates new uses of IGRT for potential improvements in treatment delivery. The necessity of daily imaging can first be determined by assessing differences in setup corrections between patient groups. Therefore, the first objective of this investigation was to evaluate the application of IGRT for setup verification by quantifying differences in patient positioning for several anatomical disease sites. Detailed analysis of setup corrections for brain, head and neck, lung, and prostate treatments is presented. In this analysis, large setup errors were observed for prostate treatments. Further assessment of prostate treatments was performed, and patient-specific causes of setup errors investigated. Setup corrections are applied via rigid shifts or rotations of the patient or machine, but anatomical deformations occur for which rigid shifts cannot correct. Fortunately, IGRT provides images on which anatomical changes occurring throughout the course of treatment can be detected. From those images, the efficacy of IGRT in ensuring accurate treatment delivery can be evaluated and improved by determining delivered doses and adapting the plan during treatment. The second objective of this dissertation was to explore new applications of IGRT to further improve treatment. By utilizing daily IGRT images, a retrospective analysis of

  3. The development and verification of a highly accurate collision prediction model for automated noncoplanar plan delivery

    SciTech Connect

    Yu, Victoria Y.; Tran, Angelia; Nguyen, Dan; Cao, Minsong; Ruan, Dan; Low, Daniel A.; Sheng, Ke

    2015-11-15

    Purpose: Significant dosimetric benefits had been previously demonstrated in highly noncoplanar treatment plans. In this study, the authors developed and verified an individualized collision model for the purpose of delivering highly noncoplanar radiotherapy and tested the feasibility of total delivery automation with Varian TrueBeam developer mode. Methods: A hand-held 3D scanner was used to capture the surfaces of an anthropomorphic phantom and a human subject, which were positioned with a computer-aided design model of a TrueBeam machine to create a detailed virtual geometrical collision model. The collision model included gantry, collimator, and couch motion degrees of freedom. The accuracy of the 3D scanner was validated by scanning a rigid cubical phantom with known dimensions. The collision model was then validated by generating 300 linear accelerator orientations corresponding to 300 gantry-to-couch and gantry-to-phantom distances, and comparing the corresponding distance measurements to their corresponding models. The linear accelerator orientations reflected uniformly sampled noncoplanar beam angles to the head, lung, and prostate. The distance discrepancies between measurements on the physical and virtual systems were used to estimate treatment-site-specific safety buffer distances with 0.1%, 0.01%, and 0.001% probability of collision between the gantry and couch or phantom. Plans containing 20 noncoplanar beams to the brain, lung, and prostate optimized via an in-house noncoplanar radiotherapy platform were converted into XML script for automated delivery and the entire delivery was recorded and timed to demonstrate the feasibility of automated delivery. Results: The 3D scanner measured the dimension of the 14 cm cubic phantom within 0.5 mm. The maximal absolute discrepancy between machine and model measurements for gantry-to-couch and gantry-to-phantom was 0.95 and 2.97 cm, respectively. The reduced accuracy of gantry-to-phantom measurements was

  4. The development and verification of a highly accurate collision prediction model for automated noncoplanar plan delivery

    PubMed Central

    Yu, Victoria Y.; Tran, Angelia; Nguyen, Dan; Cao, Minsong; Ruan, Dan; Low, Daniel A.; Sheng, Ke

    2015-01-01

    Purpose: Significant dosimetric benefits had been previously demonstrated in highly noncoplanar treatment plans. In this study, the authors developed and verified an individualized collision model for the purpose of delivering highly noncoplanar radiotherapy and tested the feasibility of total delivery automation with Varian TrueBeam developer mode. Methods: A hand-held 3D scanner was used to capture the surfaces of an anthropomorphic phantom and a human subject, which were positioned with a computer-aided design model of a TrueBeam machine to create a detailed virtual geometrical collision model. The collision model included gantry, collimator, and couch motion degrees of freedom. The accuracy of the 3D scanner was validated by scanning a rigid cubical phantom with known dimensions. The collision model was then validated by generating 300 linear accelerator orientations corresponding to 300 gantry-to-couch and gantry-to-phantom distances, and comparing the corresponding distance measurements to their corresponding models. The linear accelerator orientations reflected uniformly sampled noncoplanar beam angles to the head, lung, and prostate. The distance discrepancies between measurements on the physical and virtual systems were used to estimate treatment-site-specific safety buffer distances with 0.1%, 0.01%, and 0.001% probability of collision between the gantry and couch or phantom. Plans containing 20 noncoplanar beams to the brain, lung, and prostate optimized via an in-house noncoplanar radiotherapy platform were converted into XML script for automated delivery and the entire delivery was recorded and timed to demonstrate the feasibility of automated delivery. Results: The 3D scanner measured the dimension of the 14 cm cubic phantom within 0.5 mm. The maximal absolute discrepancy between machine and model measurements for gantry-to-couch and gantry-to-phantom was 0.95 and 2.97 cm, respectively. The reduced accuracy of gantry-to-phantom measurements was

  5. Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment.

    PubMed

    Zhou, Zhiping; Singh, Ranjodh; Souweidane, Mark M

    2017-01-01

    Convection-enhanced delivery (CED) is a technique designed to deliver drugs directly into the brain or tumors. Its ability to bypass the blood-brain barrier (BBB), one of the major hurdles in delivering drugs to the brain, has made it a promising drug delivery method for the treatment of primary brain tumors. A number of clinical trials utilizing CED of various therapeutic agents have been conducted to treat patients with supratentorial high-grade gliomas. Significant responses have been observed in certain patients in all of these trials. However, the insufficient ability to monitor drug distribution and pharmacokinetics hampers CED from achieving its potentials on a larger scale. Brainstem CED for diffuse intrinsic pontine glioma (DIPG) treatment is appealing because this tumor is compact and has no definitive treatment. The safety of brainstem CED has been established in small and large animals, and recently in early stage clinical trials. There are a few current clinical trials of brainstem CED in treating DIPG patients using targeted macromolecules such as antibodies and immunotoxins. Future advances for CED in DIPG treatment will come from several directions including: choosing the right agents for infusion; developing better agents and regimen for DIPG infusion; improving instruments and technique for easier and accurate surgical targeting and for allowing multisession or prolonged infusion to implement optimal time sequence; and better understanding and control of drug distribution, clearance and time sequence. CED-based therapies for DIPG will continue to evolve with new understanding of the technique and the disease.

  6. Production of pure quasi-monochromatic 11C beams for accurate radiation therapy and dose delivery verification

    NASA Astrophysics Data System (ADS)

    Lazzeroni, Marta; Brahme, Anders

    2015-09-01

    In the present study we develop a new technique for the production of clean quasi-monochromatic 11C positron emitter beams for accurate radiation therapy and PET-CT dose delivery imaging and treatment verification. The 11C ion beam is produced by projectile fragmentation using a primary 12C ion beam. The practical elimination of the energy spread of the secondary 11C fragments and other beam contaminating fragments is described. Monte Carlo calculation with the SHIELD-HIT10+ code and analytical methods for the transport of the ions in matter are used in the analysis. Production yields, as well as energy, velocity and magnetic rigidity distributions of the fragments generated in a cylindrical target are scored as a function of the depth within 1 cm thick slices for an optimal target consisting of a fixed 20 cm section of liquid hydrogen followed by a variable thickness section of polyethylene. The wide energy and magnetic rigidity spread of the 11C ion beam can be reduced to values around 1% by using a variable monochromatizing wedge-shaped degrader in the beam line. Finally, magnetic rigidity and particle species selection, as well as discrimination of the particle velocity through a combined Time of Flight and Radio Frequency-driven Velocity filter purify the beam from similar magnetic rigidity contaminating fragments (mainly 7Be and 3He fragments). A beam purity of about 99% is expected by the combined method.

  7. Screening with MRI for Accurate and Rapid Stroke Treatment

    PubMed Central

    Shah, Shreyansh; Luby, Marie; Poole, Karen; Morella, Teresa; Keller, Elizabeth; Benson, Richard T.; Lynch, John K.; Nadareishvili, Zurab

    2015-01-01

    Objective: The objective of this study was to demonstrate the feasibility of timely multimodal MRI screening before thrombolysis in acute stroke patients. Methods: Quality improvement processes were initiated in 2013 to reduce door-to-needle (DTN) time at the 2 hospitals where the NIH stroke team provides clinical care. Acute ischemic stroke (AIS) patients who received IV tissue plasminogen activator (tPA) ≤4.5 hours from last known normal were identified. Demographic and clinical characteristics and timing metrics were analyzed comparing the time periods before, during, and after the quality improvement processes. Results: There were 157 patients treated with IV tPA for AIS during 2012–2013, of whom 135 (86%) were screened with MRI. DTN time was significantly reduced by 40% during this period from a median of 93 minutes in the first half of 2012 to 55 minutes in the last half of 2013 (p < 0.0001) with a significant 4-fold increase in the proportion of treated patients with DTN time ≤60 minutes from 13.0% to 61.5%, respectively (p < 0.00001). Improvement in DTN time was associated with reduced door-to-MRI time, and there were no differences in demographic or clinical characteristics (p = 0.21–0.76). Conclusions: It is feasible and practical to consistently and rapidly deliver IV tPA to AIS patients within national benchmark times using MRI as the routine screening modality. The processes used in the SMART (Screening with MRI for Accurate and Rapid Stroke Treatment) Study to reduce DTN time have the potential to be widely applicable to other hospitals. PMID:25972494

  8. A novel sulfur mustard (HD) vapor inhalation exposure system for accurate inhaled dose delivery

    PubMed Central

    Perry, Mark R.; Benson, Eric M.; Kohne, Jonathon W.; Plahovinsak, Jennifer L.; Babin, Michael C.; Platoff, Gennady E.; Yeung, David T.

    2014-01-01

    Introduction A custom designed HD exposure system was used to deliver controlled inhaled doses to an animal model through an endotracheal tube. Methods Target HD vapor challenges were generated by a temperature controlled bubbler/aerosol trap, while concentration was monitored near real-time by gas chromatography. Animal breathing parameters were monitored real-time by an in-line pneumotach, pressure transducer, and Buxco pulmonary analysis computer/software. For each exposure, the challenge atmosphere was allowed to stabilize at the desired concentration while the anesthetized animal was provided humidity controlled clean air. Once the target concentration was achieved and stable, a portion of the challenge atmosphere was drawn past the endotracheal tube, where the animal inhaled the exposure ad libitum. During the exposure, HD vapor concentration and animal weight were used to calculate the needed inhaled volume to achieve the target inhaled dose (μg/kg). The exposures were halted when the inhaled volume was achieved. Results The exposure system successfully controlled HD concentrations from 22.2 to 278 mg/m3 and accurately delivered inhaled doses between 49.3 and 1120 μg/kg with actual administered doses being within 4% of the target level. Discussion This exposure system administers specific HD inhaled doses to evaluate physiological effects and for evaluation of potential medical countermeasure treatments. PMID:25291290

  9. Wind-tunnel tests and modeling indicate that aerial dispersant delivery operations are highly accurate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The United States Department of Agriculture’s high-speed wind tunnel facility in College Station, Texas, USA was used to determine droplet size distributions generated by dispersant delivery nozzles at wind speeds comparable to those used in aerial dispersant application. A laser particle size anal...

  10. Misoprostol vaginal insert for induction of labor: a delivery system with accurate dosing and rapid discontinuation.

    PubMed

    Stephenson, Megan L; Hawkins, J Seth; Powers, Barbara L; Wing, Deborah A

    2014-01-01

    Labor induction and cervical ripening are widely utilized and new methods are constantly being investigated. Prostaglandins have been shown to be effective labor induction agents and, in particular, were compared with other prostaglandin preparations; vaginal misoprostol used off-label was associated with reduced failure to achieve vaginal delivery. The challenge is to provide this medication with the correct dosing for this indication and with the ability to discontinue the medication if needed, all while ensuring essential maternal and neonatal safety. The misoprostol vaginal insert initiates cervical ripening using a delivery system that controls misoprostol release and can be rapidly removed. This article reviews the development, safety and efficacy of the misoprostol vaginal insert for induction of labor and cervical ripening, and will focus on vaginally administered prostaglandins.

  11. Accurate stone analysis: the impact on disease diagnosis and treatment.

    PubMed

    Mandel, Neil S; Mandel, Ian C; Kolbach-Mandel, Ann M

    2017-02-01

    This manuscript reviews the requirements for acceptable compositional analysis of kidney stones using various biophysical methods. High-resolution X-ray powder diffraction crystallography and Fourier transform infrared spectroscopy (FTIR) are the only acceptable methods in our labs for kidney stone analysis. The use of well-constructed spectral reference libraries is the basis for accurate and complete stone analysis. The literature included in this manuscript identify errors in most commercial laboratories and in some academic centers. We provide personal comments on why such errors are occurring at such high rates, and although the work load is rather large, it is very worthwhile in providing accurate stone compositions. We also provide the results of our almost 90,000 stone analyses and a breakdown of the number of components we have observed in the various stones. We also offer advice on determining the method used by the various FTIR equipment manufacturers who also provide a stone analysis library so that the FTIR users can feel comfortable in the accuracy of their reported results. Such an analysis on the accuracy of the individual reference libraries could positively influence the reduction in their respective error rates.

  12. Clinical Considerations of Focal Drug Delivery In Cancer Treatment.

    PubMed

    Harris, Jamie; Chiu, Bill

    2017-02-24

    According to the US Center for Disease Control, cancer deaths are the second most common cause of mortality in both adults and children. Definitive treatment of solid tumors involves surgical resection with or without systemic chemotherapy and radiation. The advent of local drug delivery presents a unique treatment modality that can offer substantial benefits in cancer management. Local drug delivery offers targeted drug delivery to cancer tissues while minimizing side effects of the medications. Three main phases in solid tumor management exist for the treating physician: initial diagnosis with tissue biopsy, surgical resection with or without chemotherapy, and management of metastatic disease. Image guided studies, using modalities such as MRI, computerized tomography, and ultrasound to sample tumors have been described. The initial diagnosis phase offers a treatment window for local drug delivery with the aid of image guidance. After the diagnosis of malignancy is made, surgical resection can become an important part of tumor management. Currently, FDA approved local drug delivery systems are being used in concert with resection for intracranial glioma. Many other applications of implantation of local drug delivery at the time of surgery in other tumors, including breast and neuroblastoma, are being investigated. Finally, for patients who present with or progress to single sites of metastatic disease, such as brain or liver metastasis, studies have shown potential applications for local drug delivery as well. This review will discuss the current state of local drug delivery in the treatment of solid tumors and possible future directions.

  13. Quality Control of High-Dose-Rate Brachytherapy: Treatment Delivery Analysis Using Statistical Process Control

    SciTech Connect

    Able, Charles M.; Bright, Megan; Frizzell, Bart

    2013-03-01

    Purpose: Statistical process control (SPC) is a quality control method used to ensure that a process is well controlled and operates with little variation. This study determined whether SPC was a viable technique for evaluating the proper operation of a high-dose-rate (HDR) brachytherapy treatment delivery system. Methods and Materials: A surrogate prostate patient was developed using Vyse ordnance gelatin. A total of 10 metal oxide semiconductor field-effect transistors (MOSFETs) were placed from prostate base to apex. Computed tomography guidance was used to accurately position the first detector in each train at the base. The plan consisted of 12 needles with 129 dwell positions delivering a prescribed peripheral dose of 200 cGy. Sixteen accurate treatment trials were delivered as planned. Subsequently, a number of treatments were delivered with errors introduced, including wrong patient, wrong source calibration, wrong connection sequence, single needle displaced inferiorly 5 mm, and entire implant displaced 2 mm and 4 mm inferiorly. Two process behavior charts (PBC), an individual and a moving range chart, were developed for each dosimeter location. Results: There were 4 false positives resulting from 160 measurements from 16 accurately delivered treatments. For the inaccurately delivered treatments, the PBC indicated that measurements made at the periphery and apex (regions of high-dose gradient) were much more sensitive to treatment delivery errors. All errors introduced were correctly identified by either the individual or the moving range PBC in the apex region. Measurements at the urethra and base were less sensitive to errors. Conclusions: SPC is a viable method for assessing the quality of HDR treatment delivery. Further development is necessary to determine the most effective dose sampling, to ensure reproducible evaluation of treatment delivery accuracy.

  14. Gastroretentive drug delivery systems for the treatment of Helicobacter pylori.

    PubMed

    Zhao, Shan; Lv, Yan; Zhang, Jian-Bin; Wang, Bing; Lv, Guo-Jun; Ma, Xiao-Jun

    2014-07-28

    Helicobacter pylori (H. pylori) is one of the most common pathogenic bacterial infections and is found in the stomachs of approximately half of the world's population. It is the primary known cause of gastritis, gastroduodenal ulcer disease and gastric cancer. However, combined drug therapy as the general treatment in the clinic, the rise of antibiotic-resistant bacteria, adverse reactions and poor patient compliance are major obstacles to the eradication of H. pylori. Oral site-specific drug delivery systems that could increase the longevity of the treatment agent at the target site might improve the therapeutic effect and avoid side effects. Gastroretentive drug delivery systems potentially prolong the gastric retention time and controlled/sustained release of a drug, thereby increasing the concentration of the drug at the application site, potentially improving its bioavailability and reducing the necessary dosage. Recommended gastroretentive drug delivery systems for enhancing local drug delivery include floating systems, bioadhesive systems and expandable systems. In this review, we summarize the important physiological parameters of the gastrointestinal tract that affect the gastric residence time. We then focus on various aspects useful in the development of gastroretentive drug delivery systems, including current trends and the progress of novel forms, especially with respect to their application for the treatment of H. pylori infections.

  15. Gastroretentive drug delivery systems for the treatment of Helicobacter pylori

    PubMed Central

    Zhao, Shan; Lv, Yan; Zhang, Jian-Bin; Wang, Bing; Lv, Guo-Jun; Ma, Xiao-Jun

    2014-01-01

    Helicobacter pylori (H. pylori) is one of the most common pathogenic bacterial infections and is found in the stomachs of approximately half of the world’s population. It is the primary known cause of gastritis, gastroduodenal ulcer disease and gastric cancer. However, combined drug therapy as the general treatment in the clinic, the rise of antibiotic-resistant bacteria, adverse reactions and poor patient compliance are major obstacles to the eradication of H. pylori. Oral site-specific drug delivery systems that could increase the longevity of the treatment agent at the target site might improve the therapeutic effect and avoid side effects. Gastroretentive drug delivery systems potentially prolong the gastric retention time and controlled/sustained release of a drug, thereby increasing the concentration of the drug at the application site, potentially improving its bioavailability and reducing the necessary dosage. Recommended gastroretentive drug delivery systems for enhancing local drug delivery include floating systems, bioadhesive systems and expandable systems. In this review, we summarize the important physiological parameters of the gastrointestinal tract that affect the gastric residence time. We then focus on various aspects useful in the development of gastroretentive drug delivery systems, including current trends and the progress of novel forms, especially with respect to their application for the treatment of H. pylori infections. PMID:25071326

  16. Enhanced skin delivery of vismodegib by microneedle treatment.

    PubMed

    Nguyen, Hiep X; Banga, Ajay K

    2015-08-01

    The present study investigated the effects of microneedle treatment (maltose microneedles, Admin Pen™ 1200, and Admin Pen™ 1500) on in vitro transdermal delivery of vismodegib with different needle lengths, skin equilibration times, and microneedle insertion durations. The influence of microneedle treatment on the dimensions of microchannels (dye binding, calcein imaging, histology, and confocal microscopy studies), transepidermal water loss, and skin permeability of vismodegib was also evaluated. Skin viscoelasticity was assessed using a rheometer, and microneedle geometry was characterized by scanning electron microscopy. Permeation studies of vismodegib through dermatomed porcine ear skin were conducted using vertical Franz diffusion cells. Skin irritation potential of vismodegib formulation was assessed using an in vitro reconstructed human epidermis model. Results of the in vitro permeation studies revealed significant enhancement in permeation of vismodegib through microneedle-treated skin. As the needle length increased from 500 to 1100 and 1400 μm, drug delivery increased from 14.50 ± 2.35 to 32.38 ± 3.33 and 74.40 ± 15.86 μg/cm(2), respectively. Positive correlation between drug permeability and microneedle treatment duration was observed. The equilibration time was also found to affect the delivery of vismodegib. Thus, changes in microneedle length, equilibration time, and duration of treatment altered transdermal delivery of vismodegib.

  17. Carrier-Based Drug Delivery System for Treatment of Acne

    PubMed Central

    Vyas, Amber; Kumar Sonker, Avinesh

    2014-01-01

    Approximately 95% of the population suffers at some point in their lifetime from acne vulgaris. Acne is a multifactorial disease of the pilosebaceous unit. This inflammatory skin disorder is most common in adolescents but also affects neonates, prepubescent children, and adults. Topical conventional systems are associated with various side effects. Novel drug delivery systems have been used to reduce the side effect of drugs commonly used in the topical treatment of acne. Topical treatment of acne with active pharmaceutical ingredients (API) makes direct contact with the target site before entering the systemic circulation which reduces the systemic side effect of the parenteral or oral administration of drug. The objective of the present review is to discuss the conventional delivery systems available for acne, their drawbacks, and limitations. The advantages, disadvantages, and outcome of using various carrier-based delivery systems like liposomes, niosomes, solid lipid nanoparticles, and so forth, are explained. This paper emphasizes approaches to overcome the drawbacks and limitations associated with the conventional system and the advances and application that are poised to further enhance the efficacy of topical acne formulations, offering the possibility of simplified dosing regimen that may improve treatment outcomes using novel delivery system. PMID:24688376

  18. Drug delivery implants in the treatment of vitreous inflammation.

    PubMed

    Wang, Jillian; Jiang, Angela; Joshi, Malav; Christoforidis, John

    2013-01-01

    The eye is a model organ for the local delivery of therapeutics. This proves beneficial when treating vitreous inflammation and other ophthalmic pathologies. The chronicity of certain diseases, however, limits the effectiveness of locally administered drugs. To maintain such treatments often requires frequent office visits and can result in increased risk of infection and toxicity to the patient. This paper focuses on the implantable devices and particulate drug delivery systems that are currently being implemented and investigated to overcome these challenges. Implants currently on the market or undergoing clinical trials include those made of nonbiodegradable polymers, containing ganciclovir, fluocinolone acetonide, triamcinolone acetonide, and ranibizumab, and biodegradable polymers, containing dexamethasone, triamcinolone acetonide, and ranibizumab. Investigational intravitreal implants and particulate drug delivery systems, such as nanoparticles, microparticles, and liposomes, are also explored in this review article.

  19. Drug Delivery Implants in the Treatment of Vitreous Inflammation

    PubMed Central

    Wang, Jillian; Jiang, Angela; Joshi, Malav; Christoforidis, John

    2013-01-01

    The eye is a model organ for the local delivery of therapeutics. This proves beneficial when treating vitreous inflammation and other ophthalmic pathologies. The chronicity of certain diseases, however, limits the effectiveness of locally administered drugs. To maintain such treatments often requires frequent office visits and can result in increased risk of infection and toxicity to the patient. This paper focuses on the implantable devices and particulate drug delivery systems that are currently being implemented and investigated to overcome these challenges. Implants currently on the market or undergoing clinical trials include those made of nonbiodegradable polymers, containing ganciclovir, fluocinolone acetonide, triamcinolone acetonide, and ranibizumab, and biodegradable polymers, containing dexamethasone, triamcinolone acetonide, and ranibizumab. Investigational intravitreal implants and particulate drug delivery systems, such as nanoparticles, microparticles, and liposomes, are also explored in this review article. PMID:24191132

  20. Convection-enhanced delivery for the treatment of glioblastoma.

    PubMed

    Vogelbaum, Michael A; Aghi, Manish K

    2015-03-01

    Effective treatment of glioblastoma (GBM) remains a formidable challenge. Survival rates remain poor despite decades of clinical trials of conventional and novel, biologically targeted therapeutics. There is considerable evidence that most of these therapeutics do not reach their targets in the brain when administered via conventional routes (intravenous or oral). Hence, direct delivery of therapeutics to the brain and to brain tumors is an active area of investigation. One of these techniques, convection-enhanced delivery (CED), involves the implantation of catheters through which conventional and novel therapeutic formulations can be delivered using continuous, low-positive-pressure bulk flow. Investigation in preclinical and clinical settings has demonstrated that CED can produce effective delivery of therapeutics to substantial volumes of brain and brain tumor. However, limitations in catheter technology and imaging of delivery have prevented this technique from being reliable and reproducible, and the only completed phase III study in GBM did not show a survival benefit for patients treated with an investigational therapeutic delivered via CED. Further development of CED is ongoing, with novel catheter designs and imaging approaches that may allow CED to become a more effective therapeutic delivery technique.

  1. Intranasal delivery of antiepileptic medications for treatment of seizures.

    PubMed

    Wermeling, Daniel P

    2009-04-01

    Acute isolated seizure, repetitive or recurrent seizures, and status epilepticus are all deemed medical emergencies. Mortality and worse neurologic outcome are directly associated with the duration of seizure activity. A number of recent reviews have described consensus statements regarding the pharmacologic treatment protocols for seizures when patients are in pre-hospital, institutional, and home-bound settings. Benzodiazepines, such as lorazepam, diazepam, midazolam, and clonazepam are considered to be medications of first choice. The rapidity by which a medication can be delivered to the systemic circulation and then to the brain plays a significant role in reducing the time needed to treat seizures and reduce opportunity for damage to the CNS. Speed of delivery, particularly outside of the hospital, is enhanced when transmucosal routes of delivery are used in place of an intravenous injection. Intranasal transmucosal delivery of benzodiazepines is useful in reducing time to drug administration and cessation of seizures in the pre-hospital setting, when actively seizing patients arrive in the emergency room, and at home where caregivers treat their dependents. This review summarizes factors to consider when choosing a benzodiazepine for intranasal administration, including formulation and device considerations, pharmacology and pharmacokinetic/pharmacodynamic profiles. A review of the most relevant clinical studies in epilepsy patients will provide context for the relative success of this technique with a number of benzodiazepines and relatively less sophisticated nasal preparations. Neuropeptides delivered intranasally, crossing the blood-brain barrier via the olfactory system, may increase the availability of medications for treatment of epilepsy. Consequently, there remains a significant unmet medical need to serve the pharamcotherapeutic requirements of epilepsy patients through commercial development and marketing of intranasal antiepileptic products.

  2. Genital herpes and its treatment in relation to preterm delivery.

    PubMed

    Li, De-Kun; Raebel, Marsha A; Cheetham, T Craig; Hansen, Craig; Avalos, Lyndsay; Chen, Hong; Davis, Robert

    2014-12-01

    To examine the risks of genital herpes and antiherpes treatment during pregnancy in relation to preterm delivery (PTD), we conducted a multicenter, member-based cohort study within 4 Kaiser Permanente regions: northern and southern California, Colorado, and Georgia. The study included 662,913 mother-newborn pairs from 1997 to 2010. Pregnant women were classified into 3 groups based on genital herpes diagnosis and treatment: genital herpes without treatment, genital herpes with antiherpes treatment, and no herpes diagnosis or treatment (unexposed controls). After controlling for potential confounders, we found that compared with being unexposed, having untreated genital herpes during first or second trimester was associated with more than double the risk of PTD (odds ratio (OR) = 2.23, 95% confidence interval (CI): 1.80, 2.76). The association was stronger for PTD due to premature rupture of membrane (OR = 3.57, 95% CI: 2.53, 5.06) and for early PTD (≤35 weeks gestation) (OR = 2.87, 95% CI: 2.22, 3.71). In contrast, undergoing antiherpes treatment during pregnancy was associated with a lower risk of PTD compared with not being treated, and the PTD risk was similar to that observed in the unexposed controls (OR = 1.11, 95% CI: 0.89, 1.38). The present study revealed increased risk of PTD associated with genital herpes infection if left untreated and a potential benefit of antiherpes medications in mitigating the effect of genital herpes infection on the risk of PTD.

  3. Can radiation therapy treatment planning system accurately predict surface doses in postmastectomy radiation therapy patients?

    SciTech Connect

    Wong, Sharon; Back, Michael; Tan, Poh Wee; Lee, Khai Mun; Baggarley, Shaun; Lu, Jaide Jay

    2012-07-01

    Skin doses have been an important factor in the dose prescription for breast radiotherapy. Recent advances in radiotherapy treatment techniques, such as intensity-modulated radiation therapy (IMRT) and new treatment schemes such as hypofractionated breast therapy have made the precise determination of the surface dose necessary. Detailed information of the dose at various depths of the skin is also critical in designing new treatment strategies. The purpose of this work was to assess the accuracy of surface dose calculation by a clinically used treatment planning system and those measured by thermoluminescence dosimeters (TLDs) in a customized chest wall phantom. This study involved the construction of a chest wall phantom for skin dose assessment. Seven TLDs were distributed throughout each right chest wall phantom to give adequate representation of measured radiation doses. Point doses from the CMS Xio Registered-Sign treatment planning system (TPS) were calculated for each relevant TLD positions and results correlated. There were no significant difference between measured absorbed dose by TLD and calculated doses by the TPS (p > 0.05 (1-tailed). Dose accuracy of up to 2.21% was found. The deviations from the calculated absorbed doses were overall larger (3.4%) when wedges and bolus were used. 3D radiotherapy TPS is a useful and accurate tool to assess the accuracy of surface dose. Our studies have shown that radiation treatment accuracy expressed as a comparison between calculated doses (by TPS) and measured doses (by TLD dosimetry) can be accurately predicted for tangential treatment of the chest wall after mastectomy.

  4. Dosimetric Impact of Interplay Effect on RapidArc Lung Stereotactic Treatment Delivery

    SciTech Connect

    Ong, Chin Loon; Verbakel, Wilko F.A.R.; Cuijpers, Johan P.; Slotman, Ben J.; Senan, Suresh

    2011-01-01

    Purpose: Volumetric modulated arc therapy (RapidArc; Varian Medical Systems, Palo Alto, CA) allows fast delivery of stereotactic radiotherapy for Stage I lung tumors. We investigated discrepancies between the calculated and delivered dose distributions, as well as the dosimetric impact of leaf interplay with breathing-induced tumor motion. Methods and Materials: In 20 consecutive patients with Stage I lung cancer who completed RapidArc delivery, 15 had tumor motion exceeding 5 mm on four-dimensional computed tomography scan. Static and dynamic measurements were performed with Gafchromic EBT film (International Specialty Products Inc., Wayne, NJ) in a Quasar motion phantom (Modus Medical Devices, London, Ontario, Canada). Static measurements were compared with calculated dose distributions, and dynamic measurements were compared with the convolution of static measurements with sinusoidal motion patterns. Besides clinical treatment plans, additional cases were optimized to create excessive multileaf collimator modulation and delivered on the phantom with peak-to-peak motions of up to 25 mm. {gamma} Analysis with a 3% dose difference and 2- or 1-mm distance to agreement was used to evaluate the accuracy of delivery and the dosimetric impact of the interplay effect. Results: In static mode film dosimetry of the two-arc delivery in the phantom showed that, on average, fewer than 3% of measurements had {gamma} greater than 1. Dynamic measurements of clinical plans showed a high degree of agreement with the convolutions: for double-arc plans, 99.5% met the {gamma} criterion. The degree of agreement was 98.5% for the plans with excessive multileaf collimator modulations and 25 mm of motion. Conclusions: Film dosimetry shows that RapidArc accurately delivers the calculated dose distribution and that interplay between leaves and tumor motion is not significant for single-fraction treatments when RapidArc is delivered with two different arcs.

  5. A system for EPID-based real-time treatment delivery verification during dynamic IMRT treatment

    SciTech Connect

    Fuangrod, Todsaporn; Woodruff, Henry C.; O’Connor, Daryl J.; Uytven, Eric van; McCurdy, Boyd M. C.; Kuncic, Zdenka; Greer, Peter B.

    2013-09-15

    Purpose: To design and develop a real-time electronic portal imaging device (EPID)-based delivery verification system for dynamic intensity modulated radiation therapy (IMRT) which enables detection of gross treatment delivery errors before delivery of substantial radiation to the patient.Methods: The system utilizes a comprehensive physics-based model to generate a series of predicted transit EPID image frames as a reference dataset and compares these to measured EPID frames acquired during treatment. The two datasets are using MLC aperture comparison and cumulative signal checking techniques. The system operation in real-time was simulated offline using previously acquired images for 19 IMRT patient deliveries with both frame-by-frame comparison and cumulative frame comparison. Simulated error case studies were used to demonstrate the system sensitivity and performance.Results: The accuracy of the synchronization method was shown to agree within two control points which corresponds to approximately ∼1% of the total MU to be delivered for dynamic IMRT. The system achieved mean real-time gamma results for frame-by-frame analysis of 86.6% and 89.0% for 3%, 3 mm and 4%, 4 mm criteria, respectively, and 97.9% and 98.6% for cumulative gamma analysis. The system can detect a 10% MU error using 3%, 3 mm criteria within approximately 10 s. The EPID-based real-time delivery verification system successfully detected simulated gross errors introduced into patient plan deliveries in near real-time (within 0.1 s).Conclusions: A real-time radiation delivery verification system for dynamic IMRT has been demonstrated that is designed to prevent major mistreatments in modern radiation therapy.

  6. Fast and accurate sensitivity analysis of IMPT treatment plans using Polynomial Chaos Expansion

    NASA Astrophysics Data System (ADS)

    Perkó, Zoltán; van der Voort, Sebastian R.; van de Water, Steven; Hartman, Charlotte M. H.; Hoogeman, Mischa; Lathouwers, Danny

    2016-06-01

    The highly conformal planned dose distribution achievable in intensity modulated proton therapy (IMPT) can severely be compromised by uncertainties in patient setup and proton range. While several robust optimization approaches have been presented to address this issue, appropriate methods to accurately estimate the robustness of treatment plans are still lacking. To fill this gap we present Polynomial Chaos Expansion (PCE) techniques which are easily applicable and create a meta-model of the dose engine by approximating the dose in every voxel with multidimensional polynomials. This Polynomial Chaos (PC) model can be built in an automated fashion relatively cheaply and subsequently it can be used to perform comprehensive robustness analysis. We adapted PC to provide among others the expected dose, the dose variance, accurate probability distribution of dose-volume histogram (DVH) metrics (e.g. minimum tumor or maximum organ dose), exact bandwidths of DVHs, and to separate the effects of random and systematic errors. We present the outcome of our verification experiments based on 6 head-and-neck (HN) patients, and exemplify the usefulness of PCE by comparing a robust and a non-robust treatment plan for a selected HN case. The results suggest that PCE is highly valuable for both research and clinical applications.

  7. Fast and accurate sensitivity analysis of IMPT treatment plans using Polynomial Chaos Expansion.

    PubMed

    Perkó, Zoltán; van der Voort, Sebastian R; van de Water, Steven; Hartman, Charlotte M H; Hoogeman, Mischa; Lathouwers, Danny

    2016-06-21

    The highly conformal planned dose distribution achievable in intensity modulated proton therapy (IMPT) can severely be compromised by uncertainties in patient setup and proton range. While several robust optimization approaches have been presented to address this issue, appropriate methods to accurately estimate the robustness of treatment plans are still lacking. To fill this gap we present Polynomial Chaos Expansion (PCE) techniques which are easily applicable and create a meta-model of the dose engine by approximating the dose in every voxel with multidimensional polynomials. This Polynomial Chaos (PC) model can be built in an automated fashion relatively cheaply and subsequently it can be used to perform comprehensive robustness analysis. We adapted PC to provide among others the expected dose, the dose variance, accurate probability distribution of dose-volume histogram (DVH) metrics (e.g. minimum tumor or maximum organ dose), exact bandwidths of DVHs, and to separate the effects of random and systematic errors. We present the outcome of our verification experiments based on 6 head-and-neck (HN) patients, and exemplify the usefulness of PCE by comparing a robust and a non-robust treatment plan for a selected HN case. The results suggest that PCE is highly valuable for both research and clinical applications.

  8. Radiation dose delivery verification in the treatment of carcinoma-cervix

    NASA Astrophysics Data System (ADS)

    Shrotriya, D.; Kumar, S.; Srivastava, R. N. L.

    2015-06-01

    The accurate dose delivery to the clinical target volume in radiotherapy can be affected by various pelvic tissues heterogeneities. An in-house heterogeneous woman pelvic phantom was designed and used to verify the consistency and computational capability of treatment planning system of radiation dose delivery in the treatment of cancer cervix. Oncentra 3D-TPS with collapsed cone convolution (CCC) dose calculation algorithm was used to generate AP/PA and box field technique plan. the radiation dose was delivered by Primus Linac (Siemens make) employing high energy 15 MV photon beam by isocenter technique. A PTW make, 0.125cc ionization chamber was used for direct measurements at various reference points in cervix, bladder and rectum. The study revealed that maximum variation between computed and measured dose at cervix reference point was 1% in both the techniques and 3% and 4% variation in AP/PA field and 5% and 4.5% in box technique at bladder and rectum points respectively.

  9. Radiation dose delivery verification in the treatment of carcinoma-cervix

    SciTech Connect

    Shrotriya, D. Srivastava, R. N. L.; Kumar, S.

    2015-06-24

    The accurate dose delivery to the clinical target volume in radiotherapy can be affected by various pelvic tissues heterogeneities. An in-house heterogeneous woman pelvic phantom was designed and used to verify the consistency and computational capability of treatment planning system of radiation dose delivery in the treatment of cancer cervix. Oncentra 3D-TPS with collapsed cone convolution (CCC) dose calculation algorithm was used to generate AP/PA and box field technique plan. the radiation dose was delivered by Primus Linac (Siemens make) employing high energy 15 MV photon beam by isocenter technique. A PTW make, 0.125cc ionization chamber was used for direct measurements at various reference points in cervix, bladder and rectum. The study revealed that maximum variation between computed and measured dose at cervix reference point was 1% in both the techniques and 3% and 4% variation in AP/PA field and 5% and 4.5% in box technique at bladder and rectum points respectively.

  10. [Treatment of rheumatic diseases with intraarticular drug delivery systems].

    PubMed

    Szabó, Andrea; Zelkó, Romána; Antal, István

    2011-01-01

    Present work provides an overall study about the types and the medicinal treatment of the rheumatic diseases especially the intraarticular formulations. Due to the localized nature of the joint, intraarticular injections are very favourable drug delivery systems. It has a big advantage over the oral medication; the systemic side effects are kept away. The review shows two types of the rheumatic diseases on the example of the healthy joint: the joint damage (osteoarthritis) and the inflamed joint (rheumatoid arthritis). There are many active ingredients for the treatment of the rheumatic diseases but the number of the intraarticular products is limited. At present are only formulations with hyaluronic acid or glucocorticoid on the market. Several physiological and biopharmaceutical aspects must be considered for the design of intraarticular injections. During and after the production many quality requirements have to be complied. On the market the formulations in solution or in suspension are available, which provide a short-term effect. The aim of the developments is to achieve long-term effect based on nano- or microparticles.

  11. Accurate and general treatment of electrostatic interaction in Hamiltonian adaptive resolution simulations

    NASA Astrophysics Data System (ADS)

    Heidari, M.; Cortes-Huerto, R.; Donadio, D.; Potestio, R.

    2016-10-01

    In adaptive resolution simulations the same system is concurrently modeled with different resolution in different subdomains of the simulation box, thereby enabling an accurate description in a small but relevant region, while the rest is treated with a computationally parsimonious model. In this framework, electrostatic interaction, whose accurate treatment is a crucial aspect in the realistic modeling of soft matter and biological systems, represents a particularly acute problem due to the intrinsic long-range nature of Coulomb potential. In the present work we propose and validate the usage of a short-range modification of Coulomb potential, the Damped shifted force (DSF) model, in the context of the Hamiltonian adaptive resolution simulation (H-AdResS) scheme. This approach, which is here validated on bulk water, ensures a reliable reproduction of the structural and dynamical properties of the liquid, and enables a seamless embedding in the H-AdResS framework. The resulting dual-resolution setup is implemented in the LAMMPS simulation package, and its customized version employed in the present work is made publicly available.

  12. Intramolecular hydrogen migration in alkylperoxy and hydroperoxyalkylperoxy radicals: accurate treatment of hindered rotors.

    PubMed

    Sharma, Sandeep; Raman, Sumathy; Green, William H

    2010-05-13

    We have calculated the thermochemistry and rate coefficients for stable molecules and reactions in the title reaction families using CBS-QB3 and B3LYP/CBSB7 methods. The accurate treatment of hindered rotors for molecules having multiple internal rotors with potentials that are not independent of each other can be problematic, and a simplified scheme is suggested to treat them. This is particularly important for hydroperoxyalkylperoxy radicals (HOOQOO). Two new thermochemical group values are suggested in this paper, and with these values, the group additivity method for calculation of enthalpy as implemented in reaction mechanism generator (RMG) gives good agreement with CBS-QB3 predictions. The barrier heights follow the Evans-Polanyi relationship for each type of intramolecular hydrogen migration reaction studied.

  13. Drug Delivery Approaches for the Treatment of Cervical Cancer

    PubMed Central

    Ordikhani, Farideh; Erdem Arslan, Mustafa; Marcelo, Raymundo; Sahin, Ilyas; Grigsby, Perry; Schwarz, Julie K.; Azab, Abdel Kareem

    2016-01-01

    Cervical cancer is a highly prevalent cancer that affects women around the world. With the availability of new technologies, researchers have increased their efforts to develop new drug delivery systems in cervical cancer chemotherapy. In this review, we summarized some of the recent research in systematic and localized drug delivery systems and compared the advantages and disadvantages of these methods. PMID:27447664

  14. Passive flow regulators for drug delivery and hydrocephalus treatment

    NASA Astrophysics Data System (ADS)

    Chappel, E.; Dumont-Fillon, D.; Mefti, S.

    2014-03-01

    Passive flow regulators are usually intended to deliver or drain a fluid at a constant rate independently from pressure variations. New designs of passive flow regulators made of a stack of a silicon membrane anodically bonded to a Pyrex substrate are proposed. A first design has been built for the derivation of cerebrospinal fluid (CSF) towards peritoneum for hydrocephalus treatment. The device allows draining CSF at the patient production rate independently from postural changes. The flow rate is regulated at 20 ml/h in the range 10 to 40 mbar. Specific features to adjust in vivo the nominal flow rate are shown. A second design including high pressure shut-off feature has been made. The intended use is drug delivery with pressurized reservoir of typically 100 to 300 mbar. In both cases, the membrane comprises several holes facing pillars in the Pyrex substrate. These pillars are machined in a cavity which ensures a gap between the membrane and the pillars at rest. The fluid in the pressurized reservoir is directly in contact with the top surface of the membrane, inducing its deflection towards Pyrex substrate and closing progressively the fluidic pathway through each hole of the membrane. Since the membrane deflection is highly non-linear, FEM simulations have been performed to determine both radial position and diameter of the membrane holes that ensure a constant flow rate for a given range of pressure.

  15. SU-E-T-250: Determining VMAT Machine Limitations of An Elekta Linear Accelerator with Agility MLC for Accurate Modeling in RayStation and Robust Delivery

    SciTech Connect

    Yang, K; Yu, Z; Chen, H; Mourtada, F

    2015-06-15

    Purpose: To implement VMAT in RayStation with the Elekta Synergy linac with the new Agility MLC, and to utilize the same vendor softwares to determine the optimum Elekta VMAT machine parameters in RayStation for accurate modeling and robust delivery. Methods: iCOMCat is utilized to create various beam patterns with user defined dose rate, gantry, MLC and jaw speed for each control point. The accuracy and stability of the output and beam profile are qualified for each isolated functional component of VMAT delivery using ion chamber and Profiler2 with isocentric mounting fixture. Service graphing on linac console is used to verify the mechanical motion accuracy. The determined optimum Elekta VMAT machine parameters were configured in RayStation v4.5.1. To evaluate the system overall performance, TG-119 test cases and nine retrospective VMAT patients were planned on RayStation, and validated using both ArcCHECK (with plug and ion chamber) and MapCHECK2. Results: Machine output and profile varies <0.3% when only variable is dose rate (35MU/min-600MU/min). <0.9% output and <0.3% profile variation are observed with additional gantry motion (0.53deg/s–5.8deg/s both directions). The output and profile variation are still <1% with additional slow leaf motion (<1.5cm/s both direction). However, the profile becomes less symmetric, and >1.5% output and 7% profile deviation is seen with >2.5cm/s leaf motion. All clinical cases achieved comparable plan quality as treated IMRT plans. The gamma passing rate is 99.5±0.5% on ArcCheck (<3% iso center dose deviation) and 99.1±0.8% on MapCheck2 using 3%/3mm gamma (10% lower threshold). Mechanical motion accuracy in all VMAT deliveries is <1°/1mm. Conclusion: Accurate RayStation modeling and robust VMAT delivery is achievable on Elekta Agility for <2.5cm/s leaf motion and full range of dose rate and gantry speed determined by the same vendor softwares. Our TG-119 and patient results have provided us with the confidence to use VMAT

  16. Ultrasonic-Activated Micellar Drug Delivery for Cancer Treatment

    PubMed Central

    Husseini, Ghaleb A.; Pitt, William G.

    2008-01-01

    The use of nanoparticles and ultrasound in medicine continues to evolve. Great strides have been made in the areas of producing micelles, nanoemulsions and solid nanoparticles that can be used in drug delivery. An effective nanocarrier allows for the delivery of a high concentration of potent medications to targeted tissue while minimizing the side effect of the agent to the rest of the body. Polymeric micelles have been shown to encapsulate therapeutic agents and maintain their structural integrity at lower concentrations. Ultrasound is currently being used in drug delivery as well as diagnostics, and has many advantages that elevate its importance in drug delivery. The technique is non-invasive, thus no surgery is needed; the ultrasonic waves can be easily controlled by advanced electronic technology so that they can be focused on the desired target volume. Additionally, the physics of ultrasound are widely used and well understood; thus ultrasonic application can be tailored towards a particular drug delivery system. In this article, we review the recent progress made in research that utilizes both polymeric micelles and ultrasonic power in drug delivery. PMID:18506804

  17. Health literacy in HIV treatment: accurate understanding of key biological treatment principles is not required for good ART adherence.

    PubMed

    Laws, M Barton; Danielewicz, Michael; Rana, Aadia; Kogelman, Laura; Wilson, Ira B

    2015-04-01

    Findings on the relationship between health literacy and outcomes in HIV have been inconsistent. Health literacy has previously been operationalized as general functional literacy, but has not included content knowledge about HIV disease and treatment. Semi-structured interviews with people living with HIV in 2 U.S. cities, including questions about the etiology, pathophysiology and treatment of HIV. We compared responses to biomedical conceptions. The 32 respondents were demographically diverse. Although most understood that HIV degrades the immune system, none could explain the nature of a virus, or the mechanism of antiretroviral (ARV) drug action. Fewer than half accurately reported that it is desirable to have a high CD4+ cell count and low viral load. A minority understood the concept of drug resistance. While most believed that strict adherence to ARV regimens was important to maintain health, three believed that periodic treatment interruption was beneficial, and three believed they should not take ARVs when they used alcohol or illicit drugs. Respondents generally had very limited, and often inaccurate biomedical understanding of HIV disease. Most reported good regimen adherence but did not have any mechanistic rationale for it. The failure to find a consistent relationship between health literacy and ARV adherence may be largely because most people simply follow their doctors' instructions, without the need for deep understanding.

  18. Health Literacy in HIV Treatment: Accurate Understanding of Key Biological Treatment Principles is Not Required for Good ART Adherence

    PubMed Central

    Laws, M. Barton; Danielewicz, Michael; Rana, Aadia; Kogelman, Laura; Wilson, Ira B.

    2016-01-01

    Findings on the relationship between health literacy and outcomes in HIV have been inconsistent. Health literacy has previously been operationalized as general functional literacy, but has not included content knowledge about HIV disease and treatment. Semi-structured interviews with people living with HIV in 2 U.S. cities, including questions about the etiology, pathophysiology and treatment of HIV. We compared responses to biomedical conceptions. The 32 respondents were demographically diverse. Although most understood that HIV degrades the immune system, none could explain the nature of a virus, or the mechanism of antiretroviral (ARV) drug action. Fewer than half accurately reported that it is desirable to have a high CD4+ cell count and low viral load. A minority understood the concept of drug resistance. While most believed that strict adherence to ARV regimens was important to maintain health, three believed that periodic treatment interruption was beneficial, and three believed they should not take ARVs when they used alcohol or illicit drugs. Respondents generally had very limited, and often inaccurate biomedical understanding of HIV disease. Most reported good regimen adherence but did not have any mechanistic rationale for it. The failure to find a consistent relationship between health literacy and ARV adherence may be largely because most people simply follow their doctors’ instructions, without the need for deep understanding. PMID:25354736

  19. CPR methodology with new steady-state criterion and more accurate statistical treatment of channel bow

    SciTech Connect

    Baumgartner, S.; Bieli, R.; Bergmann, U. C.

    2012-07-01

    An overview is given of existing CPR design criteria and the methods used in BWR reload analysis to evaluate the impact of channel bow on CPR margins. Potential weaknesses in today's methodologies are discussed. Westinghouse in collaboration with KKL and Axpo - operator and owner of the Leibstadt NPP - has developed an optimized CPR methodology based on a new criterion to protect against dryout during normal operation and with a more rigorous treatment of channel bow. The new steady-state criterion is expressed in terms of an upper limit of 0.01 for the dryout failure probability per year. This is considered a meaningful and appropriate criterion that can be directly related to the probabilistic criteria set-up for the analyses of Anticipated Operation Occurrences (AOOs) and accidents. In the Monte Carlo approach a statistical modeling of channel bow and an accurate evaluation of CPR response functions allow the associated CPR penalties to be included directly in the plant SLMCPR and OLMCPR in a best-estimate manner. In this way, the treatment of channel bow is equivalent to all other uncertainties affecting CPR. Emphasis is put on quantifying the statistical distribution of channel bow throughout the core using measurement data. The optimized CPR methodology has been implemented in the Westinghouse Monte Carlo code, McSLAP. The methodology improves the quality of dryout safety assessments by supplying more valuable information and better control of conservatisms in establishing operational limits for CPR. The methodology is demonstrated with application examples from the introduction at KKL. (authors)

  20. A New Method for Accurate Treatment of Flow Equations in Cylindrical Coordinates Using Series Expansions

    NASA Technical Reports Server (NTRS)

    Constantinescu, G.S.; Lele, S. K.

    2000-01-01

    The motivation of this work is the ongoing effort at the Center for Turbulence Research (CTR) to use large eddy simulation (LES) techniques to calculate the noise radiated by jet engines. The focus on engine exhaust noise reduction is motivated by the fact that a significant reduction has been achieved over the last decade on the other main sources of acoustic emissions of jet engines, such as the fan and turbomachinery noise, which gives increased priority to jet noise. To be able to propose methods to reduce the jet noise based on results of numerical simulations, one first has to be able to accurately predict the spatio-temporal distribution of the noise sources in the jet. Though a great deal of understanding of the fundamental turbulence mechanisms in high-speed jets was obtained from direct numerical simulations (DNS) at low Reynolds numbers, LES seems to be the only realistic available tool to obtain the necessary near-field information that is required to estimate the acoustic radiation of the turbulent compressible engine exhaust jets. The quality of jet-noise predictions is determined by the accuracy of the numerical method that has to capture the wide range of pressure fluctuations associated with the turbulence in the jet and with the resulting radiated noise, and by the boundary condition treatment and the quality of the mesh. Higher Reynolds numbers and coarser grids put in turn a higher burden on the robustness and accuracy of the numerical method used in this kind of jet LES simulations. As these calculations are often done in cylindrical coordinates, one of the most important requirements for the numerical method is to provide a flow solution that is not contaminated by numerical artifacts. The coordinate singularity is known to be a source of such artifacts. In the present work we use 6th order Pade schemes in the non-periodic directions to discretize the full compressible flow equations. It turns out that the quality of jet-noise predictions

  1. Nose-to-brain drug delivery by nanoparticles in the treatment of neurological disorders.

    PubMed

    Ong, Wei-Yi; Shalini, Suku-Maran; Costantino, Luca

    2014-01-01

    Many potential drugs for the treatment of neurological diseases are unable to reach the brain in sufficient enough concentrations to be therapeutic because of the blood brain barrier. On the other hand, direct delivery of drugs to the brain provides the possibility of a greater therapeutic-toxic ratio than with systemic drug delivery. The use of intranasal delivery of therapeutic agents to the brain provides a means of bypassing the blood brain barrier in a non-invasive manner. In this respect, nanosized drug carriers were shown to enhance the delivery of drugs to CNS compared to equivalent drug solution formulations. Neurological conditions that have been studied in animal models that could benefit from nose-to-brain delivery of nanotherapeutics include pain, epilepsy, neurodegenerative disease and infectious diseases. The delivery of drugs to the brain via the nose-to-brain route holds great promise, on the basis of preclinical research by means of drug delivery systems such as polymeric nanoparticles and clinical data related to intranasal delivery to CNS of large molecular weight biologics administered in solution, but safety issues about toxicity on nasal mucosa, Np transport into the brain, delivery only to specific brain regions and variability in the adsorbed dose still represent research topics that need to be considered, with a view of clinical translation of these delivery systems.

  2. Women who conceived with infertility treatment were more likely to receive planned cesarean deliveries in Taiwan.

    PubMed

    Chien, Li-Yin; Lee, Yu-Hsiang; Lin, Yu-Hung; Tai, Chen-Jei

    2015-06-01

    The objective of this study was to examine the effect of conception with infertility treatment on planned cesarean delivery. The participants were from a panel of primiparous pregnant women in northern Taiwan. The data analysis included 771 women with a singleton pregnancy, of whom 160 had a planned cesarean delivery and 611 who had a vaginal delivery. The study women answered structured questionnaires during the second and third trimesters of pregnancy, and at one-month postpartum. Women who conceived with infertility treatment were more likely to have planned cesarean deliveries than women who conceived without it (44.7% versus 18.1%, p < 0.001; crude odds ratio: 3.66, 95% confidence interval [CI]: 2.24-5.98). After adjustment for maternal age over 35 years, whether they were currently unmarried, selection of time for birth in advance, gestational hypertension, and birthweight < 2500 g, women who conceived with infertility treatment were 2.95 times (95% CI: 1.47-5.92) more likely to have planned cesarean deliveries. The increased risk for planned cesarean deliveries among singleton women who conceived with infertility treatment cannot be explained by older maternal age or higher number of morbidities during pregnancy. Counseling for women who conceive with infertility treatments may be needed to decrease unnecessary cesarean deliveries.

  3. Telemedicine for Improved Delivery of Psychosocial Treatments for Post Traumatic Stress Disorder

    DTIC Science & Technology

    2014-05-01

    08-2-0076 TITLE: Telemedicine for Improved Delivery of Psychosocial Treatments for Post Traumatic Stress Disorder PRINCIPAL INVESTIGATOR...SUBTITLE Telemedicine for Improved Delivery of Psychosocial Treatments for Post-Traumatic Stress Disorder 5a. CONTRACT NUMBER 5b. GRANT...ABSTRACT: Background: Posttraumatic stress disorder (PTSD) is considered a major public health problem in the U.S. because it has fairly high prevalence

  4. Delivery of Peptides Via the Oral Route: Diabetes Treatment by Peptide-Loaded Nanoparticles.

    PubMed

    Bouttefeux, Oriane; Beloqui, Ana; Preat, Veronique

    2016-01-01

    Over the last years, the interest of the pharmaceutical industry in the use of therapeutic peptides in diabetes treatment has been increased. However, these are restricted to parenteral administration. In order to mimic the natural physiological response, many efforts have been made towards oral peptide delivery in diabetes treatment. This review article aims to give an overview on the progress in the nanomedicine field towards the design and optimization of nanoparticle-based drug delivery systems capable of overcoming the harsh gastrointestinal environment and achieving an adequate bioavailability following oral administration. The reported data clearly illustrate the promise of nanomedicine for antidiabetic oral peptide delivery.

  5. A Monte Carlo tool for evaluating VMAT and DIMRT treatment deliveries including planar detectors

    NASA Astrophysics Data System (ADS)

    Asuni, G.; van Beek, T. A.; Venkataraman, S.; Popescu, I. A.; McCurdy, B. M. C.

    2013-06-01

    The aim of this work is to describe and validate a new general research tool that performs Monte Carlo (MC) simulations for volumetric modulated arc therapy (VMAT) and dynamic intensity modulated radiation therapy (DIMRT), simultaneously tracking dose deposition in both the patient CT geometry and an arbitrary planar detector system. The tool is generalized to handle either entrance or exit detectors and provides the simulated dose for the individual control-points of the time-dependent VMAT and DIMRT deliveries. The MC simulation tool was developed with the EGSnrc radiation transport. For the individual control point simulation, we rotate the patient/phantom volume only (i.e. independent of the gantry and planar detector geometries) using the gantry angle in the treatment planning system (TPS) DICOM RP file such that each control point has its own unique phantom file. After MC simulation, we obtained the total dose to the phantom by summing dose contributions for all control points. Scored dose to the sensitive layer of the planar detector is available for each control point. To validate the tool, three clinical treatment plans were used including VMAT plans for a prostate case and a head-and-neck case, and a DIMRT plan for a head-and-neck case. An electronic portal imaging device operated in ‘movie’ mode was used with the VMAT plans delivered to cylindrical and anthropomorphic phantoms to validate the code using an exit detector. The DIMRT plan was delivered to a novel transmission detector, to validate the code using an entrance detector. The total MC 3D absolute doses in patient/phantom were compared with the TPS doses, while 2D MC doses were compared with planar detector doses for all individual control points, using the gamma evaluation test with 3%/3 mm criteria. The MC 3D absolute doses demonstrated excellent agreement with the TPS doses for all the tested plans, with about 95% of voxels having γ <1 for the plans. For planar dosimetry image comparisons

  6. A Monte Carlo tool for evaluating VMAT and DIMRT treatment deliveries including planar detectors.

    PubMed

    Asuni, G; van Beek, T A; Venkataraman, S; Popescu, I A; McCurdy, B M C

    2013-06-07

    The aim of this work is to describe and validate a new general research tool that performs Monte Carlo (MC) simulations for volumetric modulated arc therapy (VMAT) and dynamic intensity modulated radiation therapy (DIMRT), simultaneously tracking dose deposition in both the patient CT geometry and an arbitrary planar detector system. The tool is generalized to handle either entrance or exit detectors and provides the simulated dose for the individual control-points of the time-dependent VMAT and DIMRT deliveries. The MC simulation tool was developed with the EGSnrc radiation transport. For the individual control point simulation, we rotate the patient/phantom volume only (i.e. independent of the gantry and planar detector geometries) using the gantry angle in the treatment planning system (TPS) DICOM RP file such that each control point has its own unique phantom file. After MC simulation, we obtained the total dose to the phantom by summing dose contributions for all control points. Scored dose to the sensitive layer of the planar detector is available for each control point. To validate the tool, three clinical treatment plans were used including VMAT plans for a prostate case and a head-and-neck case, and a DIMRT plan for a head-and-neck case. An electronic portal imaging device operated in 'movie' mode was used with the VMAT plans delivered to cylindrical and anthropomorphic phantoms to validate the code using an exit detector. The DIMRT plan was delivered to a novel transmission detector, to validate the code using an entrance detector. The total MC 3D absolute doses in patient/phantom were compared with the TPS doses, while 2D MC doses were compared with planar detector doses for all individual control points, using the gamma evaluation test with 3%/3 mm criteria. The MC 3D absolute doses demonstrated excellent agreement with the TPS doses for all the tested plans, with about 95% of voxels having γ <1 for the plans. For planar dosimetry image comparisons

  7. Methods to model and predict the ViewRay treatment deliveries to aid patient scheduling and treatment planning.

    PubMed

    Liu, Shi; Wu, Yu; Wooten, H Omar; Green, Olga; Archer, Brent; Li, Harold; Yang, Deshan

    2016-03-01

    A software tool is developed, given a new treatment plan, to predict treatment delivery time for radiation therapy (RT) treatments of patients on ViewRay magnetic resonance image-guided radiation therapy (MR-IGRT) delivery system. This tool is necessary for managing patient treatment scheduling in our clinic. The predicted treatment delivery time and the assessment of plan complexities could also be useful to aid treatment planning. A patient's total treatment delivery time, not including time required for localization, is modeled as the sum of four components: 1) the treatment initialization time; 2) the total beam-on time; 3) the gantry rotation time; and 4) the multileaf collimator (MLC) motion time. Each of the four components is predicted separately. The total beam-on time can be calculated using both the planned beam-on time and the decay-corrected dose rate. To predict the remain-ing components, we retrospectively analyzed the patient treatment delivery record files. The initialization time is demonstrated to be random since it depends on the final gantry angle of the previous treatment. Based on modeling the relationships between the gantry rotation angles and the corresponding rotation time, linear regression is applied to predict the gantry rotation time. The MLC motion time is calculated using the leaves delay modeling method and the leaf motion speed. A quantitative analysis was performed to understand the correlation between the total treatment time and the plan complexity. The proposed algorithm is able to predict the ViewRay treatment delivery time with the average prediction error 0.22 min or 1.82%, and the maximal prediction error 0.89 min or 7.88%. The analysis has shown the correlation between the plan modulation (PM) factor and the total treatment delivery time, as well as the treatment delivery duty cycle. A possibility has been identified to significantly reduce MLC motion time by optimizing the positions of closed MLC pairs. The accuracy of

  8. Methods to model and predict the ViewRay treatment deliveries to aid patient scheduling and treatment planning.

    PubMed

    Liu, Shi; Wu, Yu; Wooten, H Omar; Green, Olga; Archer, Brent; Li, Harold; Yang, Deshan

    2016-03-08

    A software tool is developed, given a new treatment plan, to predict treatment delivery time for radiation therapy (RT) treatments of patients on ViewRay magnetic resonance image-guided radiation therapy (MR-IGRT) delivery system. This tool is necessary for managing patient treatment scheduling in our clinic. The predicted treatment delivery time and the assessment of plan complexities could also be useful to aid treatment planning. A patient's total treatment delivery time, not including time required for localization, is modeled as the sum of four components: 1) the treatment initialization time; 2) the total beam-on time; 3) the gantry rotation time; and 4) the multileaf collimator (MLC) motion time. Each of the four components is predicted separately. The total beam-on time can be calculated using both the planned beam-on time and the decay-corrected dose rate. To predict the remain-ing components, we retrospectively analyzed the patient treatment delivery record files. The initialization time is demonstrated to be random since it depends on the final gantry angle of the previous treatment. Based on modeling the relationships between the gantry rotation angles and the corresponding rotation time, linear regression is applied to predict the gantry rotation time. The MLC motion time is calculated using the leaves delay modeling method and the leaf motion speed. A quantitative analysis was performed to understand the correlation between the total treatment time and the plan complexity. The proposed algorithm is able to predict the ViewRay treatment delivery time with the average prediction error 0.22min or 1.82%, and the maximal prediction error 0.89 min or 7.88%. The analysis has shown the correlation between the plan modulation (PM) factor and the total treatment delivery time, as well as the treatment delivery duty cycle. A possibility has been identified to significantly reduce MLC motion time by optimizing the positions of closed MLC pairs. The accuracy of

  9. Delivery

    PubMed Central

    Miller, Thomas A

    2013-01-01

    Enthusiasm greeted the development of synthetic organic insecticides in the mid-twentieth century, only to see this give way to dismay and eventually scepticism and outright opposition by some. Regardless of how anyone feels about this issue, insecticides and other pesticides have become indispensable, which creates something of a dilemma. Possibly as a result of the shift in public attitude towards insecticides, genetic engineering of microbes was first met with scepticism and caution among scientists. Later, the development of genetically modified crop plants was met with an attitude that hardened into both acceptance and hard-core resistance. Transgenic insects, which came along at the dawn of the twenty-first century, encountered an entrenched opposition. Those of us responsible for studying the protection of crops have been affected more or less by these protagonist and antagonistic positions, and the experiences have often left one thoughtfully mystified as decisions are made by non-participants. Most of the issues boil down to concerns over delivery mechanisms. © 2013 Society of Chemical Industry PMID:23852646

  10. Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma.

    PubMed

    Byrne, James D; Jajja, Mohammad R N; Schorzman, Allison N; Keeler, Amanda W; Luft, J Christopher; Zamboni, William C; DeSimone, Joseph M; Yeh, Jen Jen

    2016-02-23

    Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, Ki-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.

  11. Large-scale extraction of accurate drug-disease treatment pairs from biomedical literature for drug repurposing

    PubMed Central

    2013-01-01

    Background A large-scale, highly accurate, machine-understandable drug-disease treatment relationship knowledge base is important for computational approaches to drug repurposing. The large body of published biomedical research articles and clinical case reports available on MEDLINE is a rich source of FDA-approved drug-disease indication as well as drug-repurposing knowledge that is crucial for applying FDA-approved drugs for new diseases. However, much of this information is buried in free text and not captured in any existing databases. The goal of this study is to extract a large number of accurate drug-disease treatment pairs from published literature. Results In this study, we developed a simple but highly accurate pattern-learning approach to extract treatment-specific drug-disease pairs from 20 million biomedical abstracts available on MEDLINE. We extracted a total of 34,305 unique drug-disease treatment pairs, the majority of which are not included in existing structured databases. Our algorithm achieved a precision of 0.904 and a recall of 0.131 in extracting all pairs, and a precision of 0.904 and a recall of 0.842 in extracting frequent pairs. In addition, we have shown that the extracted pairs strongly correlate with both drug target genes and therapeutic classes, therefore may have high potential in drug discovery. Conclusions We demonstrated that our simple pattern-learning relationship extraction algorithm is able to accurately extract many drug-disease pairs from the free text of biomedical literature that are not captured in structured databases. The large-scale, accurate, machine-understandable drug-disease treatment knowledge base that is resultant of our study, in combination with pairs from structured databases, will have high potential in computational drug repurposing tasks. PMID:23742147

  12. Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases.

    PubMed

    Meredith, M Elizabeth; Salameh, Therese S; Banks, William A

    2015-07-01

    The blood-brain barrier (BBB) is a major impediment to the therapeutic delivery of peptides and proteins to the brain. Intranasal delivery often provides a non-invasive means to bypass the BBB. Advantages of using intranasal delivery include minimizing exposure to peripheral organs and tissues, thus reducing systemic side effects. It also allows substances that typically have rapid degradation in the blood time to exert their effect. Intranasal delivery provides the ability to target proteins and peptides to specific regions of the brain when administered with substrates like cyclodextrins. In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP. We have described their rationale for use, distribution in the brain after intranasal injection, how intranasal administration differed from other modes of delivery, and their use in clinical trials, if applicable. Intranasal delivery of drugs, peptides, and other proteins could be very useful in the future for the prevention or treatment of brain related diseases.

  13. Drug Delivery for Treatment of Inner Ear Disease: Current State of Knowledge

    PubMed Central

    McCall, Andrew A.; Leary Swan, Erin E.; Borenstein, Jeffrey T.; Sewell, William F.; Kujawa, Sharon G.; McKenna, Michael J.

    2009-01-01

    Delivery of medications to the inner ear has been an area of considerable growth in both the research and clinical realms over the past several decades. Systemic delivery of medication destined for treatment of the inner ear is the foundation upon which newer delivery techniques have been developed. Due to systemic side effects, investigators and clinicians have begun developing and utilizing techniques to deliver therapeutic agents locally. Alongside the now commonplace use of intratympanic gentamicin for Meniere's disease and the emerging use of intratympanic steroids for sudden sensorineural hearing loss, novel technologies, such as hydrogels and nanoparticles, are being explored. At the horizon of inner ear drug delivery techniques, intracochlear devices that leverage recent advances in microsystems technology are being developed to apply medications directly into the inner ear. Potential uses for such devices include neurotrophic factor and steroid delivery with cochlear implantation, RNA interference technologies, and stem cell therapy. The historical, current, and future delivery techniques and uses of drug delivery for treatment of inner ear disease serve as the basis for this review. PMID:19952751

  14. QA issues for computer-controlled treatment delivery: this is not your old R/V system any more!

    PubMed

    Fraass, Benedick A

    2008-01-01

    State-of-the-art radiotherapy treatment delivery has changed dramatically during the past decade, moving from manual individual field setup and treatment to automated computer-controlled delivery of complex treatments, including intensity-modulated radiotherapy and other similarly complex delivery strategies. However, the quality assurance methods typically used to ensure treatment is performed precisely and correctly have not evolved in a similarly dramatic way. This paper reviews the old manual treatment process and use of record-and-verify systems, and describes differences with modern computer-controlled treatment delivery. The process and technology used for computer-controlled treatment delivery are analyzed in terms of potential (and actual) problems, as well as relevant published guidance on quality assurance. The potential for improved quality assurance for computer-controlled delivery is discussed.

  15. [Prevention and treatment of hypotension during Caesarean delivery].

    PubMed

    Erler, Ines; Gogarten, Wiebke

    2007-03-01

    Regional anesthesia for Caesarean delivery is often accompanied by a reduction in maternal blood pressure. Maternal hypotension may lead to a reduction in uteroplacental blood flow with consecutive fetal acidosis. In order to avoid reductions in uteroplacental blood flow, tremendous research has been performed, showing that the avoidance of aortocaval compression, compression of the lower extremities, and prehydration with colloids are effective in reducing maternal hypotension. Further means include the recent introduction of low dose spinal anesthesia with a combination of small amounts of local anesthetics and opioids. Nevertheless, maternal hypotension is not always preventable and the use of vasopressors is still frequently required. Although ephedrine has been considered the vasopressor of choice over the last decades, current studies show that fetal acidosis is less frequently encountered with the use of phenylephrine, which should thus be considered as a first-line agent.

  16. Treatment planning for SBRT using automated field delivery: A case study

    SciTech Connect

    Ritter, Timothy A.; Owen, Dawn; Brooks, Cassandra M.; Stenmark, Matthew H.

    2015-04-01

    Stereotactic body radiation therapy (SBRT) treatment planning and delivery can be accomplished using a variety of techniques that achieve highly conformal dose distributions. Herein, we describe a template-based automated treatment field approach that enables rapid delivery of more than 20 coplanar fields. A case study is presented to demonstrate how modest adaptations to traditional SBRT planning can be implemented to take clinical advantage of this technology. Treatment was planned for a left-sided lung lesion adjacent to the chest wall using 25 coplanar treatment fields spaced at 11° intervals. The plan spares the contralateral lung and is in compliance with the conformality standards set forth in Radiation Therapy and Oncology Group protocol 0915, and the dose tolerances found in the report of the American Association of Physicists in Medicine Task Group 101. Using a standard template, treatment planning was accomplished in less than 20 minutes, and each 10 Gy fraction was delivered in approximately 5.4 minutes. For those centers equipped with linear accelerators capable of automated treatment field delivery, the use of more than 20 coplanar fields is a viable SBRT planning approach and yields excellent conformality and quality combined with rapid planning and treatment delivery. Although the case study discusses a laterally located lung lesion, this technique can be applied to centrally located tumors with similar results.

  17. Recent advances in delivery of drug-nucleic acid combinations for cancer treatment.

    PubMed

    Li, Jing; Wang, Yan; Zhu, Yu; Oupický, David

    2013-12-10

    Cancer treatment that uses a combination of approaches with the ability to affect multiple disease pathways has been proven highly effective in the treatment of many cancers. Combination therapy can include multiple chemotherapeutics or combinations of chemotherapeutics with other treatment modalities like surgery or radiation. However, despite the widespread clinical use of combination therapies, relatively little attention has been given to the potential of modern nanocarrier delivery methods, like liposomes, micelles, and nanoparticles, to enhance the efficacy of combination treatments. This lack of knowledge is particularly notable in the limited success of vectors for the delivery of combinations of nucleic acids with traditional small molecule drugs. The delivery of drug-nucleic acid combinations is particularly challenging due to differences in the physicochemical properties of the two types of agents. This review discusses recent advances in the development of delivery methods using combinations of small molecule drugs and nucleic acid therapeutics to treat cancer. This review primarily focuses on the rationale used for selecting appropriate drug-nucleic acid combinations as well as progress in the development of nanocarriers suitable for simultaneous delivery of drug-nucleic acid combinations.

  18. Nanotechnology-based drug delivery systems for the treatment of Alzheimer’s disease

    PubMed Central

    Fonseca-Santos, Bruno; Gremião, Maria Palmira Daflon; Chorilli, Marlus

    2015-01-01

    Alzheimer’s disease is a neurological disorder that results in cognitive and behavioral impairment. Conventional treatment strategies, such as acetylcholinesterase inhibitor drugs, often fail due to their poor solubility, lower bioavailability, and ineffective ability to cross the blood–brain barrier. Nanotechnological treatment methods, which involve the design, characterization, production, and application of nanoscale drug delivery systems, have been employed to optimize therapeutics. These nanotechnologies include polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, microemulsion, nanoemulsion, and liquid crystals. Each of these are promising tools for the delivery of therapeutic devices to the brain via various routes of administration, particularly the intranasal route. The objective of this study is to present a systematic review of nanotechnology-based drug delivery systems for the treatment of Alzheimer’s disease. PMID:26345528

  19. Quantitative analysis of beam delivery parameters and treatment process time for proton beam therapy

    SciTech Connect

    Suzuki, Kazumichi; Gillin, Michael T.; Sahoo, Narayan; Zhu, X. Ronald; Lee, Andrew K.; Lippy, Denise

    2011-07-15

    Purpose: To evaluate patient census, equipment clinical availability, maximum daily treatment capacity, use factor for major beam delivery parameters, and treatment process time for actual treatments delivered by proton therapy systems. Methods: The authors have been recording all beam delivery parameters, including delivered dose, energy, range, spread-out Bragg peak widths, gantry angles, and couch angles for every treatment field in an electronic medical record system. We analyzed delivery system downtimes that had been recorded for every equipment failure and associated incidents. These data were used to evaluate the use factor of beam delivery parameters, the size of the patient census, and the equipment clinical availability of the facility. The duration of each treatment session from patient walk-in and to patient walk-out of the treatment room was measured for 82 patients with cancers at various sites. Results: The yearly average equipment clinical availability in the last 3 yrs (June 2007-August 2010) was 97%, which exceeded the target of 95%. Approximately 2200 patients had been treated as of August 2010. The major disease sites were genitourinary (49%), thoracic (25%), central nervous system (22%), and gastrointestinal (2%). Beams have been delivered in approximately 8300 treatment fields. The use factor for six beam delivery parameters was also evaluated. Analysis of the treatment process times indicated that approximately 80% of this time was spent for patient and equipment setup. The other 20% was spent waiting for beam delivery and beam on. The total treatment process time can be expressed by a quadratic polynomial of the number of fields per session. The maximum daily treatment capacity of our facility using the current treatment processes was estimated to be 133 {+-} 35 patients. Conclusions: This analysis shows that the facility has operated at a high performance level and has treated a large number of patients with a variety of diseases. The use

  20. Reassessing the Role of Intra-Arterial Drug Delivery for Glioblastoma Multiforme Treatment

    PubMed Central

    Ellis, Jason A.; Banu, Matei; Hossain, Shaolie S.; Singh-Moon, Rajinder; Lavine, Sean D.; Bruce, Jeffrey N.; Joshi, Shailendra

    2015-01-01

    Effective treatment for glioblastoma (GBM) will likely require targeted delivery of several specific pharmacological agents simultaneously. Intra-arterial (IA) delivery is one technique for targeting the tumor site with multiple agents. Although IA chemotherapy for glioblastoma (GBM) has been attempted since the 1950s, the predicted benefits remain unproven in clinical practice. This review focuses on innovative approaches to IA drug delivery in treating GBM. Guided by novel in vitro and in vivo optical measurements, newer pharmacokinetic models promise to better define the complex relationship between background cerebral blood flow and drug injection parameters. Advanced optical technologies and tracers, unique nanoparticles designs, new cellular targets, and rational drug formulations are continuously modifying the therapeutic landscape for GBM. Personalized treatment approaches are emerging; however, such tailored approaches will largely depend on effective drug delivery techniques and on the ability to simultaneously deliver multidrug regimens. These new paradigms for tumor-selective drug delivery herald dramatic improvements in the effectiveness of IA chemotherapy for GBM. Therefore, within this context of so-called “precision medicine,” the role of IA delivery for GBM is thoroughly reassessed. PMID:26819758

  1. Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain.

    PubMed

    Upadhyay, Urvashi M; Tyler, Betty; Patta, Yoda; Wicks, Robert; Spencer, Kevin; Scott, Alexander; Masi, Byron; Hwang, Lee; Grossman, Rachel; Cima, Michael; Brem, Henry; Langer, Robert

    2014-11-11

    Metastases represent the most common brain tumors in adults. Surgical resection alone results in 45% recurrence and is usually accompanied by radiation and chemotherapy. Adequate chemotherapy delivery to the CNS is hindered by the blood-brain barrier. Efforts at delivering chemotherapy locally to gliomas have shown modest increases in survival, likely limited by the infiltrative nature of the tumor. Temozolomide (TMZ) is first-line treatment for gliomas and recurrent brain metastases. Doxorubicin (DOX) is used in treating many types of breast cancer, although its use is limited by severe cardiac toxicity. Intracranially implanted DOX and TMZ microcapsules are compared with systemic administration of the same treatments in a rodent model of breast adenocarcinoma brain metastases. Outcomes were animal survival, quantified drug exposure, and distribution of cleaved caspase 3. Intracranial delivery of TMZ and systemic DOX administration prolong survival more than intracranial DOX or systemic TMZ. Intracranial TMZ generates the more robust induction of apoptotic pathways. We postulate that these differences may be explained by distribution profiles of each drug when administered intracranially: TMZ displays a broader distribution profile than DOX. These microcapsule devices provide a safe, reliable vehicle for intracranial chemotherapy delivery and have the capacity to be efficacious and superior to systemic delivery of chemotherapy. Future work should include strategies to improve the distribution profile. These findings also have broader implications in localized drug delivery to all tissue, because the efficacy of a drug will always be limited by its ability to diffuse into surrounding tissue past its delivery source.

  2. Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain

    PubMed Central

    Upadhyay, Urvashi M.; Tyler, Betty; Patta, Yoda; Wicks, Robert; Spencer, Kevin; Scott, Alexander; Masi, Byron; Hwang, Lee; Grossman, Rachel; Cima, Michael; Brem, Henry; Langer, Robert

    2014-01-01

    Metastases represent the most common brain tumors in adults. Surgical resection alone results in 45% recurrence and is usually accompanied by radiation and chemotherapy. Adequate chemotherapy delivery to the CNS is hindered by the blood–brain barrier. Efforts at delivering chemotherapy locally to gliomas have shown modest increases in survival, likely limited by the infiltrative nature of the tumor. Temozolomide (TMZ) is first-line treatment for gliomas and recurrent brain metastases. Doxorubicin (DOX) is used in treating many types of breast cancer, although its use is limited by severe cardiac toxicity. Intracranially implanted DOX and TMZ microcapsules are compared with systemic administration of the same treatments in a rodent model of breast adenocarcinoma brain metastases. Outcomes were animal survival, quantified drug exposure, and distribution of cleaved caspase 3. Intracranial delivery of TMZ and systemic DOX administration prolong survival more than intracranial DOX or systemic TMZ. Intracranial TMZ generates the more robust induction of apoptotic pathways. We postulate that these differences may be explained by distribution profiles of each drug when administered intracranially: TMZ displays a broader distribution profile than DOX. These microcapsule devices provide a safe, reliable vehicle for intracranial chemotherapy delivery and have the capacity to be efficacious and superior to systemic delivery of chemotherapy. Future work should include strategies to improve the distribution profile. These findings also have broader implications in localized drug delivery to all tissue, because the efficacy of a drug will always be limited by its ability to diffuse into surrounding tissue past its delivery source. PMID:25349381

  3. Poster — Thur Eve — 33: The Influence of a Modeled Treatment Couch on Dose Distributions During IMRT and RapidArc Treatment Delivery

    SciTech Connect

    Aldosary, Ghada; Nobah, Ahmad; Al-Zorkani, Faisal; Moftah, Belal; Devic, Slobodan

    2014-08-15

    Treatment couches have been known to perturb dose delivery in patients. This effect is most pronounced in techniques such as IMRT and RapidArc. Although modern treatment planning systems (TPS) include data for a “default” treatment couch, actual couches are not manufactured identically. Thus, variations in their Hounsfield Unit (HU) values may exist. This study demonstrates a practical and simple method of acquiring reliable HU data for any treatment couch. We also investigate the effects of both the default and modeled treatment couches on absorbed dose. Experimental verifications show that by neglecting to incorporate the treatment couch in the TPS, dose differences of up to 9.5% and 7.3% were present for 4 MV and 10 MV photon beams, respectively. Furthermore, a clinical study based on a cohort of 20 RapidArc and IMRT (brain, pelvis and abdominal) cases is performed. 2D dose distributions show that without the couch in the planning phase, differences ≤ 4.6% and 5.9% for RapidArc and IMRT cases are present for the same cases that the default couch was added to. Additionally, in comparison to the default couch, employing the modeled couch in the calculation process influences dose distributions by ≤ 2.7% and 8% for RapidArc and IMRT cases, respectively. This result was found to be site specific; where an accurate couch proves to be preferable for IMRT brain plans. As such, adding the couch during dose calculation decreases dose calculation errors, and a precisely modeled treatment couch offers higher dose delivery accuracy for brain treatment using IMRT.

  4. Convection-enhanced delivery of immunotoxins and radioisotopes for treatment of malignant gliomas.

    PubMed

    Vandergrift, William A; Patel, Sunil J; Nicholas, Joyce S; Varma, Abhay K

    2006-04-15

    The treatment of malignant gliomas has advanced significantly in the past 15 years. The simultaneous development of new targeting agents and techniques to deliver these high-molecular-weight compounds has led to improved efficacy and promising results in Phase III trials. Convection-enhanced delivery (CED) of macromolecules has emerged as the leading delivery technique for the treatment of malignant gliomas. A summary of the basic principles of CED and a review of the current human trials of protein targeting agents are provided.

  5. Accurate Measurement of Canal Length during Root Canal Treatment: An In Vivo Study

    PubMed Central

    Sadaf, Durre; Ahmad, Muhammad Zubair

    2015-01-01

    Objectives: To assess the consistency and accuracy of Electronic Apex Locator (EAL) (Root ZXII) in individual canals and its association with other clinical variables. Study Design: Cross-Sectional study. Place of study: Dental section of the Aga Khan University Hospital, Karachi, Pakistan. Materials and Methods: Working length was measured by EAL in 180 patients requiring endodontic therapy in molar and premolar teeth. The effects of clinical variables e.g. gender and pulpal status on the consistency and accuracy of EAL were recorded. Performance of apex locator was considered “Consistent” when the scale bar was stable and moved only in correspondence to the movement of file in the root canal. Accuracy was determined by inserting the file at the working length determined by the EAL and periapical view of radiograph was taken using paralleling technique. Estimated working length was considered accurate when the file tip was located 0-2mm short of the radiographic apex. If the file was overextended from the radiographic apex, it showed dysfunction of the EAL. Results: Consistency of EAL was found 97.6% in distobuccal canals, 91.1% in palatal canals, 73.7% in mesiolingual canals, 83.3% in mesiobuccal and 80.2% in distal canals. Accuracy of EAL was 91.4% in mesiolingual canal, 92% in mesiobuccal, and 90.2% in Palatal and 93.2% in distal canal. Conclusion: Consistency of electronic apex locator vary in different canals, however consistent measurements are highly accurate. No significant association was found between other clinical variables with the consistency and accuracy of EAL.

  6. Breathing-Synchronized Delivery: A Potential Four-Dimensional Tomotherapy Treatment Technique

    SciTech Connect

    Zhang Tiezhi . E-mail: tiezhi.zhang@beaumont.edu; Lu Weiguo; Olivera, Gustavo H.; Keller, Harry; Jeraj, Robert; Manon, Rafael; Mehta, Minesh; Mackie, Thomas R.; Paliwal, Bhudatt

    2007-08-01

    Purpose: To introduce a four-dimensional (4D) tomotherapy treatment technique with improved motion control and patient tolerance. Methods and Materials: Computed tomographic images at 10 breathing phases were acquired for treatment planning. The full exhalation phase was chosen as the planning phase, and the CT images at this phase were used as treatment-planning images. Region of interest delineation was the same as in traditional treatment planning, except that no breathing motion margin was used in clinical target volume-planning target volume expansion. The correlation between delivery and breathing phases was set assuming a constant gantry speed and a fixed breathing period. Deformable image registration yielded the deformation fields at each phase relative to the planning phase. With the delivery/breathing phase correlation and voxel displacements at each breathing phase, a 4D tomotherapy plan was obtained by incorporating the motion into inverse treatment plan optimization. A combined laser/spirometer breathing tracking system has been developed to monitor patient breathing. This system is able to produce stable and reproducible breathing signals representing tidal volume. Results: We compared the 4D tomotherapy treatment planning method with conventional tomotherapy on a static target. The results showed that 4D tomotherapy can achieve dose distributions on a moving target similar to those obtained with conventional delivery on a stationary target. Regular breathing motion is fully compensated by motion-incorporated breathing-synchronized delivery planning. Four-dimensional tomotherapy also has close to 100% duty cycle and does not prolong treatment time. Conclusion: Breathing-synchronized delivery is a feasible 4D tomotherapy treatment technique with improved motion control and patient tolerance.

  7. Deep soil mixing for reagent delivery and contaminant treatment

    SciTech Connect

    Korte, N.; Gardner, F.G.; Cline, S.R.; West, O.R.

    1997-12-31

    Deep soil mixing was evaluated for treating clay soils contaminated with TCE and its byproducts at the Department of Energy`s Kansas City Plant. The objective of the project was to evaluate the extent of limitations posed by the stiff, silty-clay soil. Three treatment approaches were tested. The first was vapor stripping. In contrast to previous work, however, laboratory treatability studies indicated that mixing saturated, clay soil was not efficient unless powdered lime was added. Thus, powder injection of lime was attempted in conjunction with the mixing/stripping operation. In separate treatment cells, potassium permanganate solution was mixed with the soil as a means of destroying contaminants in situ. Finally, microbial treatment was studied in a third treatment zone. The clay soil caused operational problems such as breakage of the shroud seal and frequent reagent blowouts. Nevertheless, treatment efficiencies of more than 70% were achieved in the saturated zone with chemical oxidation. Although expensive ($1128/yd{sup 3}), there are few alternatives for soils of this type.

  8. Quality control procedures for dynamic treatment delivery techniques involving couch motion.

    PubMed

    Yu, Victoria Y; Fahimian, Benjamin P; Xing, Lei; Hristov, Dimitre H

    2014-08-01

    In this study, the authors introduce and demonstrate quality control procedures for evaluating the geometric and dosimetric fidelity of dynamic treatment delivery techniques involving treatment couch motion synchronous with gantry and multileaf collimator (MLC). Tests were designed to evaluate positional accuracy, velocity constancy and accuracy for dynamic couch motion under a realistic weight load. A test evaluating the geometric accuracy of the system in delivering treatments over complex dynamic trajectories was also devised. Custom XML scripts that control the Varian TrueBeam™ STx (Serial #3) axes in Developer Mode were written to implement the delivery sequences for the tests. Delivered dose patterns were captured with radiographic film or the electronic portal imaging device. The couch translational accuracy in dynamic treatment mode was 0.01 cm. Rotational accuracy was within 0.3°, with 0.04 cm displacement of the rotational axis. Dose intensity profiles capturing the velocity constancy and accuracy for translations and rotation exhibited standard deviation and maximum deviations below 3%. For complex delivery involving MLC and couch motions, the overall translational accuracy for reproducing programmed patterns was within 0.06 cm. The authors conclude that in Developer Mode, TrueBeam™ is capable of delivering dynamic treatment delivery techniques involving couch motion with good geometric and dosimetric fidelity.

  9. [Antenatal corticosteroids in respiratory distress syndrome prevention: efficacy in relation to treatment--delivery interval].

    PubMed

    Heljić, Suada; Maksić, Hajrija; Misanović, Verica; Dizdarević, Jadranka

    2009-01-01

    Antenatal corticosteroids given to women, who are 24 to 34 weeks pregnant and may deliver within the next 24 hours to 7 days, are associated with significant reduction in rates of respiratory distress syndrome, intraventricular hemorrhage and mortality of pre-term babies. The aim of this study is assessment of antenatal corticosteroid effectiveness in reduction of RDS incidence in optimal delivery-treatment interval, in comparison to babies delivered before and after the optimal treatment interval has elapsed. This investigation included 80 pre-term babies between 26 and 34 gestational weeks whose mothers received corticosteroids before delivery. Control group consisted of 92 children of the same gestational age, whose mothers did not received corticosteroids antenatally. Babies of diabetic mothers, babies with IUGR and babies with congenital abnormalities were excluded. RDS was significantly less frequent in babies antenatally treated by corticosteroids (x2 31,473 p < 0.0001 coefficient contingency 0.366) then in babies whose mothers did not received corticosteroids before delivery. The majority of babies, 54.67% (p < 0.01) were born in optimal interval, 24 hours to 7 days from the beginning of the treatment, 32.0% (24/75) children were born within 24 hours and 13.3% (10/75) were born more then 7 days after the start of treatment. Comparing the incidence of RDS between groups of children born in optimal treatment-delivery interval (1 -7 days) and in the group of children born within 24 hours or after 7 days from the beginning of the treatment, no significant difference was found. The effect was clinically comparable, which suggests the possibility of reduction treatment-delivery interval in acute clinical conditions.

  10. Skin Delivery of Kojic Acid-Loaded Nanotechnology-Based Drug Delivery Systems for the Treatment of Skin Aging

    PubMed Central

    Gonçalez, M. L.; Corrêa, M. A.; Chorilli, M.

    2013-01-01

    The aging process causes a number of changes in the skin, including oxidative stress and dyschromia. The kojic acid (KA) is iron chelator employed in treatment of skin aging, and inhibits tyrosinase, promotes depigmentation. Nanotechnology-based drug delivery systems, such as liquid crystalline systems (LCSs), can modulate drug permeation through the skin and improve the drug activity. This study is aimed at structurally developing and characterizing a kojic acid-loaded LCS, consists of water (W), cetostearyl isononanoate (oil—O) and PPG-5-CETETH-20 (surfactant-S) and evaluating its in vitro skin permeation and retention. Three regions of the diagram were selected for characterization: A (35% O, 50% S, 15% W), B (30% O, 50% S, 20% W) and C (20% O, 50% S, 30% W), to which 2% KA was added. The formulations were subjected to polarized light microscopy, which indicated the presence of a hexagonal mesophase. Texture and bioadhesion assay showed that formulation B is suitable for topical application. According to the results from the in vitro permeation and retention of KA, the formulations developed can modulate the permeation of KA in the skin. The in vitro cytotoxic assays showed that KA-unloaded LCS and KA-loaded LCS didn't present cytotoxicity. PPG-5-CETETH-20-based systems may be a promising platform for KA skin delivery. PMID:24369010

  11. Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma.

    PubMed

    Arshad, Azeem; Yang, Bin; Bienemann, Alison S; Barua, Neil U; Wyatt, Marcella J; Woolley, Max; Johnson, Dave E; Edler, Karen J; Gill, Steven S

    2015-01-01

    We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas.

  12. Mangled extremity severity score: an accurate guide to treatment of the severely injured upper extremity.

    PubMed

    Slauterbeck, J R; Britton, C; Moneim, M S; Clevenger, F W

    1994-08-01

    The mangled extremity severity score (MESS) is a scoring system that can be applied to mangled extremities and help one determine which mangled limbs will eventually come to amputation. The MESS is a graduated grading system based on skeletal and soft tissue injury, shock, ischemia, and age. The records of 37 patients having sustained 43 open fractures or mangled upper extremity injuries, seen and treated at the University of New Mexico's Regional Trauma Center between April 1987 and September 1990, have been reviewed. All nine extremity injuries with a MESS of greater than or equal to seven were amputated, and 34 of 34 with a MESS of less than seven were salvaged. Nine Grade IIIC and six mangled extremities were identified in our study. Five of these Grade IIIC and four of the mangled extremities with a MESS of greater than or equal to seven were amputated. All Grade IIIC or mangled extremities with a MESS of less than seven were salvaged. In conclusion, the MESS is an early and accurate predictor for identifying the extremities that may be best treated by amputation.

  13. Maimonides: an early but accurate view on the treatment of haemorrhoids

    PubMed Central

    Magrill, Dan; Sekaran, Prabhu

    2007-01-01

    Moses Maimonides was not only one of the most influential religious figures of the middle ages, but also a pioneer in a wide variety of medical practices. A brief history of his life, and what is known about his medical education, is given here. His paper on haemorrhoids is summarised, as well as a review of the current understanding of the pathogenesis, prevention and treatment of this common condition. The comparison of Maimonides' writings to modern understanding of not only the prevention and treatment of haemorrhoids, but also his approach to the patient as a whole in terms of pre‐ and postoperative care, demonstrate how ahead of his time this great philosopher was. PMID:17488868

  14. Transrectal high-intensity focused ultrasound ablation of prostate cancer: effective treatment requiring accurate imaging.

    PubMed

    Rouvière, Olivier; Souchon, Rémi; Salomir, Rarès; Gelet, Albert; Chapelon, Jean-Yves; Lyonnet, Denis

    2007-09-01

    Transrectal HIFU ablation has become a reasonable option for the treatment of localized prostate cancer in non-surgical patients, with 5-year disease-free survival similar to that of radiation therapy. It is also a promising salvage therapy of local recurrence after radiation therapy. These favourable results are partly due to recent improvements in prostate cancer imaging. However, further improvements are needed in patient selection, pre-operative localization of the tumor foci, assessment of the volume treated and early detection of recurrence. A better knowledge of the factors influencing the HIFU-induced tissue destruction and a better pre-operative assessment of them by imaging techniques should improve treatment outcome. Whereas prostate HIFU ablation is currently performed under transrectal ultrasound guidance, MR guidance with real-time operative monitoring of temperature will be available in the near future. If this technique will give better targeting and more uniform tissue destruction, its cost-effectiveness will have to be carefully evaluated. Finally, a recently reported synergistic effect between HIFU ablation and chemotherapy opens possibilities for treatment in high-risk or clinically advanced tumors.

  15. Nanostructured Platforms for the Sustained and Local Delivery of Antibiotics in the Treatment of Osteomyelitis

    PubMed Central

    Uskoković, Vuk

    2015-01-01

    This article provides a critical view of the current state of the development of nanoparticulate and other solid-state carriers for the local delivery of antibiotics in the treatment of osteomyelitis. Mentioned are the downsides of traditional means for treating bone infection, which involve systemic administration of antibiotics and surgical debridement, along with the rather imperfect local delivery options currently available in the clinic. Envisaged are more sophisticated carriers for the local and sustained delivery of antimicrobials, including bioresorbable polymeric, collagenous, liquid crystalline, and bioglass- and nanotube-based carriers, as well as those composed of calcium phosphate, the mineral component of bone and teeth. A special emphasis is placed on composite multifunctional antibiotic carriers of a nanoparticulate nature and on their ability to induce osteogenesis of hard tissues demineralized due to disease. An ideal carrier of this type would prevent the long-term, repetitive, and systemic administration of antibiotics and either minimize or completely eliminate the need for surgical debridement of necrotic tissue. Potential problems faced by even hypothetically “perfect” antibiotic delivery vehicles are mentioned too, including (i) intracellular bacterial colonies involved in recurrent, chronic osteomyelitis; (ii) the need for mechanical and release properties to be adjusted to the area of surgical placement; (iii) different environments in which in vitro and in vivo testings are carried out; (iv) unpredictable synergies between drug delivery system components; and (v) experimental sensitivity issues entailing the increasing subtlety of the design of nanoplatforms for the controlled delivery of therapeutics. PMID:25746204

  16. Novel in Situ Gel Drug Delivery System for Breast Cancer Treatment

    DTIC Science & Technology

    2007-07-01

    for Breast Cancer Treatment PRINCIPAL INVESTIGATOR: Alekha K. Dash, Ph.D. CONTRACTING ORGANIZATION: Creighton University...COVERED (From - To) 1 JUL 2005 - 30 JUN 2007 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Novel in Situ Gel Drug Delivery System for Breast Cancer

  17. Evaluation of domperidone dosages and delivery methods for the treatment of fescue toxicosis in beef heifers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study was to develop a practical method of domperidone delivery to ameliorate the symptoms of fescue toxicosis in beef heifers. Experiment 1 used 42 crossbred heifers assigned to 1 of 7 treatment groups (n = 6/trt); positive control (0.44 mg domperidone/kg BW daily s.c.), nega...

  18. PLGA-loaded nanomedicines in melanoma treatment: Future prospect for efficient drug delivery

    PubMed Central

    Das, Sreemanti; Khuda-Bukhsh, Anisur Rahman

    2016-01-01

    Current treatment methods for melanoma have some limitations such as less target-specific action, severe side effects and resistance to drugs. Significant progress has been made in exploring novel drug delivery systems based on suitable biochemical mechanisms using nanoparticles ranging from 10 to 400 nm for drug delivery and imaging, utilizing their enhanced penetration and retention properties. Poly-lactide-co-glycolide (PLGA), a copolymer of poly-lactic acid and poly-glycolic acid, provides an ideally suited performance-based design for better penetration into skin cells, thereby having a greater potential for the treatment of melanoma. Moreover, encapsulation protects the drug from deactivation by biological reactions and interactions with biomolecules, ensuring successful delivery and bioavailability for effective treatment. Controlled and sustained delivery of drugs across the skin barrier that otherwise prohibits entry of larger molecules can be successfully made with adequately stable biocompatible nanocarriers such as PLGA for taking drugs through the small cutaneous pores permitting targeted deposition and prolonged drug action. PLGA is now being extensively used in photodynamic therapy and targeted therapy through modulation of signal proteins and drug-DNA interactions. Recent advances made on these nanomedicines and their advantages in the treatment of skin melanoma are highlighted and discussed in this review. PMID:27934796

  19. QA Issues for Computer-Controlled Treatment Delivery: This Isn’t Your Old R/V System Any More !

    PubMed Central

    Fraass, Benedick A.

    2009-01-01

    State of the art radiotherapy treatment delivery has changed dramatically over the last decade, moving from manual individual field setup and treatment to automated computer-controlled delivery of complex treatments including intensity modulated radiation therapy (IMRT) and other similarly complex delivery strategies. However, the quality assurance (QA) methods typically used to make sure treatment is performed precisely and correctly have not evolved in a similarly dramatic way. This paper reviews the old manual treatment process and use of record and verify systems, and describes differences with modern computer-controlled treatment delivery (CCTD). The process and technology used for CCTD are analyzed in terms of potential (and actual) problems as well as relevant published guidance on QA. The potential for improved QA for computer-controlled delivery is discussed. PMID:18406948

  20. Polyphenols delivery by polymeric materials: challenges in cancer treatment.

    PubMed

    Vittorio, Orazio; Curcio, Manuela; Cojoc, Monica; Goya, Gerardo F; Hampel, Silke; Iemma, Francesca; Dubrovska, Anna; Cirillo, Giuseppe

    2017-11-01

    Nanotechnology can offer different solutions for enhancing the therapeutic efficiency of polyphenols, a class of natural products widely explored for a potential applicability for the treatment of different diseases including cancer. While possessing interesting anticancer properties, polyphenols suffer from low stability and unfavorable pharmacokinetics, and thus suitable carriers are required when planning a therapeutic protocol. In the present review, an overview of the different strategies based on polymeric materials is presented, with the aim to highlight the strengths and the weaknesses of each approach and offer a platform of ideas for researchers working in the field.

  1. An Efficient and Accurate Formalism for the Treatment of Large Amplitude Intramolecular Motion.

    PubMed

    Reinisch, Guillaume; Miki, Kenji; Vignoles, Gérard L; Wong, Bryan M; Simmons, Chris S

    2012-08-14

    We propose a general approach to describe large amplitude motions (LAM) with multiple degrees of freedom (DOF) in molecules or reaction intermediates, which is useful for the computation of thermochemical or kinetic data. The kinetic part of the LAM Lagrangian is derived using a Z-matrix internal coordinate representation within a new numerical procedure. This derivation is exact for a classical system, and the uncertainties on the prediction of observable quantities largely arise from uncertainties on the LAM potential energy surface (PES) itself. In order to rigorously account for these uncertainties, we present an approach based on Bayesian theory to infer a parametrized physical model of the PES using ab initio calculations. This framework allows for quantification of uncertainties associated with a PES model as well as the forward propagation of these uncertainties to the quantity of interest. A selection and generalization of some treatments accounting for the coupling of the LAM with other internal or external DOF are also presented. Finally, we discuss and validate the approach with two applications: the calculation of the partition function of 1,3-butadiene and the calculation of the high-pressure reaction rate of the CH(3) + H → CH(4) recombination.

  2. An Efficient and Accurate Formalism for the Treatment of Large Amplitude Intramolecular Motion

    PubMed Central

    2012-01-01

    We propose a general approach to describe large amplitude motions (LAM) with multiple degrees of freedom (DOF) in molecules or reaction intermediates, which is useful for the computation of thermochemical or kinetic data. The kinetic part of the LAM Lagrangian is derived using a Z-matrix internal coordinate representation within a new numerical procedure. This derivation is exact for a classical system, and the uncertainties on the prediction of observable quantities largely arise from uncertainties on the LAM potential energy surface (PES) itself. In order to rigorously account for these uncertainties, we present an approach based on Bayesian theory to infer a parametrized physical model of the PES using ab initio calculations. This framework allows for quantification of uncertainties associated with a PES model as well as the forward propagation of these uncertainties to the quantity of interest. A selection and generalization of some treatments accounting for the coupling of the LAM with other internal or external DOF are also presented. Finally, we discuss and validate the approach with two applications: the calculation of the partition function of 1,3-butadiene and the calculation of the high-pressure reaction rate of the CH3 + H → CH4 recombination. PMID:22904694

  3. Mobile Delivery of Treatment for Alcohol Use Disorders

    PubMed Central

    Quanbeck, Andrew; Chih, Ming-Yuan; Isham, Andrew; Johnson, Roberta; Gustafson, David

    2014-01-01

    Several systems for treating alcohol-use disorders (AUDs) exist that operate on mobile phones. These systems are categorized into four groups: text-messaging monitoring and reminder systems, text-messaging intervention systems, comprehensive recovery management systems, and game-based systems. Text-messaging monitoring and reminder systems deliver reminders and prompt reporting of alcohol consumption, enabling continuous monitoring of alcohol use. Text-messaging intervention systems additionally deliver text messages designed to promote abstinence and recovery. Comprehensive recovery management systems use the capabilities of smart-phones to provide a variety of tools and services that can be tailored to individuals, including in-the-moment assessments and access to peer discussion groups. Game-based systems engage the user using video games. Although many commercial applications for treatment of AUDs exist, few (if any) have empirical evidence of effectiveness. The available evidence suggests that although texting-based applications may have beneficial effects, they are probably insufficient as interventions for AUDs. Comprehensive recovery management systems have the strongest theoretical base and have yielded the strongest and longest-lasting effects, but challenges remain, including cost, understanding which features account for effects, and keeping up with technological advances. PMID:26259005

  4. Intranasal clobazam delivery in the treatment of status epilepticus.

    PubMed

    Florence, Kiruba; Manisha, Lalan; Kumar, Babbar Anil; Ankur, Kaul; Kumar, Mishra Anil; Ambikanandan, Misra

    2011-02-01

    The aim of the present investigation was to prepare and characterize clobazam mucoadhesive microemulsion (CZMME) to assess brain drug uptake and protection against pentylenetetrazole (PTZ)-induced convulsions in mice. Clobazam microemulsion (CZME) and CZMME were prepared by titration method and characterized. Brain uptake and pharmacokinetic parameters were calculated from drug concentration in mice brain versus time plots following intranasal administration of radiolabeled CZME and CZMME, intravenous and intranasal administration of radiolabeled clobazam solution. Gamma scintigraphy imaging of rabbit brain following intranasal administration was performed. Formulations were investigated for the onset of seizures in PTZ-challenged mice. Brain targeting efficiency and direct nose-to-brain transport percentage for mucoadhesive microemulsion suggested an improved brain uptake following intranasal administration. The findings were supported by gamma scintigraphy images. Delay in onset of PTZ-induced seizures with CZMME compared with positive control and placebo-treated groups confirmed the improved brain uptake. However, extensive animal studies followed by clinical trials are necessary to develop a product suitable for emergencies of acute seizures in status epilepticus and patients suffering from drug tolerance and hepatic impairment on long-term use in treatment of epilepsy, schizophrenia, and anxiety.

  5. Opioid delivery in the treatment of cancer breakthrough pain: a review of routes of administration.

    PubMed

    Nicholson, Bruce; Agarwala, Sanjiv S

    2011-01-01

    Analgesics delivered via the oral route of administration (capsules, tablets, or solutions) are most commonly used to treat cancer breakthrough pain (BTP); however, the effectiveness of oral opioids may be limited by slow gastrointestinal absorption and first-pass metabolic effects. Although the limitations presented by oral opioid delivery are acknowledged and formulations and delivery systems that mirror the temporal characteristics of the majority of cancer BTP episodes are available, short-acting oral opioids are the accepted standard of care. The purpose of this review is to provide an overview of the different routes of opioid administration used in the treatment of cancer BTP and briefly discuss the characteristics of different delivery systems.

  6. Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment

    PubMed Central

    Kang, Lin; Gao, Zhonggao; Huang, Wei; Jin, Mingji; Wang, Qiming

    2015-01-01

    The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells, which is usually caused by abnormal gene expression. RNA interference mediated by siRNA and miRNA can selectively knock down the carcinogenic genes by targeting specific mRNAs. Therefore, combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy. Due to poor stability and solubility associated with gene agents and drugs, suitable protective carriers are needed and have been widely researched for the co-delivery. In this review, we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents, as well as the advances in co-delivery systems. PMID:26579443

  7. Volatile Anesthetics and the Treatment of Severe Bronchospasm: A Concept of Targeted Delivery

    PubMed Central

    Mondoñedo, Jarred R.; McNeil, John S.; Amin, Samir D.; Herrmann, Jacob; Simon, Brett A.; Kaczka, David W.

    2014-01-01

    Status asthmaticus (SA) is a severe, refractory form of asthma that can result in rapid respiratory deterioration and death. Treatment of SA with inhaled anesthetics is a potentially life-saving therapy, but remarkably few data are available about its mechanism of action or optimal administration. In this paper, we will review the clinical use of inhaled anesthetics for treatment of SA, the potential mechanisms by which they dilate constricted airways, and the side effects associated with their administration. We will also introduce the concept of ‘targeted’ delivery of these agents to the conducting airways, a process which may maximize their therapeutic effects while minimizing associated systemic side effects. Such a delivery regimen has the potential to define a rapidly translatable treatment paradigm for this life-threatening disorder. PMID:26744597

  8. Antibiotic Treatment and Length of Hospital Stay in Relation to Delivery Mode and Prematurity

    PubMed Central

    Ahlén, Katia M.; Örtqvist, Anne K.; Gong, Tong; Wallas, Alva; Ye, Weimin; Lundholm, Cecilia; Almqvist, Catarina

    2016-01-01

    Aim To investigate how 1) maternal delivery mode and 2) prematurity in infants are associated to antibiotic treatment and length of hospital stay. Methods Women having given birth and infants 0–12 months discharged from hospital between July 2005 and November 2011 were identified from the Swedish National Patient Register. Medical records were reviewed for 203 women and 527 infants. The risk ratio (RR) between antibiotic treatment and 1) delivery mode in women; 2) prematurity in infants was calculated. Length of stay and days of antibiotic therapy were compared by Wilcoxon rank-sum test. Results Women: There was an association between emergency caesarean section (CS) and antibiotic treatment (RR 5.0 95% confidence interval (CI) 2.2–11.5), but not for elective CS. Length of stay was longer for CS (emergency and elective) compared to vaginal delivery (p<0.01). Infants: RR for antibiotic treatment in preterm compared to term infants was 1.4 (95% CI 1.0–1.9). Length of stay (p<0.01), but not days of therapy (p = 0.17), was higher in preterm compared to term infants. Conclusion We found that emergency CS increased the probability of maternal antibiotic treatment during hospitalisation, but no difference was found between term and preterm infants. The results are well aligned with current guidelines and may be considered in future studies on the effects of antibiotics. PMID:27716779

  9. Shrinking the Psoriasis Assessment Gap: Early Gene-Expression Profiling Accurately Predicts Response to Long-Term Treatment.

    PubMed

    Correa da Rosa, Joel; Kim, Jaehwan; Tian, Suyan; Tomalin, Lewis E; Krueger, James G; Suárez-Fariñas, Mayte

    2017-02-01

    There is an "assessment gap" between the moment a patient's response to treatment is biologically determined and when a response can actually be determined clinically. Patients' biochemical profiles are a major determinant of clinical outcome for a given treatment. It is therefore feasible that molecular-level patient information could be used to decrease the assessment gap. Thanks to clinically accessible biopsy samples, high-quality molecular data for psoriasis patients are widely available. Psoriasis is therefore an excellent disease for testing the prospect of predicting treatment outcome from molecular data. Our study shows that gene-expression profiles of psoriasis skin lesions, taken in the first 4 weeks of treatment, can be used to accurately predict (>80% area under the receiver operating characteristic curve) the clinical endpoint at 12 weeks. This could decrease the psoriasis assessment gap by 2 months. We present two distinct prediction modes: a universal predictor, aimed at forecasting the efficacy of untested drugs, and specific predictors aimed at forecasting clinical response to treatment with four specific drugs: etanercept, ustekinumab, adalimumab, and methotrexate. We also develop two forms of prediction: one from detailed, platform-specific data and one from platform-independent, pathway-based data. We show that key biomarkers are associated with responses to drugs and doses and thus provide insight into the biology of pathogenesis reversion.

  10. Accurate treatments of electrostatics for computer simulations of biological systems: A brief survey of developments and existing problems

    NASA Astrophysics Data System (ADS)

    Yi, Sha-Sha; Pan, Cong; Hu, Zhong-Han

    2015-12-01

    Modern computer simulations of biological systems often involve an explicit treatment of the complex interactions among a large number of molecules. While it is straightforward to compute the short-ranged Van der Waals interaction in classical molecular dynamics simulations, it has been a long-lasting issue to develop accurate methods for the longranged Coulomb interaction. In this short review, we discuss three types of methodologies for the accurate treatment of electrostatics in simulations of explicit molecules: truncation-type methods, Ewald-type methods, and mean-field-type methods. Throughout the discussion, we brief the formulations and developments of these methods, emphasize the intrinsic connections among the three types of methods, and focus on the existing problems which are often associated with the boundary conditions of electrostatics. This brief survey is summarized with a short perspective on future trends along the method developments and applications in the field of biological simulations. Project supported by the National Natural Science Foundation of China (Grant Nos. 91127015 and 21522304) and the Open Project from the State Key Laboratory of Theoretical Physics, and the Innovation Project from the State Key Laboratory of Supramolecular Structure and Materials.

  11. A computational model of drug delivery through microcirculation to compare different tumor treatments.

    PubMed

    Cattaneo, L; Zunino, P

    2014-11-01

    Starting from the fundamental laws of filtration and transport in biological tissues, we develop a computational model to capture the interplay between blood perfusion, fluid exchange with the interstitial volume, mass transport in the capillary bed, through the capillary walls and into the surrounding tissue. These phenomena are accounted at the microscale level, where capillaries and interstitial volume are viewed as two separate regions. The capillaries are described as a network of vessels carrying blood flow. We apply the model to study drug delivery to tumors. The model can be adapted to compare various treatment options. In particular, we consider delivery using drug bolus injection and nanoparticle injection into the blood stream. The computational approach is suitable for a systematic quantification of the treatment performance, enabling the analysis of interstitial drug concentration levels, metabolization rates and cell surviving fractions. Our study suggests that for the treatment based on bolus injection, the drug dose is not optimally delivered to the tumor interstitial volume. Using nanoparticles as intermediate drug carriers overrides the shortcomings of the previous delivery approach. This work shows that the proposed theoretical and computational framework represents a promising tool to compare the efficacy of different cancer treatments.

  12. SU-E-T-151: Breathing Synchronized Delivery (BSD) Planning for RapicArc Treatment

    SciTech Connect

    Lu, W; Chen, M; Jiang, S

    2015-06-15

    Purpose: To propose a workflow for breathing synchronized delivery (BSD) planning for RapicArc treatment. Methods: The workflow includes three stages: screening/simulation, planning, and delivery. In the screening/simulation stage, a 4D CT with the corresponding breathing pattern is acquired for each of the selected patients, who are able to follow their own breathing pattern. In the planning stage, one breathing phase is chosen as the reference, and contours are delineated on the reference image. Deformation maps to other phases are performed along with contour propagation. Based on the control points of the initial 3D plan for the reference phase and the respiration trace, the correlation with respiration phases, the leaf sequence and gantry angles is determined. The beamlet matrices are calculated with the corresponding breathing phase and deformed to the reference phase. Using the 4D dose evaluation tool and the original 3D plan DVHs criteria, the leaf sequence is further optimized to meet the planning objectives and the machine constraints. In the delivery stage, the patients are instructed to follow the programmed breathing patterns of their own, and all other parts are the same as the conventional Rapid-Arc delivery. Results: Our plan analysis is based on comparison of the 3D plan with a static target (SD), 3D plan with motion delivery (MD), and the BSD plan. Cyclic motion of range 0 cm to 3 cm was simulated for phantoms and lung CT. The gain of the BSD plan over MD is significant and concordant for both simulation and lung 4DCT, indicating the benefits of 4D planning. Conclusion: Our study shows that the BSD plan can approach the SD plan quality. However, such BSD scheme relies on the patient being able to follow the same breathing curve that is used in the planning stage during radiation delivery. Funded by Varian Medical Systems.

  13. Nanotechnology-based drug delivery systems for treatment of oral cancer: a review

    PubMed Central

    Calixto, Giovana; Bernegossi, Jéssica; Fonseca-Santos, Bruno; Chorilli, Marlus

    2014-01-01

    Oral cancer (oral cavity and oropharynx) is a common and aggressive cancer that invades local tissue, can cause metastasis, and has a high mortality rate. Conventional treatment strategies, such as surgery and chemoradiotherapy, have improved over the past few decades; however, they remain far from optimal. Currently, cancer research is focused on improving cancer diagnosis and treatment methods (oral cavity and oropharynx) nanotechnology, which involves the design, characterization, production, and application of nanoscale drug delivery systems. In medicine, nanotechnologies, such as polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, gold nanoparticles, hydrogels, cyclodextrin complexes, and liquid crystals, are promising tools for diagnostic probes and therapeutic devices. The objective of this study is to present a systematic review of nanotechnology-based drug delivery systems for oral cancers. PMID:25143724

  14. Delivery of Intraocular Triamcinolone Acetonide in the Treatment of Macular Edema

    PubMed Central

    Pickrell, Aaron; Harris, Alon; Ngo, Sandra; Amireskandari, Annahita; Stewart, Erin; Siesky, Brent

    2012-01-01

    Macular edema (ME) is one of the eventual outcomes of various intraocular and systemic pathologies. The pathogenesis for ME is not yet entirely understood; however, some of the common risk factors for its development have been identified. While this investigation will not discuss the numerous etiologies of ME in detail, it appraises the two most widely studied delivery modalities of intraocular corticosteroids in the treatment of ME—intravitreal injection (IVI) and sub-Tenon’s infusion (STI). A thorough review of the medical literature was conducted to identify the efficacy and safety of IVI and STI, specifically for the administration of triamcinolone acetonide (TA), in the setting of ME in an attempt to elucidate a preferred steroid delivery modality for treatment of ME. PMID:24300190

  15. Treatment planning, optimization, and beam delivery technqiues for intensity modulated proton therapy

    NASA Astrophysics Data System (ADS)

    Sengbusch, Evan R.

    Physical properties of proton interactions in matter give them a theoretical advantage over photons in radiation therapy for cancer treatment, but they are seldom used relative to photons. The primary barriers to wider acceptance of proton therapy are the technical feasibility, size, and price of proton therapy systems. Several aspects of the proton therapy landscape are investigated, and new techniques for treatment planning, optimization, and beam delivery are presented. The results of these investigations suggest a means by which proton therapy can be delivered more efficiently, effectively, and to a much larger proportion of eligible patients. An analysis of the existing proton therapy market was performed. Personal interviews with over 30 radiation oncology leaders were conducted with regard to the current and future use of proton therapy. In addition, global proton therapy market projections are presented. The results of these investigations serve as motivation and guidance for the subsequent development of treatment system designs and treatment planning, optimization, and beam delivery methods. A major factor impacting the size and cost of proton treatment systems is the maximum energy of the accelerator. Historically, 250 MeV has been the accepted value, but there is minimal quantitative evidence in the literature that supports this standard. A retrospective study of 100 patients is presented that quantifies the maximum proton kinetic energy requirements for cancer treatment, and the impact of those results with regard to treatment system size, cost, and neutron production is discussed. This study is subsequently expanded to include 100 cranial stereotactic radiosurgery (SRS) patients, and the results are discussed in the context of a proposed dedicated proton SRS treatment system. Finally, novel proton therapy optimization and delivery techniques are presented. Algorithms are developed that optimize treatment plans over beam angle, spot size, spot spacing

  16. Strategies for delivery of therapeutics into the central nervous system for treatment of lysosomal storage disorders.

    PubMed

    Muro, Silvia

    2012-06-01

    Lysosomal storage disorders (LSDs) are a group of about fifty life-threatening conditions caused by genetic defects affecting lysosomal components. The underscoring molecular deficiency leads to widespread cellular dysfunction through most tissues in the body, including peripheral organs and the central nervous system (CNS). Efforts during the last few decades have rendered a remarkable advance regarding our knowledge, medical awareness, and early detection of these genetic defects, as well as development of several treatment modalities. Clinical and experimental strategies encompassing enzyme replacement, gene and cell therapies, substrate reduction, and chemical chaperones are showing considerable potential in attenuating the peripheral pathology. However, a major drawback has been encountered regarding the suboptimal impact of these approaches on the CNS pathology. Particular anatomical and biochemical constraints of this tissue pose a major obstacle to the delivery of therapeutics into the CNS. Approaches to overcome these obstacles include modalities of local administration, strategies to enhance the blood-CNS permeability, intranasal delivery, use of exosomes, and those exploiting targeting of transporters and transcytosis pathways in the endothelial lining. The later two approaches are being pursued at the time by coupling therapeutic agents to affinity moieties and drug delivery systems capable of targeting these natural transport routes. This approach is particularly promising, as using paths naturally active at this interface may render safe and effective delivery of LSD therapies into the CNS.

  17. Curcumin loaded mesoporous silica: an effective drug delivery system for cancer treatment.

    PubMed

    Kotcherlakota, Rajesh; Barui, Ayan Kumar; Prashar, Sanjiv; Fajardo, Mariano; Briones, David; Rodríguez-Diéguez, Antonio; Patra, Chitta Ranjan; Gómez-Ruiz, Santiago

    2016-03-01

    In the present study, we report the delivery of anti-cancer drug curcumin to cancer cells using mesoporous silica materials. A series of mesoporous silica material based drug delivery systems (S2, S4 and S6) were first designed and developed through the amine functionalization of KIT-6, MSU-2 and MCM-41 followed by the loading of curcumin. The curcumin loaded materials were characterized with several physico-chemical techniques and thoroughly screened on cancer cells to evaluate their in vitro drug delivery efficacy. All the curcumin loaded silica materials exhibited higher cellular uptake and inhibition of cancer cell viability compared to pristine curcumin. The effective internalization of curcumin in cancer cells through the mesoporous silica materials initiated the generation of intracellular reactive oxygen species and the down regulation of poly ADP ribose polymerase (PARP) enzyme levels compared to free curcumin leading to the activation of apoptosis. This study shows that the anti-cancer activity of curcumin can be potentiated by loading onto mesoporous silica materials. Therefore, we strongly believe that mesoporous silica based curcumin loaded drug delivery systems may have future potential applications for the treatment of cancers.

  18. Nanoparticle-Mediated Systemic Delivery of siRNA for Treatment of Cancers and Viral Infections

    PubMed Central

    Draz, Mohamed Shehata; Fang, Binbin Amanda; Zhang, Pengfei; Hu, Zhi; Gu, Shenda; Weng, Kevin C.; Gray, Joe W.; Chen, Fanqing Frank

    2014-01-01

    RNA interference (RNAi) is an endogenous post-transcriptional gene regulatory mechanism, where non-coding, double-stranded RNA molecules interfere with the expression of certain genes in order to silence it. Since its discovery, this phenomenon has evolved as powerful technology to diagnose and treat diseases at cellular and molecular levels. With a lot of attention, short interfering RNA (siRNA) therapeutics has brought a great hope for treatment of various undruggable diseases, including genetic diseases, cancer, and resistant viral infections. However, the challenge of their systemic delivery and on how they are integrated to exhibit the desired properties and functions remains a key bottleneck for realizing its full potential. Nanoparticles are currently well known to exhibit a number of unique properties that could be strategically tailored into new advanced siRNA delivery systems. This review summarizes the various nanoparticulate systems developed so far in the literature for systemic delivery of siRNA, which include silica and silicon-based nanoparticles, metal and metal oxides nanoparticles, carbon nanotubes, graphene, dendrimers, polymers, cyclodextrins, lipids, hydrogels, and semiconductor nanocrystals. Challenges and barriers to the delivery of siRNA and the role of different nanoparticles to surmount these challenges are also included in the review. PMID:25057313

  19. Investigating end-to-end accuracy of image guided radiation treatment delivery using a micro-irradiator

    NASA Astrophysics Data System (ADS)

    Rankine, L. J.; Newton, J.; Bache, S. T.; Das, S. K.; Adamovics, J.; Kirsch, D. G.; Oldham, M.

    2013-11-01

    There is significant interest in delivering precisely targeted small-volume radiation treatments, in the pre-clinical setting, to study dose-volume relationships with tumour control and normal tissue damage. For these studies it is vital that image guidance systems and target positioning are accurately aligned (IGRT), in order to deliver dose precisely and accurately according to the treatment plan. In this work we investigate the IGRT targeting accuracy of the X-RAD 225 Cx system from Precision X-Ray using high-resolution 3D dosimetry techniques. Small cylindrical PRESAGE® dosimeters were used with optical-CT readout (DMOS) to verify the accuracy of 2.5, 1.0, and 5.0 mm X-RAD cone attachments. The dosimeters were equipped with four target points, visible on both CBCT and optical-CT, at which a 7-field coplanar treatment plan was delivered with the respective cone. Targeting accuracy (distance to agreement between the target point and delivery isocenter) and cone alignment (isocenter precision under gantry rotation) were measured using the optical-CT images. Optical-CT readout of the first 2.5 mm cone dosimeter revealed a significant targeting error of 2.1 ± 0.6 mm and a cone misalignment of 1.3 ± 0.1 mm. After the IGRT hardware and software had been recalibrated, these errors were reduced to 0.5 ± 0.1 and 0.18 ± 0.04 mm respectively, within the manufacturer specified 0.5 mm. Results from the 1.0 mm cone were 0.5 ± 0.3 mm targeting accuracy and 0.4 ± 0.1 mm cone misalignment, within the 0.5 mm specification. The results from the 5.0 mm cone were 1.0 ± 0.2 mm targeting accuracy and 0.18 ± 0.06 mm cone misalignment, outside of accuracy specifications. Quality assurance of small field IGRT targeting and delivery accuracy is a challenging task. The use of a 3D dosimetry technique, where targets are visible on both CBCT and optical-CT, enabled identification and quantification of a targeting error in 3D. After correction, the targeting accuracy of the

  20. A Bayesian approach to real-time 3D tumor localization via monoscopic x-ray imaging during treatment delivery

    SciTech Connect

    Li, Ruijiang; Fahimian, Benjamin P.; Xing, Lei

    2011-07-15

    Purpose: Monoscopic x-ray imaging with on-board kV devices is an attractive approach for real-time image guidance in modern radiation therapy such as VMAT or IMRT, but it falls short in providing reliable information along the direction of imaging x-ray. By effectively taking consideration of projection data at prior times and/or angles through a Bayesian formalism, the authors develop an algorithm for real-time and full 3D tumor localization with a single x-ray imager during treatment delivery. Methods: First, a prior probability density function is constructed using the 2D tumor locations on the projection images acquired during patient setup. Whenever an x-ray image is acquired during the treatment delivery, the corresponding 2D tumor location on the imager is used to update the likelihood function. The unresolved third dimension is obtained by maximizing the posterior probability distribution. The algorithm can also be used in a retrospective fashion when all the projection images during the treatment delivery are used for 3D localization purposes. The algorithm does not involve complex optimization of any model parameter and therefore can be used in a ''plug-and-play'' fashion. The authors validated the algorithm using (1) simulated 3D linear and elliptic motion and (2) 3D tumor motion trajectories of a lung and a pancreas patient reproduced by a physical phantom. Continuous kV images were acquired over a full gantry rotation with the Varian TrueBeam on-board imaging system. Three scenarios were considered: fluoroscopic setup, cone beam CT setup, and retrospective analysis. Results: For the simulation study, the RMS 3D localization error is 1.2 and 2.4 mm for the linear and elliptic motions, respectively. For the phantom experiments, the 3D localization error is < 1 mm on average and < 1.5 mm at 95th percentile in the lung and pancreas cases for all three scenarios. The difference in 3D localization error for different scenarios is small and is not

  1. Pregnancy and delivery complications and treatment approach in attention deficit hyperactivity disorder.

    PubMed

    Aktepe, Evrim; Ozkorumak, Evrim; Tanriöver-Kandil, Sema

    2009-01-01

    Pregnancy, delivery complications and treatment approach were evaluated in 153 cases diagnosed with attention deficit hyperactivity disorder in the State Hospital of Antalya in the Child and Adolescent Psychiatry Polyclinic. Most of the cases had been delivered vaginally (74.5%). The most frequent delivery complication was asphyxia/hypoxia (15.6%). The agent most frequently preferred in the treatment regimen was methylphenidate (82.4%), which is a psychostimulant. The other drugs used were risperidone (29.4%), selective serotonin reuptake inhibitors (16.4%) and imipramine (4.6%). The most frequent side effect resulting from methylphenidate use was a decrease in appetite (34.9%). Attention deficit hyperactivity disorder often presents with comorbid disorders; in these cases, nonstimulant agents had to be added to methylphenidate for better treatment outcomes. Use of selective serotonin reuptake inhibitors in combined treatment and in cases with comorbidities is in agreement with the literature. Further studies of combined treatment regimens in attention deficit hyperactivity disorder are needed.

  2. Postoperative Irradiation of Gynecologic Malignancies: Improving Treatment Delivery Using Aperture-Based Intensity-Modulated Radiotherapy

    SciTech Connect

    Nadeau, Sylvain . E-mail: sylvainn@rrsb.nb.ca; Bouchard, Myriam; Germain, Isabelle; Raymond, Paul-Emile; Beaulieu, Frederic; Beaulieu, Luc; Roy, Rene; Gingras, Luc

    2007-06-01

    Purpose: To evaluate dosimetric and treatment delivery advantages of aperture-based intensity-modulated radiotherapy (AB-IMRT) for the treatment of patients receiving whole pelvic radiotherapy for gynecologic malignancies. Methods and Materials: Nineteen patients undergoing pelvic radiotherapy after resection of endometrial cancers were selected. A 45-Gy dose was prescribed to the target volume delineated on a planning CT scan. An in-house inverse planning system, Ballista, was used to develop a treatment plan using aperture-based multileaf collimator segments. This approach was compared with conventional four-field, enlarged four-field, and static beamlet-based IMRT (BB-IMRT) techniques in terms of target coverage, dose-volume histogram statistics for surrounding normal tissues, and numbers of segments and monitor units (MU). Results: Three quarters (76.4%) of the planning target volume received the prescription dose with conventional four-field plans. With adequate target coverage, the Ballista plans significantly reduced the volume of bowel and bladder irradiated at the prescribed dose (p < 0.001), whereas the two approaches provided equivalent results for the rectum (p 0.5). On the other hand, AB-IMRT and BB-IMRT plans showed only small differences in dose-volume histogram statistics of unknown clinical impact, whereas Ballista plan delivery required on average 73% and 59% fewer segments and MU, respectively. Conclusion: With respect to conventional techniques, AB-IMRT for the treatment of gynecologic malignancies provides dosimetric advantages similar to those with BB-IMRT but with clear treatment delivery improvements.

  3. Ungual and trans-ungual iontophoretic delivery of terbinafine for the treatment of onychomycosis.

    PubMed

    Nair, Anroop B; Kim, Hyun D; Chakraborty, Bireswar; Singh, Jagpal; Zaman, Muhammad; Gupta, Aditya; Friden, Phillip M; Murthy, S Narasimha

    2009-11-01

    The application of iontophoresis was demonstrated in the nail drug delivery of terbinafine (TH) recently. This study explored a systematic assessment of this approach to enhance the drug delivery using a novel topical formulation, and the subsequent release of TH from the drug loaded nails. For the first time, a nail on-agar plate model was used to study the release of drug from the iontophoresis (0.5 mA/cm(2)) loaded nails. In addition, the activity of the drug released from the drug loaded nail plate was studied against Trichophyton rubrum. An increase in applied current density and current duration enhanced the transport of TH into and through the nail plate. In vitro release of drug from the iontophoretic loaded nails into agar plates exhibited 2-phase release pattern. The amount of drug released in both of the in vitro models was comparable, and the nails loaded using iontophoresis continued to release levels of TH > 2 orders of magnitude above the minimum inhibitory concentration over at least 52 days. Results indicate that iontophoresis enhances the delivery of terbinafine into and through the nail plate and suggest that the use of this treatment approach could result in a safe and more efficacious outcome with less frequent treatments.

  4. Pectin matrix as oral drug delivery vehicle for colon cancer treatment.

    PubMed

    Wong, Tin Wui; Colombo, Gaia; Sonvico, Fabio

    2011-03-01

    Colon cancer is the fourth most common cancer globally with 639,000 deaths reported annually. Typical chemotherapy is provided by injection route to reduce tumor growth and metastasis. Recent research investigates the oral delivery profiles of chemotherapeutic agents. In comparison to injection, oral administration of drugs in the form of a colon-specific delivery system is expected to increase drug bioavailability at target site, reduce drug dose and systemic adverse effects. Pectin is suitable for use as colon-specific drug delivery vehicle as it is selectively digested by colonic microflora to release drug with minimal degradation in upper gastrointestinal tract. The present review examines the physicochemical attributes of formulation needed to retard drug release of pectin matrix prior to its arrival at colon, and evaluate the therapeutic value of pectin matrix in association with colon cancer. The review suggests that multi-particulate calcium pectinate matrix is an ideal carrier to orally deliver drugs for site-specific treatment of colon cancer as (1) crosslinking of pectin by calcium ions in a matrix negates drug release in upper gastrointestinal tract, (2) multi-particulate carrier has a slower transit and a higher contact time for drug action in colon than single-unit dosage form, and (3) both pectin and calcium have an indication to reduce the severity of colon cancer from the implication of diet and molecular biology studies. Pectin matrix demonstrates dual advantages as drug carrier and therapeutic for use in treatment of colon cancer.

  5. Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness.

    PubMed

    Khalin, Igor; Alyautdin, Renad; Kocherga, Ganna; Bakar, Muhamad Abu

    2015-01-01

    Neurodegenerative causes of blindness and deafness possess a major challenge in their clinical management as proper treatment guidelines have not yet been found. Brain-derived neurotrophic factor (BDNF) has been established as a promising therapy against neurodegenerative disorders including hearing and visual loss. Unfortunately, the blood-retinal barrier and blood-cochlear barrier, which have a comparable structure to the blood-brain barrier prevent molecules of larger sizes (such as BDNF) from exiting the circulation and reaching the targeted cells. Anatomical features of the eye and ear allow use of local administration, bypassing histo-hematic barriers. This paper focuses on highlighting a variety of strategies proposed for the local administration of the BDNF, like direct delivery, viral gene therapy, and cell-based therapy, which have been shown to successfully improve development, survival, and function of spiral and retinal ganglion cells. The similarities and controversies for BDNF treatment of posterior eye diseases and inner ear diseases have been analyzed and compared. In this review, we also focus on the possibility of translation of this knowledge into clinical practice. And finally, we suggest that using nanoparticulate drug-delivery systems may substantially contribute to the development of clinically viable techniques for BDNF delivery into the cochlea or posterior eye segment, which, ultimately, can lead to a long-term or permanent rescue of auditory and optic neurons from degeneration.

  6. Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness

    PubMed Central

    Khalin, Igor; Alyautdin, Renad; Kocherga, Ganna; Bakar, Muhamad Abu

    2015-01-01

    Neurodegenerative causes of blindness and deafness possess a major challenge in their clinical management as proper treatment guidelines have not yet been found. Brain-derived neurotrophic factor (BDNF) has been established as a promising therapy against neurodegenerative disorders including hearing and visual loss. Unfortunately, the blood–retinal barrier and blood–cochlear barrier, which have a comparable structure to the blood–brain barrier prevent molecules of larger sizes (such as BDNF) from exiting the circulation and reaching the targeted cells. Anatomical features of the eye and ear allow use of local administration, bypassing histo-hematic barriers. This paper focuses on highlighting a variety of strategies proposed for the local administration of the BDNF, like direct delivery, viral gene therapy, and cell-based therapy, which have been shown to successfully improve development, survival, and function of spiral and retinal ganglion cells. The similarities and controversies for BDNF treatment of posterior eye diseases and inner ear diseases have been analyzed and compared. In this review, we also focus on the possibility of translation of this knowledge into clinical practice. And finally, we suggest that using nanoparticulate drug-delivery systems may substantially contribute to the development of clinically viable techniques for BDNF delivery into the cochlea or posterior eye segment, which, ultimately, can lead to a long-term or permanent rescue of auditory and optic neurons from degeneration. PMID:25995632

  7. Comparative analysis of the methods of drug and protein delivery for the treatment of cancer, genetic diseases and diagnostics.

    PubMed

    Todorova, Roumiana

    2011-11-01

    The methods of protein and drug delivery for the treatment of cancer, genetic diseases and diagnostics were summarized. The potential of protein transduction is discussed and the recent developments in the field are reviewed. An overview is provided of the non-viral delivery methods such as liposomes, polymer-based delivery, cell-penetrating peptides, bacterial secretion, cells, virosomes, physical methods including electroporation, microinjection, osmotic lysis, nanoparticles, sonoporation to locally inject therapeutic molecules. The characteristic properties of non-viral vectors and their use for the delivery of therapeutic molecules for the diagnosis and treatment of disorders and to target tumors are also discussed. The potential of the transduced peptides and proteins was used as new therapeutic compounds against infectious diseases, to complement deficiencies in specific genes, to specifically kill tumour cells, for gene therapy. The protein delivery vectors can enhance the transfection at low concentrations and help to develop future gene delivery systems with reduced toxicity. Vitamin B12, folic acid, biotin, and riboflavin are essential in the treatment of cancer. Ultrasound has a potential in the delivery of therapeutic agents. The new developing technologies of drug delivery and targeting offer the possibility to improve the therapeutic possibilities of the existing drugs and to develop novel therapeutics.

  8. Treatment of acute massive pulmonary embolism by streptokinase during labour and delivery.

    PubMed

    Hall, R J; Young, C; Sutton, G C; Cambell, S

    1972-12-16

    A 29-year-old woman sustained an acute massive pulmonary embolism in the 32nd week of pregnancy. Rapid clinical improvement followed the use of streptokinase. Treatment was continued for 41 hours, including labour and the first three hours after delivery. There was slow but severe postpartum haemorrhage. Partial uterine atony occurred, and may have been due, at least in part, to fibrin degradation products arising from thrombolysis. No adverse effects were noted in the baby.Our experience suggests that streptokinase may be given during labour but that an oxytocic agent may be needed; and that reversal of fibrinolysis before delivery is best achieved by the use of aprotinin (Trasylol) rather than aminocaproic acid.

  9. SU-E-J-17: Intra-Fractional Prostate Movement Correction During Treatment Delivery Period for Prostate Cancer Using the Intra-Fractional Orthogonal KV-MV Image Pairs

    SciTech Connect

    Zhang, J; Azawi, S; Cho-Lim, J; Wei, R; Williams, R; Frank, E

    2015-06-15

    Purpose: To evaluate the intra-fractional prostate movement range during the beam delivery and implement new IGRT method to correct the prostate movement during the hypofractionated prostate treatment delivery. Methods: To evaluate the prostate internal motion range during the beam delivery, 11 conventional treatments were utilized. Two-arc RapidArc plans were used for the treatment delivery. Orthogonal KV imaging is performed in the middle of the treatment to correct intra-fractional prostate movement. However, it takes gantry-mounted on-board imaging system relative long time to finish the orthogonal KV imaging because of gantry rotation. To avoid gantry movement and accelerate the IGRT processing time, orthogonal KV-MV image pair is tested using the OBI daily QA Cube phantom. Results: The average prostate movement between two orthogonal KV image pairs was 0.38cm (0.20cm ∼ 0.85cm). And the interval time between them was 6.71 min (4.64min ∼ 9.22 min). 2-arc beam delivery time is within 3 minutes for conventional RapidArc treatment delivery. Hypofractionated treatment or SBRT need 4 partial arc and possible non-coplanar technology, which need much longer beam delivery time. Therefore prostate movement might be larger. New orthogonal KV-MV image pair is a new method to correct the prostate movement in the middle of the beam delivery if real time tracking method is not available. Orthogonal KV-MV image pair doesn’t need gantry rotation. Images were acquired quickly which minimized possible new prostate movement. Therefore orthogonal KV-MV image pair is feasible for IGRT. Conclusion: Hypofractionated prostate treatment with less PTV margin always needs longer beam delivery time. Therefore prostate movement correction during the treatment delivery is critical. Orthogonal KV-MV imaging pair is efficient and accurate to correct the prostate movement during treatment beam delivery. Due to limited fraction number and high dose per fraction, the MV imaging dose is

  10. Localized Co-delivery of Doxorubicin, Cisplatin, and Methotrexate by Thermosensitive Hydrogels for Enhanced Osteosarcoma Treatment.

    PubMed

    Ma, Hecheng; He, Chaoliang; Cheng, Yilong; Yang, Zhiming; Zang, Junting; Liu, Jianguo; Chen, Xuesi

    2015-12-16

    Localized cancer treatments with combination drugs have recently emerged as crucial approaches for effective inhibition of tumor growth and reoccurrence. In this study, we present a new strategy for the osteosarcoma treatment by localized co-delivery of multiple drugs, including doxorubicin (DOX), cisplatin (CDDP) and methotraxate (MTX), using thermosensitive PLGA-PEG-PLGA hydrogels. The release profiles of the drugs from the hydrogels were investigated in vitro. It was found that the multidrug coloaded hydrogels exhibited synergistic effects on cytotoxicity against osteosarcoma Saos-2 and MG-63 cells in vitro. After a single peritumoral injection of the drug-loaded hydrogels into nude mice bearing human osteosarcoma Saos-2 xenografts, the hydrogels coloaded with DOX, CDDP, and MTX displayed the highest tumor suppression efficacy in vivo for up to 16 days, as well as led to enhanced tumor apoptosis and increased regulation of the expressions of apoptosis-related genes. Moreover, the monitoring on the mice body change and the ex vivo histological analysis of the key organs indicated that the localized treatments caused less systemic toxicity and no obvious damage to the normal organs. Therefore, the approach of localized co-delivery of DOX, CDDP, and MTX by the thermosensitive hydrogels may be a promising approach for enhanced osteosarcoma treatment.

  11. Buparvaquone Nanostructured Lipid Carrier: Development of an Affordable Delivery System for the Treatment of Leishmaniases.

    PubMed

    Monteiro, Lis Marie; Löbenberg, Raimar; Cotrim, Paulo Cesar; Barros de Araujo, Gabriel Lima; Bou-Chacra, Nádia

    2017-01-01

    Buparvaquone (BPQ), a veterinary drug, was formulated as nanostructured lipid carriers (NLC) for leishmaniases treatment. The formulation design addressed poor water solubility of BPQ and lack of human drug delivery system. The DSC/TG and microscopy methods were used for solid lipids screening. Softisan® 154 showed highest BPQ solubility in both methods. The BPQ solubility in liquid lipids using HPLC revealed Miglyol® 812 as the best option. Response surface methodology (RSM) was used to identify the optimal Softisan154 : Miglyol 812 ratios (7 : 10 to 2 : 1) and Kolliphor® P188 and Tween® 80 concentration (>3.0% w/w) aiming for z-average in the range of 100-300 nm for macrophage delivery. The NLC obtained by high-pressure homogenization showed low z-averages (<350 nm), polydispersity (<0.3), and encapsulation efficiency close to 100%. DSC/TG and microscopy in combination proved to be a powerful tool to select the solid lipid. The relationship among the variables, demonstrated by a linear mathematical model using RSM, allowed generating a design space. This design space showed the limits in which changes in the variables influenced the z-average. Therefore, these drug delivery systems have the potential to improve the availability of affordable medicines due to the low cost of raw materials, using well established, reliable, and feasible scale-up technology.

  12. Biologically responsive carrier-mediated anti-angiogenesis shRNA delivery for tumor treatment

    PubMed Central

    Che, Junyi; Tao, Anqi; Chen, Shun; Li, Xiaoming; Zhao, Yi; Yuan, Weien

    2016-01-01

    Small interfering RNA (siRNA) has increased the hope for highly-efficient treatment of gene-related diseases. However, the stable and efficient delivery of therapeutic nucleic acids is a prerequisite for the successful clinical translation of RNA interfering therapy. To achieve this, we condensed the low molecular weight polyethyleneimine (PEI, Mw < 2000) with 2,6-pyridinedicarboxaldehyde (PDA) to synthesize a biologically responsive and degradable cationic polymer (abbreviated to PDAPEI) which was utilized as a gene vector for the delivery of a VEGF-A shRNA expression plasmid DNA (pDNA). The resulting electrostatic interaction between PDAPEI and pDNA led to the self-assembly of nanoscale polyplexes with suitable particle size and stable zeta potential. The PDAPEI/pDNA polyplexes demonstrated an outstanding gene transfection and silencing efficiency at 30 w/w ratio, as well as negligible cytotoxicity. Also, the designed polymer showed no stimulation to the innate immune system. Moreover, compared with PEI 25 KDa, the polyplexes accomplished comparatively better anti-angiogenesis efficacy, which resulted in the inhibition of tumor growth in subcutaneous tumor mice models. In conclusion, PDAPEI has great potential to be a gene delivery vector for cancer therapy. PMID:27759095

  13. Buparvaquone Nanostructured Lipid Carrier: Development of an Affordable Delivery System for the Treatment of Leishmaniases

    PubMed Central

    Löbenberg, Raimar; Cotrim, Paulo Cesar

    2017-01-01

    Buparvaquone (BPQ), a veterinary drug, was formulated as nanostructured lipid carriers (NLC) for leishmaniases treatment. The formulation design addressed poor water solubility of BPQ and lack of human drug delivery system. The DSC/TG and microscopy methods were used for solid lipids screening. Softisan® 154 showed highest BPQ solubility in both methods. The BPQ solubility in liquid lipids using HPLC revealed Miglyol® 812 as the best option. Response surface methodology (RSM) was used to identify the optimal Softisan154 : Miglyol 812 ratios (7 : 10 to 2 : 1) and Kolliphor® P188 and Tween® 80 concentration (>3.0% w/w) aiming for z-average in the range of 100–300 nm for macrophage delivery. The NLC obtained by high-pressure homogenization showed low z-averages (<350 nm), polydispersity (<0.3), and encapsulation efficiency close to 100%. DSC/TG and microscopy in combination proved to be a powerful tool to select the solid lipid. The relationship among the variables, demonstrated by a linear mathematical model using RSM, allowed generating a design space. This design space showed the limits in which changes in the variables influenced the z-average. Therefore, these drug delivery systems have the potential to improve the availability of affordable medicines due to the low cost of raw materials, using well established, reliable, and feasible scale-up technology. PMID:28255558

  14. MicroRNAs as therapeutics for future drug delivery systems in treatment of lung diseases.

    PubMed

    Dua, Kamal; Hansbro, Nicole G; Foster, Paul S; Hansbro, Philip M

    2017-02-01

    The rapid advancement in the area of microRNAs (miRNAs) from discovery to their translation into therapeutic moieties reflects their significance as important regulators in the management of disease pathology. The miRNAs can potentially be a new class of drugs in the near future for the treatment of various lung diseases, but it lacks the current knowledge how these identified therapeutic moieties can be designed into an effective, patient complaint and targeted drug delivery system. miRNAs have characteristic features like small size and low molecular weight which makes them easily translated into an effective drug delivery system. In this review, we have summarised the concept of miRNAs and different approaches which can be employed to deliver miRNAs effectively and safely to the target cells including the challenges associated with their development in particular emphasis on pulmonary diseases. Such approaches will be of interest for both the biological and formulation scientists to understand and explore the new vistas in the area of miRNA delivery for pulmonary inflammatory diseases.

  15. Use of Liposomes as Drug Delivery Vehicles for Treatment of Melanoma

    PubMed Central

    Tran, Melissa A.; Watts, Rebecca J.; Robertson, Gavin P.

    2009-01-01

    Melanoma is a progressive disease that claims many lives each year due to lack of therapeutics effective for the long-term treatment of patients. Currently, the best treatment option is early detection followed by surgical removal. Better melanoma therapies that are effectively delivered to tumors with minimal toxicity for patients are urgently needed. Nanotechnologies provide one approach to encapsulate therapeutic agents leading to improvements in circulation time, enhanced tumor uptake, avoidance of the reticulo-endothelial system, and minimization of toxicity. Liposomes in particular are a promising nanotechnology that can be used for more effective delivery of therapeutic agents to treat melanoma. Liposomes delivering chemotherapies, siRNA, asODNs, DNA, and radioactive particles are just some of the promising new nanotechnology based therapies under development for the treatment of melanoma that are discussed in this review. PMID:19493316

  16. Skin mechanics measured in vivo using torsion: a new and accurate model more sensitive to age, sex and moisturizing treatment.

    PubMed

    Salter, D C; McArthur, H C; Crosse, J E; Dickens, A D

    1993-10-01

    Summary Measurements of skin mechanics are required to understand better cracking and flaking of the epidermis and loss of 'elasticity'with age in the dermis. Improvements in torsional testing are described here. The resulting data was fitted to algebraic models, the parameters of which can serve both as a concise description of the responses and as a means of relating them to skin structure and physiology. This investigation looks into the suitability of seven such algebraic models. Five of the models examined here appear to be new. Using the commercially available Dia-Stron DTM Torque Meter with our own software, model parameters were studied as indicators of the effects of age and sex in 41 people, and of skin moisturizing treatments in a further 10 people. The two models in the literature were both found to be substantially less accurate and sensitive representations of experimental data than one of the new models proposed here based on the Weibull distribution. This 'WB model'was consistently the one best able to distinguish differences and detect changes which were statistically significant. The WB model appears to be the most powerful and efficient available. Use of this model makes it possible to demonstrate in vivo a statistically significant mechanical difference between male and pre-menopausal female skin using only one parameter (p= 0.0163, with 18 males and 19 females) and to demonstrate a statistically significant mechanical difference between successive decades of age in female skin using only one parameter (p= 0.0124, n= 24). The two parameters of the model most sensitive to skin structure, function and treatment have been combined to form the axes of a 'Skin condition chart'. Any person can be located on this chart at a point indicating their overall skin condition in mechanical terms and any changes in that condition can be clearly demonstrated by movement across the plot.

  17. Nanovectors for anti-cancer drug delivery in the treatment of advanced pancreatic adenocarcinoma

    PubMed Central

    Hsueh, Chung-Tzu; Selim, Julie H; Tsai, James Y; Hsueh, Chung-Tsen

    2016-01-01

    Liposome, albumin and polymer polyethylene glycol are nanovector formulations successfully developed for anti-cancer drug delivery. There are significant differences in pharmacokinetics, efficacy and toxicity between pre- and post-nanovector modification. The alteration in clinical pharmacology is instrumental for the future development of nanovector-based anticancer therapeutics. We have reviewed the results of clinical studies and translational research in nanovector-based anti-cancer therapeutics in advanced pancreatic adenocarcinoma, including nanoparticle albumin-bound paclitaxel and nanoliposomal irinotecan. Furthermore, we have appraised the ongoing studies incorporating novel agents with nanomedicines in the treatment of pancreatic adenocarcinoma. PMID:27610018

  18. Investigation of pulsed IMRT and VMAT for re-irradiation treatments: dosimetric and delivery feasibilities

    NASA Astrophysics Data System (ADS)

    Lin, Mu-Han; Price, Robert A., Jr.; Li, Jinsheng; Kang, Shengwei; Li, Jie; Ma, C.-M.

    2013-11-01

    Many tumor cells demonstrate hyperradiosensitivity at doses below ˜50 cGy. Together with the increased normal tissue repair under low dose rate, the pulsed low dose rate radiotherapy (PLDR), which separates a daily fractional dose of 200 cGy into 10 pulses with 3 min interval between pulses (˜20 cGy/pulse and effective dose rate 6.7 cGy min-1), potentially reduces late normal tissue toxicity while still providing significant tumor control for re-irradiation treatments. This work investigates the dosimetric and technical feasibilities of intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT)-based PLDR treatments using Varian Linacs. Twenty one cases (12 real re-irradiation cases) including treatment sites of pancreas, prostate, pelvis, lung, head-and-neck, and breast were recruited for this study. The lowest machine operation dose rate (100 MU min-1) was employed in the plan delivery. Ten-field step-and-shoot IMRT and dual-arc VMAT plans were generated using the Eclipse TPS with routine planning strategies. The dual-arc plans were delivered five times to achieve a 200 cGy daily dose (˜20 cGy arc-1). The resulting plan quality was evaluated according to the heterogeneity and conformity indexes (HI and CI) of the planning target volume (PTV). The dosimetric feasibility of retaining the hyperradiosensitivity for PLDR was assessed based on the minimum and maximum dose in the target volume from each pulse. The delivery accuracy of VMAT and IMRT at the 100 MU min-1 machine operation dose rate was verified using a 2D diode array and ion chamber measurements. The delivery reproducibility was further investigated by analyzing the Dynalog files of repeated deliveries. A comparable plan quality was achieved by the IMRT (CI 1.10-1.38 HI 1.04-1.10) and the VMAT (CI 1.08-1.26 HI 1.05-1.10) techniques. The minimum/maximum PTV dose per pulse is 7.9 ± 5.1 cGy/33.7 ± 6.9 cGy for the IMRT and 12.3 ± 4.1 cGy/29.2 ± 4.7 cGy for the VMAT. Six out of

  19. Cell mediated therapeutics for cancer treatment: Tumor homing cells as therapeutic delivery vehicles

    NASA Astrophysics Data System (ADS)

    Balivada, Sivasai

    Many cell types were known to have migratory properties towards tumors and different research groups have shown reliable results regarding cells as delivery vehicles of therapeutics for targeted cancer treatment. Present report discusses proof of concept for 1. Cell mediated delivery of Magnetic nanoparticles (MNPs) and targeted Magnetic hyperthermia (MHT) as a cancer treatment by using in vivo mouse cancer models, 2. Cells surface engineering with chimeric proteins for targeted cancer treatment by using in vitro models. 1. Tumor homing cells can carry MNPs specifically to the tumor site and tumor burden will decrease after alternating magnetic field (AMF) exposure. To test this hypothesis, first we loaded Fe/Fe3O4 bi-magnetic NPs into neural progenitor cells (NPCs), which were previously shown to migrate towards melanoma tumors. We observed that NPCs loaded with MNPs travel to subcutaneous melanoma tumors. After alternating magnetic field (AMF) exposure, the targeted delivery of MNPs by the NPCs resulted in a mild decrease in tumor size (Chapter-2). Monocytes/macrophages (Mo/Ma) are known to infiltrate tumor sites, and also have phagocytic activity which can increase their uptake of MNPs. To test Mo/Ma-mediated MHT we transplanted Mo/Ma loaded with MNPs into a mouse model of pancreatic peritoneal carcinomatosis. We observed that MNP-loaded Mo/Ma infiltrated pancreatic tumors and, after AMF treatment, significantly prolonged the lives of mice bearing disseminated intraperitoneal pancreatic tumors (Chapter-3). 2. Targeted cancer treatment could be achieved by engineering tumor homing cell surfaces with tumor proteases cleavable, cancer cell specific recombinant therapeutic proteins. To test this, Urokinase and Calpain (tumor specific proteases) cleavable; prostate cancer cell (CaP) specific (CaP1 targeting peptide); apoptosis inducible (Caspase3 V266ED3)- rCasp3V266ED3 chimeric protein was designed in silico. Hypothesized membrane anchored chimeric protein (rCasp3V

  20. Treatment delivery software for a new clinical grade ultrasound system for thermoradiotherapy.

    PubMed

    Novák, Petr; Moros, Eduardo G; Straube, William L; Myerson, Robert J

    2005-11-01

    A detailed description of a clinical grade Scanning Ultrasound Reflector Linear Array System (SURLAS) applicator was given in a previous paper [Med. Phys. 32, 230-240 (2005)]. In this paper we concentrate on the design, development, and testing of the personal computer (PC) based treatment delivery software that runs the therapy system. The SURLAS requires the coordinated interaction between the therapy applicator and several peripheral devices for its proper and safe operation. One of the most important tasks was the coordination of the input power sequences for the elements of two parallel opposed ultrasound arrays (eight 1.5 cm x 2 cm elements/array, array 1 and 2 operate at 1.9 and 4.9 MHz, respectively) in coordination with the position of a dual-face scanning acoustic reflector. To achieve this, the treatment delivery software can divide the applicator's treatment window in up to 64 sectors (minimum size of 2 cm x 2 cm), and control the power to each sector independently by adjusting the power output levels from the channels of a 16-channel radio-frequency generator. The software coordinates the generator outputs with the position of the reflector as it scans back and forth between the arrays. Individual sector control and dual frequency operation allows the SURLAS to adjust power deposition in three dimensions to superficial targets coupled to its treatment window. The treatment delivery software also monitors and logs several parameters such as temperatures acquired using a 16-channel thermocouple thermometry unit. Safety (in particular to patients) was the paramount concern and design criterion. Failure mode and effects analysis (FMEA) was applied to the applicator as well as to the entire therapy system in order to identify safety issues and rank their relative importance. This analysis led to the implementation of several safety mechanisms and a software structure where each device communicates with the controlling PC independently of the others. In case

  1. Ethosomes-based topical delivery system of antihistaminic drug for treatment of skin allergies.

    PubMed

    Goindi, Shishu; Dhatt, Bhavnita; Kaur, Amanpreet

    2014-01-01

    Cetirizine is indicated for the treatment of allergic conditions such as insect bites and stings, atopic and contact dermatitis, eczema, urticaria. This investigation deals with development of a novel ethosome-based topical formulation of cetirizine dihydrochloride for effective delivery. The optimised formulation consisting of drug, phospholipon 90 G™ and ethanol was characterised for drug content, entrapment efficiency, pH, vesicular size, spreadability and rheological behaviour. The ex vivo permeation studies through mice skin showed highest permeation flux (16.300 ± 0.300 µg/h/cm(2)) and skin retention (20.686 ± 0.517 µg/cm(2)) for cetirizine-loaded ethosomal vesicles as compared to conventional formulations. The in vivo pharmacodynamic evaluation of optimised formulation was assessed against oxazolone-induced atopic dermatitis (AD) in mice. The parameters evaluated were reduction in scratching score, erythema score, skin hyperplasia and dermal eosinophil count. Our results suggest that ethosomes are effective carriers for dermal delivery of antihistaminic drug, cetirizine, for the treatment of AD.

  2. A novel treatment for metastatic lymph nodes using lymphatic delivery and photothermal therapy

    PubMed Central

    Oladipo, Adewale O.; Oluwafemi, Oluwatobi S.; Songca, Sandile P.; Sukhbaatar, Ariunbuyan; Mori, Shiro; Okajima, Junnosuke; Komiya, Atsuki; Maruyama, Shigenao; Kodama, Tetsuya

    2017-01-01

    Systemic delivery of an anti-cancer agent often leads to only a small fraction of the administered dose accumulating in target sites. Delivering anti-cancer agents through the lymphatic network can achieve more efficient drug delivery for the treatment of lymph node metastasis. We show for the first time that polymeric gold nanorods (PAuNRs) can be delivered efficiently from an accessory axillary lymph node to a tumor-containing proper axillary lymph node, enabling effective treatment of lymph node metastasis. In a mouse model of metastasis, lymphatic spread of tumor was inhibited by lymphatic-delivered PAuNRs and near-infrared laser irradiation, with the skin temperature controlled by cooling. Unlike intravenous injection, lymphatic injection delivered PAuNRs at a high concentration within a short period. The results show that lymphatic administration has the potential to deliver anti-cancer agents to metastatic lymph nodes for inhibition of tumor growth and could be developed into a new therapeutic method. PMID:28368042

  3. Sorafenib and gadolinium co-loaded liposomes for drug delivery and MRI-guided HCC treatment.

    PubMed

    Xiao, Yanan; Liu, Yongjun; Yang, Shaomei; Zhang, Bo; Wang, Tianqi; Jiang, Dandan; Zhang, Jing; Yu, Dexin; Zhang, Na

    2016-05-01

    To improve the poor water solubility of sorafenib and to monitor its distribution and the early feedback effects on its in vivo treatment efficacy in a precise manner, sorafenib (SF) and gadolinium (Gd) co-loaded liposomes (SF/Gd-liposomes) were prepared. The simultaneous imaging and therapy efficacies of the SF/Gd-liposomes were tested. The solubility of SF in SF/Gd-liposomes was significantly increased from 0.21 μg/mL to 250 μg/mL. The imaging capability of SF/Gd-liposomes were tested by in-vitro and the in-vivo imaging ability tests and the results confirmed that SF/Gd-liposomes could be served as an effective contrast agent. The design of SF/Gd-liposomes allowed the MRI-guided in vivo visualization of the delivery and biodistribution of liposome. In the in vivo antitumor studies, SF/Gd-liposomes had better antitumor effects in H22 tumor-bearing mice than SF solution (oral or i.v. administration) (P<0.05). These findings indicated that the SF/Gd-liposomes could be used as the promising nano-carriers for the MRI-guided in vivo visualization of the delivery and HCC treatment.

  4. An overview of drug delivery vehicles for cancer treatment: Nanocarriers and nanoparticles including photovoltaic nanoparticles.

    PubMed

    Chowdhury, Silvia; Yusof, Faridah; Salim, Wan Wardatul Amani Wan; Sulaiman, Nadzril; Faruck, Mohammad Omer

    2016-11-01

    Cancer is a complicated disease for which finding a cure presents challenges. In recent decades, new ways to treat cancer are being sought; one being nanomedicine, which manipulates nanoparticles to target a cancer and release drugs directly to the cancer cells. A number of cancer treatments based on nanomedicine are under way and mostly are in preclinical trials owing to challenges in administration, safety, and effectiveness. One alternative method for drug delivery is the use of photovoltaic nanoparticles, which has the potential to deliver drugs via light activation. The concepts are based on standard photovoltaic cell that holds opposite charges on its surfaces and releases drugs when charge intensity or polarity changes upon photo-stimulation such as from a laser source or sunlight. This review will cover some recent progress in cancer treatment using nanoparticles, including photovoltaic nanoparticles.

  5. The relationship of therapeutic alliance and treatment delivery fidelity with treatment retention in a multisite trial of twelve-step facilitation.

    PubMed

    Campbell, Barbara K; Guydish, Joseph; Le, Thao; Wells, Elizabeth A; McCarty, Dennis

    2015-03-01

    This study examined associations of therapeutic alliance and treatment delivery fidelity with treatment retention in Stimulant Abusers to Engage in Twelve-Step (STAGE-12), a community-based trial of 12-Step Facilitation (TSF) conducted within the National Drug Abuse Treatment Clinical Trials Network (CTN). The STAGE-12 trial randomized 234 stimulant abusers enrolled in 10 outpatient drug treatment programs to an eight-session, group and individual TSF intervention. During the study, TSF participants rated therapeutic alliance using the Helping Alliance questionnaire-II. After the study, independent raters evaluated treatment delivery fidelity of all TSF sessions on adherence, competence, and therapist empathy. Poisson regression modeling examined relationships of treatment delivery fidelity and therapeutic alliance with treatment retention (measured by number of sessions attended) for 174 participants with complete fidelity and alliance data. Therapeutic alliance (p = .005) and therapist competence (p = .010) were significantly associated with better treatment retention. Therapist adherence was associated with poorer retention in a nonsignificant trend (p = .061). In conclusion, stronger therapeutic alliance and higher therapist competence in the delivery of a TSF intervention were associated with better treatment retention whereas treatment adherence was not. Training and fidelity monitoring of TSF should focus on general therapist skills and therapeutic alliance development to maximize treatment retention. (PsycINFO Database Record

  6. Treatment of chest wall tuberculosis with transdermal ultrasound-mediated drug delivery

    PubMed Central

    HAN, YI; ZHAO, QIUYUE; YU, DAPING; LIU, ZHIDONG

    2015-01-01

    Chest wall tuberculosis (TB) is an endemic disease with a large number of variants. The condition affects numerous parts of the body and can penetrate the skin to form chronic open ulcers. Current treatment methods include oral anti-TB drugs and surgery. However, conventional drug treatments are not effective due to the difficulty in achieving an effective local concentration, and certain patients are unable to tolerate surgery. The recurrence rate for chest wall TB is high following surgery, and may result in the prolonged healing of wounds in certain patients, as well as chronic sinusitis and fistula formation. To identify a safe, simple, less invasive and more clinically effective treatment method, the present study investigated transdermal ultrasound-mediated anti-TB drug delivery. A total of 186 patients were selected and randomly divided into transdermal ultrasound, surgery and oral anti-TB drug only groups. Rifampicin was the drug delivered by transdermal ultrasound. The cure and efficiency rates were shown to be 87.10 and 93.55%, respectively, in the ultrasound treatment group. No statistically significant difference was observed in the cure rates between the transdermal ultrasound and surgery groups; however, a statistically significant difference was identified in the cure rates between the transdermal ultrasound and oral anti-TB drug only groups. Therefore, transdermal ultrasound technology was shown to deliver anti-TB drugs quickly and directly, which resulted in a high local concentration of the drug, overcoming the problem of obtaining an effective local drug concentration. The observations demonstrated that transdermal ultrasound-mediated drug delivery is an effective method by which to control TB, particularly when compared with traditional oral anti-TB therapy and surgery. PMID:25780447

  7. TU-A-304-02: Treatment Simulation, Planning and Delivery for SBRT

    SciTech Connect

    Yang, Y.

    2015-06-15

    Increased use of SBRT and hypo fractionation in radiation oncology practice has posted a number of challenges to medical physicist, ranging from planning, image-guided patient setup and on-treatment monitoring, to quality assurance (QA) and dose delivery. This symposium is designed to provide updated knowledge necessary for the safe and efficient implementation of SBRT in various linac platforms, including the emerging digital linacs equipped with high dose rate FFF beams. Issues related to 4D CT, PET and MRI simulations, 3D/4D CBCT guided patient setup, real-time image guidance during SBRT dose delivery using gated/un-gated VMAT or IMRT, and technical advancements in QA of SBRT (in particular, strategies dealing with high dose rate FFF beams) will be addressed. The symposium will help the attendees to gain a comprehensive understanding of the SBRT workflow and facilitate their clinical implementation of the state-of-art imaging and planning techniques. Learning Objectives: Present background knowledge of SBRT, describe essential requirements for safe implementation of SBRT, and discuss issues specific to SBRT treatment planning and QA. Update on the use of multi-dimensional (3D and 4D) and multi-modality (CT, beam-level X-ray imaging, pre- and on-treatment 3D/4D MRI, PET, robotic ultrasound, etc.) for reliable guidance of SBRT. Provide a comprehensive overview of emerging digital linacs and summarize the key geometric and dosimetric features of the new generation of linacs for substantially improved SBRT. Discuss treatment planning and quality assurance issues specific to SBRT. Research grant from Varian Medical Systems.

  8. QA Issues for Computer-Controlled Treatment Delivery: This Is Not Your Old R/V System Any More{exclamation_point}

    SciTech Connect

    Fraass, Benedick A.

    2008-05-01

    State-of-the-art radiotherapy treatment delivery has changed dramatically during the past decade, moving from manual individual field setup and treatment to automated computer-controlled delivery of complex treatments, including intensity-modulated radiotherapy and other similarly complex delivery strategies. However, the quality assurance methods typically used to ensure treatment is performed precisely and correctly have not evolved in a similarly dramatic way. This paper reviews the old manual treatment process and use of record-and-verify systems, and describes differences with modern computer-controlled treatment delivery. The process and technology used for computer-controlled treatment delivery are analyzed in terms of potential (and actual) problems, as well as relevant published guidance on quality assurance. The potential for improved quality assurance for computer-controlled delivery is discussed.

  9. Feasibility of two modes of treatment delivery for child anxiety in primary care.

    PubMed

    Chavira, Denise A; Drahota, Amy; Garland, Ann F; Roesch, Scott; Garcia, Maritza; Stein, Murray B

    2014-09-01

    In this study, we examine the feasibility of cognitive behavior therapy (CBT) for children with anxiety in primary care, using two modes of treatment delivery. A total of 48 parents and youth (8-13) with anxiety disorders were randomly assigned to receive 10-sessions of CBT either delivered by a child anxiety specialist in the primary care clinic or implemented by the parent with therapist support by telephone (i.e., face-to-face or therapist-supported bibliotherapy). Feasibility outcomes including satisfaction, barriers to treatment participation, safety, and dropout were assessed. Independent evaluators, blind to treatment condition, administered the Anxiety Disorders Interview Schedule for Children (ADIS) and the Clinical Global Impression of Improvement (CGI-I) at baseline, post-treatment and 3-month follow-up; clinical self-report questionnaires were also administered. Findings revealed high satisfaction, low endorsement of barriers, low drop out rates, and no adverse events across the two modalities. According to the CGI-I, 58.3%-75% of participants were considered responders (i.e., much or very much improved) at the various time points. Similar patterns were found for remission from "primary anxiety disorder" and "all anxiety disorders" as defined by the ADIS. Clinically significant improvement was seen on the various parent and child self-report measures of anxiety. Findings suggest that both therapy modalities are feasible and associated with significant treatment gains in the primary care setting. (clinicaltrials.gov unique identifier: NCT00769925).

  10. Nanomedicine and drug delivery strategies for treatment of inflammatory bowel disease.

    PubMed

    Takedatsu, Hidetoshi; Mitsuyama, Keiichi; Torimura, Takuji

    2015-10-28

    Crohn's disease and ulcerative colitis are two important categories of human inflammatory bowel disease (IBD). Because the precise mechanisms of the inflammation and immune responses in IBD have not been fully elucidated, the treatment of IBD primarily aims to inhibit the pathogenic factors of the inflammatory cascade. Inconsistencies exist regarding the response and side effects of the drugs that are currently used to treat IBD. Recent studies have suggested that the use of nanomedicine might be advantageous for the treatment of intestinal inflammation because nano-sized molecules can effectively penetrate epithelial and inflammatory cells. We reviewed nanomedicine treatments, such as the use of small interfering RNAs, antisense oligonucleotides, and anti-inflammatory molecules with delivery systems in experimental colitis models and clinical trials for IBD based on a systematic search. The efficacy and usefulness of the treatments reviewed in this manuscript have been demonstrated in experimental colitis models and clinical trials using various types of nanomedicine. Nanomedicine is expected to become a new therapeutic approach to the treatment of IBD.

  11. Successful remote delivery of a treatment for phonological alexia via telerehab.

    PubMed

    Getz, Heidi; Snider, Sarah; Brennan, David; Friedman, Rhonda

    2016-08-01

    A growing body of literature supports the effectiveness of the remote delivery of rehabilitation services, i.e., telerehab. Aphasia treatment is particularly well suited for telerehab because of the verbal and visual nature of speech-language therapy, but scientific research investigating aphasia telerehab is in its infancy. No studies to date have evaluated whether treatment of acquired reading disorders by a live clinician can be feasibly, effectively, or efficiently conducted via telerehab. Here we address this gap in the literature by reporting our success remotely remediating the reading deficits of two participants with phonological alexia. We adapted for the telerehab setting a previously validated treatment for phonological alexia (Friedman, Sample, & Lott, 2002 ), which uses a paired-associate design to train reading of problematic words. Both telerehab participants significantly improved their reading of trained words in similar time frames as previous participants (Friedman et al., 2002 ; Kurland et al., 2008 ; Lott, Sample, Oliver, Lacey, & Friedman, 2008 ); furthermore, both participants reported high satisfaction with the telerehab setting. Although telerehab with alexic patients poses unique challenges, we conclude that treatment for alexia via telerehab is nevertheless feasible, may be equally effective as in-person treatment, and saves substantial resources for participants as well as clinicians.

  12. Feasibility of Two Modes of Treatment Delivery for Child Anxiety in Primary Care

    PubMed Central

    Chavira, Denise A.; Drahota, Amy; Garland, Ann; Roesch, Scott; Garcia, Maritza; Stein, Murray B.

    2014-01-01

    In this study, we examine the feasibility of cognitive behavior therapy (CBT) for children with anxiety in primary care, using two modes of treatment delivery. A total of 48 parents and youth (8–13) with anxiety disorders were randomly assigned to receive 10-sessions of CBT either delivered by a child anxiety specialist in the primary care clinic or implemented by the parent with therapist support by telephone (i.e., face-to-face or therapist-supported bibliotherapy). Feasibility outcomes including satisfaction, barriers to treatment participation, safety, and dropout were assessed. Independent evaluators, blind to treatment condition, administered the Anxiety Disorders Interview Schedule for Children (ADIS) and the Clinical Global Impression of Improvement (CGI-I) at baseline, post-treatment and 3-month follow-up; clinical self-report questionnaires were also administered. Findings revealed high satisfaction, low endorsement of barriers, low drop out rates, and no adverse events across the two modalities. According to the CGI-I, 58.3%–75% of participants were considered responders (i.e., much or very much improved) at the various time points. Similar patterns were found for remission from “primary anxiety disorder” and “all anxiety disorders” as defined by the ADIS. Clinically significant improvement was seen on the various parent and child self-report measures of anxiety. Findings suggest that both therapy modalities are feasible and associated with significant treatment gains in the primary care setting. PMID:25075802

  13. Intranasal delivery of N-terminal modified leptin-pluronic conjugate for treatment of obesity.

    PubMed

    Yuan, Dongfen; Yi, Xiang; Zhao, Yuling; Poon, Chi-Duen; Bullock, Kristin M; Hansen, Kim M; Salameh, Therese S; Farr, Susan A; Banks, William A; Kabanov, Alexander V

    2017-03-24

    Leptin is an adipocyte-secreted hormone that is delivered via a specific transport system across the blood-brain barrier (BBB) to the brain where it acts on the hypothalamus receptors to control appetite and thermogenesis. Peripheral resistance to leptin due to its impaired brain delivery prevents therapeutic use of leptin in overweight and moderately obese patients. To address this problem, we modified the N-terminal amine of leptin with Pluronic P85 (LepNP85) and administered this conjugate intranasally using the nose-to-brain (INB) route to bypass the BBB. We compared this conjugate with the native leptin, the N-terminal leptin conjugate with poly(ethylene glycol) (LepNPEG5K), and two conjugates of leptin with Pluronic P85 attached randomly to the lysine amino groups of the hormone. Compared to the random conjugates of leptin with P85, LepNP85 has shown higher affinity upon binding with the leptin receptor, and similarly to native hormone activated hypothalamus receptors after direct injection into brain. After INB delivery, LepNP85 conjugate was transported to the brain and accumulated in the hypothalamus and hippocampus to a greater extent than the native leptin and LepNPEG5K and activated leptin receptors in hypothalamus at lower dose than native leptin. Our work suggests that LepNP85 can access the brain directly after INB delivery and confirms our hypothesis that the improvement in brain accumulation of this conjugate is due to its enhanced brain absorption. In conclusion, the LepNP85 with optimized conjugation chemistry is a promising candidate for treatment of obesity.

  14. Sui generis: gene therapy and delivery systems for the treatment of glioblastoma.

    PubMed

    Kane, J Robert; Miska, Jason; Young, Jacob S; Kanojia, Deepak; Kim, Julius W; Lesniak, Maciej S

    2015-03-01

    Gene therapy offers a multidimensional set of approaches intended to treat and cure glioblastoma (GBM), in combination with the existing standard-of-care treatment (surgery and chemoradiotherapy), by capitalizing on the ability to deliver genes directly to the site of neoplasia to yield antitumoral effects. Four types of gene therapy are currently being investigated for their potential use in treating GBM: (i) suicide gene therapy, which induces the localized generation of cytotoxic compounds; (ii) immunomodulatory gene therapy, which induces or augments an enhanced antitumoral immune response; (iii) tumor-suppressor gene therapy, which induces apoptosis in cancer cells; and (iv) oncolytic virotherapy, which causes the lysis of tumor cells. The delivery of genes to the tumor site is made possible by means of viral and nonviral vectors for direct delivery of therapeutic gene(s), tumor-tropic cell carriers expressing therapeutic gene(s), and "intelligent" carriers designed to increase delivery, specificity, and tumoral toxicity against GBM. These vehicles are used to carry genetic material to the site of pathology, with the expectation that they can provide specific tropism to the desired site while limiting interaction with noncancerous tissue. Encouraging preclinical results using gene therapies for GBM have led to a series of human clinical trials. Although there is limited evidence of a therapeutic benefit to date, a number of clinical trials have convincingly established that different types of gene therapies delivered by various methods appear to be safe. Due to the flexibility of specialized carriers and genetic material, the technology for generating new and more effective therapies already exists.

  15. Bolaamphiphile-based nanocomplex delivery of phosphorothioate gapmer antisense oligonucleotides as a treatment for Clostridium difficile

    PubMed Central

    Hegarty, John P; Krzeminski, Jacek; Sharma, Arun K; Guzman-Villanueva, Diana; Weissig, Volkmar; Stewart, David B

    2016-01-01

    Despite being a conceptually appealing alternative to conventional antibiotics, a major challenge toward the successful implementation of antisense treatments for bacterial infections is the development of efficient oligonucleotide delivery systems. Cationic vesicles (bolasomes) composed of dequalinium chloride (“DQAsomes”) have been used to deliver plasmid DNA across the cardiolipin-rich inner membrane of mitochondria. As cardiolipin is also a component of many bacterial membranes, we investigated the application of cationic bolasomes to bacteria as an oligonucleotide delivery system. Antisense sequences designed in silico to target the expression of essential genes of the bacterial pathogen, Clostridium difficile, were synthesized as 2′-O-methyl phosphorothioate gapmer antisense oligonucleotides (ASO). These antisense gapmers were quantitatively assessed for their ability to block mRNA translation using luciferase reporter and C. difficile protein expression plasmid constructs in a coupled transcription–translation system. Cationic bolaamphiphile compounds (dequalinium derivatives) of varying alkyl chain length were synthesized and bolasomes were prepared via probe sonication of an aqueous suspension. Bolasomes were characterized by particle size distribution, zeta potential, and binding capacities for anionic oligonucleotide. Bolasomes and antisense gapmers were combined to form antisense nanocomplexes. Anaerobic C. difficile log phase cultures were treated with serial doses of gapmer nanocomplexes or equivalent amounts of empty bolasomes for 24 hours. Antisense gapmers for four gene targets achieved nanomolar minimum inhibitory concentrations for C. difficile, with the lowest values observed for oligonucleotides targeting polymerase genes rpoB and dnaE. No inhibition of bacterial growth was observed from treatments at matched dosages of scrambled gapmer nanocomplexes or plain, oligonucleotide-free bolasomes compared to untreated control cultures. We

  16. Design of a light delivery system for the photodynamic treatment of the Crohn's disease

    NASA Astrophysics Data System (ADS)

    Gabrecht, Tanja; Borle, Francois; van den Bergh, Hubert; Michetti, Pierre; Ortner, Maria-Anna; Wagnières, Georges

    2007-07-01

    Crohn's disease is an inflammatory bowel disease originating from an overwhelming response of the mucosal immune system. Low dose photodynamic therapy (PDT) may modify the mucosal immune response and thus serve as a therapy for Crohn's disease. Most patients with Crohn's disease show inflammatory reactions in the terminal ileum or colon where PDT treatment is feasible by low-invasive endoscopic techniques. However, the tube like geometry of the colon, it's folding, and the presences of multiple foci of Crohn's lesions along the colon require the development of adequate light delivery techniques. We present a prototype light delivery system for endoscopic clinical PDT in patients with Crohn's disease. The system is based on a cylindrical light diffuser inserted into a diffusing balloon catheter. Homogenous irradiation is performed with a 4 W diode laser at 635 nm. Light dosimetry is performed using a calibrated integrating sphere. The system can be used with conventional colonoscopes and colonovideoscopes having a 3.8 mm diameter working channel. The feasibility of PDT in colon with our prototype was demonstrated in first clinical trials.

  17. Sustained delivery of cytarabine-loaded vesicular phospholipid gels for treatment of xenografted glioma.

    PubMed

    Qi, Na; Cai, Cuifang; Zhang, Wei; Niu, Yantao; Yang, Jingyu; Wang, Lihui; Tian, Bin; Liu, Xiaona; Lin, Xia; Zhang, Yu; Zhang, Yan; He, Haibing; Chen, Kang; Tang, Xing

    2014-09-10

    This study described the development of vesicular phospholipid gels (VPGs) for sustained delivery of cytarabine (Ara-C) for the treatment of xenografted glioma. Ara-C-loaded VPGs in the state of a semisolid phospholipid dispersion looked like numerous vesicles tightly packing together under the freeze-fracture electron microscopy (FF-TEM), their release profiles displayed sustained drug release up to 384 h in vitro. The biodistribution of Ara-C in the rat brain showed that Ara-C-loaded VPGs could maintain therapeutic concentrations up to 5mm distance from the implantation site in brain tissue within 28 days. At the same time, fluorescence micrograph confirmed drug distribution in brain tissue visually. Furthermore, after single administration, Ara-C-loaded VPGs group significantly inhibited the U87-MG glioma growth in right flank in comparison with Ara-C solution (p<0.01). It was explained that the entrapped drug in VPGs could avoid degradation from cytidine deaminase and sustained release of drug from Ara-C-loaded VPGs could maintain the effective therapeutic levels for a long time around the tumor. In conclusion, Ara-C-loaded VPGs, with the properties of sustained release, high penetration capacity, nontoxicity and no shape restriction of the surgical cavity, are promising local delivery systems for post-surgical sustained chemotherapy against glioma.

  18. Implantable and transdermal polymeric drug delivery technologies for the treatment of central nervous system disorders.

    PubMed

    Govender, Thiresen; Choonara, Yahya E; Kumar, Pradeep; Bijukumar, Divya; du Toit, Lisa C; Modi, Girish; Naidoo, Dinesh; Pillay, Viness

    2016-06-07

    The complexity of the brain and the membranous blood-brain barrier (BBB) has proved to be a significant limitation to the systemic delivery of pharmaceuticals to the brain rendering them sub-therapeutic and ineffective in the treatment of neurological diseases. Apart from this, lack of innovation in product development to counteract the problem is also a major contributing factor to a poor therapeutic outcome. Various innovative strategies show potential in treating some of the neurological disorders; however, drug delivery remains the most popular. To attain therapeutic drug levels in the central nervous system, large, intolerable systemic doses are generally administered. The major factors responsible for the success maintenance therapy of neurological diseases included controlled and sustained release of neurotherapeutics, reduced frequency of administration, higher bioavailability, and patient compliances. Conventional oral or injectable formulations cannot satisfy all the requirements in many circumstances. This article reviews the therapeutic implantable polymeric and transdermal devices employed in an attempt to effectively achieve therapeutic quantities of drug across the BBB over a prolonged period, to improve patient disease prognosis.

  19. Pulmonary delivery of cisplatin-hyaluronan conjugates via endotracheal instillation for the treatment of lung cancer

    PubMed Central

    Xie, Yumei; Aillon, Kristin L.; Cai, Shuang; Christian, Jason M.; Davies, Neal M.; Berkland, Cory J.; Forrest, M. Laird

    2010-01-01

    Cisplatin (CDDP) intravenous treatments suffer several dose-limiting toxicity issues. Hyaluronan (HA), a naturally occurring biopolymer in the interstitium, is primarily cleared by the lymphatic system. An alteration in input rate and administration route through pulmonary delivery of hyaluronan-cisplatin conjugate (HA-Pt) may increase local lung CDDP concentrations and decrease systemic toxicity. Sprague-Dawley rats were split into four groups: i.v. CDDP (3.5 mg/kg), i.v. HA-Pt conjugate (3.5 mg/kg equivalent CDDP), lung instillation CDDP and lung instillation HA-Pt conjugate. Total platinum level in the lungs of the HA-Pt lung instillation group was 5.7-fold and 1.2-fold higher than the CDDP intravenous group at 24 h and 96 h, respectively. A 1.1-fold increase of Pt accumulation in lung draining nodes for the HA-Pt lung instillation group was achieved at 24 h relative to the CDDP i.v. group. In the brain and kidneys, the CDDP i.v. group had higher tissue/plasma ratios compared to the HA-Pt lung instillation group. Augmented tissue distribution from CDDP i.v. could translate into enhanced tissue toxicity compared to the altered input rate and distribution of the intrapulmonary nanoformulation. In conclusion, a local pulmonary CDDP delivery system was developed with increased platinum concentration in the lungs and draining nodes compared to i.v. therapy. PMID:20363303

  20. Investigation of Plasma Treatment on Micro-Injection Moulded Microneedle for Drug Delivery

    PubMed Central

    Nair, Karthik; Whiteside, Benjamin; Grant, Colin; Patel, Rajnikant; Tuinea-Bobe, Cristina; Norris, Keith; Paradkar, Anant

    2015-01-01

    Plasma technology has been widely used to increase the surface energy of the polymer surfaces for many industrial applications; in particular to increase in wettability. The present work was carried out to investigate how surface modification using plasma treatment modifies the surface energy of micro-injection moulded microneedles and its influence on drug delivery. Microneedles of polyether ether ketone and polycarbonate and have been manufactured using micro-injection moulding and samples from each production batch have been subsequently subjected to a range of plasma treatment. These samples were coated with bovine serum albumin to study the protein adsorption on these treated polymer surfaces. Sample surfaces structures, before and after treatment, were studied using atomic force microscope and surface energies have been obtained using contact angle measurement and calculated using the Owens-Wendt theory. Adsorption performance of bovine serum albumin and release kinetics for each sample set was assessed using a Franz diffusion cell. Results indicate that plasma treatment significantly increases the surface energy and roughness of the microneedles resulting in better adsorption and release of BSA. PMID:26529005

  1. SU-E-T-106: An Institutional Review of Using Commercially Available Software to Evaluate Treatment Plan Quality for Various Treatment Sites and Beam Deliveries

    SciTech Connect

    Esquivel, C; Patton, L; Walker, S; Lawson, S

    2015-06-15

    Purpose: Use Sun Nuclear Quality Reports™ with PlanIQ™ to evaluate different treatment delivery techniques for various treatment sites. Methods: Fifteen random patients with different treatment sites were evaluated. These include the Head/Neck, prostate, pelvis, lung, esophagus, axilla, bladder and abdomen. Initially, these sites were planned on the Pinnacle {sup 3} V9.6 treatment planning system and utilized nine 6MV step-n-shoot IMRT fields. The RT plan, dose and structure sets were sent to Quality Reports™ where a DVH was recreated and the plans were compared to a unique Plan Algorithm for each treatment site. Each algorithm has its own plan quality metrics and objectives, which include the PTV coverage, PTV maximum dose, the prescription dose outside the target, doses to the critical structures, and the global maximum dose and its location. Each plan was scored base on meeting each objective. Plans may have been reoptimized and reevaluated with Quality Reports™ based on the initial score. PlanIQ™ was used to evaluate if any objective not met was achievable or difficult to obtain. A second plan using VMAT delivery was created for each patient and scored with Quality Reports™. Results: There were a wide range of scores for the different treatment sites with some scoring better for IMRT plans and some better for the VMAT deliveries. The variation in the scores could be attributed to the treatment site, location, and shape of the target. Most deliveries were chosen for the VMAT due to the short treatment times and quick patient throughput with acceptable plan scores. Conclusion: The tools are provided for both physician and dosimetrist to objectively evaluate the use of VMAT delivery versus the step-n-shoot IMRT delivery for various sites. PlanIQ validates if objectives can be met. For the physicist, a concise pass/fail report is created for plan evaluation.

  2. Thermal treatment of galactose-branched polyelectrolyte microcapsules to improve drug delivery with reserved targetability.

    PubMed

    Zhang, Fu; Wu, Qi; Liu, Li-Jun; Chen, Zhi-Chun; Lin, Xian-Fu

    2008-06-05

    A novel multilayered drug delivery system by LbL assembly of galactosylated polyelectrolyte, which is possible to have the potential in hepatic targeting by the presence of galactose residues at the microcapsule's surface, is designed. Thermal treatment was performed on the capsules and a dramatic thermal shrinkage up to 60% decrease of capsule diameter above 50 degrees C was observed. This thermal behavior was then used to manipulate drug loading capacity and release rate. Heating after drug loading could seal the capsule shell, enhancing the loading capacity and reducing the release rate significantly. Excellent affinity between galactose-binding lectin and heated galactose-containing microcapsules were observed, indicating a stable targeting potential even after high temperature elevating up to 90 degrees C.

  3. The role of Cobalt-60 source in Intensity Modulated Radiation Therapy: From modeling finite sources to treatment planning and conformal dose delivery

    NASA Astrophysics Data System (ADS)

    Dhanesar, Sandeep Kaur

    Cobalt-60 (Co-60) units played an integral role in radiation therapy from the mid-1950s to the 1970s. Although they continue to be used to treat cancer in some parts of the world, their role has been significantly reduced due to the invention of medical linear accelerators. A number of groups have indicated a strong potential for Co-60 units in modern radiation therapy. The Medical Physics group at the Cancer Center of the Southeastern Ontario and Queen's University has shown the feasibility of Intensity Modulated Radiation Therapy (IMRT) via simple conformal treatment planning and dose delivery using a Co-60 unit. In this thesis, initial Co-60 tomotherapy planning investigations on simple uniform phantoms are extended to actual clinical cases based on patient CT data. The planning is based on radiation dose data from a clinical Co-60 unit fitted with a multileaf collimator (MLC) and modeled in the EGSnrc Monte Carlo system. An in house treatment planning program is used to calculate IMRT dose distributions. Conformal delivery in a single slice on a uniform phantom based on sequentially delivered pencil beams is verified by Gafchromic film. Volumetric dose distributions for Co-60 serial tomotherapy are then generated for typical clinical sites that had been treated at our clinic by conventional 6MV IMRT using Varian Eclipse treatment plans. The Co-60 treatment plans are compared with the clinical IMRT plans using conventional matrices such as dose volume histograms (DVH). Dose delivery based on simultaneously opened MLC leaves is also explored and a novel MLC segmentation method is proposed. In order to increase efficiency of dose calculations, a novel convolution based fluence model for treatment planning is also proposed. The ion chamber measurements showed that the Monte Carlo modeling of the beam data under the MIMiC MLC is accurate. The film measurements from the uniform phantom irradiations confirm that IMRT plans from our in-house treatment planning system

  4. Advances in the psychosocial treatment of addiction: the role of technology in the delivery of evidence-based psychosocial treatment.

    PubMed

    Marsch, Lisa A; Dallery, Jesse

    2012-06-01

    The clinical community has a growing array of psychosocial interventions with a strong evidence base available for the treatment of SUDs. Considerable opportunity exists for leveraging technology in the delivery of evidence-based interventions to promote widespread reach and impact of evidence-based care. Data from this line of research to date are promising, and underscore the potential public health impact of technology-based therapeutic tools. To fully realize the potential of technology-delivered interventions, several areas of inquiry remain important. First, scientifically sound strategies should be explored to ensure technology-based interventions are optimally designed to produce maximal behavior change. Second, efficient and effective methods should be identified to integrate technology-based interventions into systems of care in a manner that is most responsive to the needs of individual users. Third, payment, privacy, and regulatory systems should be refined and extended to go beyond electronic medical records and telehealth/distance care models, and support the deployment of technology-based systems to enhance the quality, efficiency and cost-effectiveness of care. Fourth, the mechanisms underlying behavior change derived from technology-based treatments should be explicated, including new mechanisms that may be tapped via novel, technology-based tools. Such work will be critical in isolating mechanisms that are useful in predicting treatment response, and in ensuring that key ingredients are present in technology-based interventions as they are made widely available.

  5. Cobalt-60 tomotherapy: Clinical treatment planning and phantom dose delivery studies

    SciTech Connect

    Dhanesar, Sandeep; Darko, Johnson; Joshi, Chandra P.; Kerr, Andrew; John Schreiner, L.

    2013-08-15

    Purpose: Investigations have shown that a Cobalt-60 (Co-60) radioactive source has the potential to play a role in intensity modulated radiation therapy (IMRT). In this paper, Co-60 tomotherapy's conformal dose delivery potential is evaluated by delivering conformal dose plans on a cylindrical homogeneous phantom containing clinical structures similar to those found in a typical head and neck (H and N) cancer. Also, the clinical potential of Co-60 tomotherapy is investigated by generating 2D clinical treatment plans for H and N and prostate anatomical regions. These plans are compared with the 6 MV based treatment plans for modalities such as linear accelerator-based tomotherapy and broad beam IMRT, and 15 MV based 3D conformal radiation therapy (3DCRT).Methods: For experimental validation studies, clinical and nonclinical conformal dose patterns were delivered on circular, homogeneous phantoms containing GafChromic film. For clinical planning study, dose calculations were performed with the EGSnrc Monte Carlo program, where a Theratronics 780C Co-60 unit and a 6 MV linear accelerator were modeled with a MIMiC binary multileaf collimator. An inhouse inverse treatment planning system was used to optimize tomotherapy plans using the same optimization parameters for both Co-60 and 6 MV beams. The IMRT and 3DCRT plans for the clinical cases were generated entirely in the Eclipse treatment planning system based on inhouse IMRT and 3DCRT site specific protocols.Results: The doses delivered to the homogeneous phantoms agreed with the calculations, indicating that it is possible to deliver highly conformal doses with the Co-60 unit. The dose distributions for Co-60 tomotherapy clinical plans for both clinical cases were similar to those obtained with 6 MV based tomotherapy and IMRT, and much more conformal compared to 3DCRT plans. The dose area histograms showed that the Co-60 plans achieve the dose objectives for the targets and organs at risk.Conclusions: These results

  6. Combinational Spinal GAD65 Gene Delivery and Systemic GABA-Mimetic Treatment for Modulation of Spasticity

    PubMed Central

    Kakinohana, Osamu; Hefferan, Michael P.; Miyanohara, Atsushi; Nejime, Tetsuya; Marsala, Silvia; Juhas, Stefan; Juhasova, Jana; Motlik, Jan; Kucharova, Karolina; Strnadel, Jan; Platoshyn, Oleksandr; Lazar, Peter; Galik, Jan; Vinay, Laurent; Marsala, Martin

    2012-01-01

    Background Loss of GABA-mediated pre-synaptic inhibition after spinal injury plays a key role in the progressive increase in spinal reflexes and the appearance of spasticity. Clinical studies show that the use of baclofen (GABAB receptor agonist), while effective in modulating spasticity is associated with major side effects such as general sedation and progressive tolerance development. The goal of the present study was to assess if a combined therapy composed of spinal segment-specific upregulation of GAD65 (glutamate decarboxylase) gene once combined with systemic treatment with tiagabine (GABA uptake inhibitor) will lead to an antispasticity effect and whether such an effect will only be present in GAD65 gene over-expressing spinal segments. Methods/Principal Findings Adult Sprague-Dawley (SD) rats were exposed to transient spinal ischemia (10 min) to induce muscle spasticity. Animals then received lumbar injection of HIV1-CMV-GAD65 lentivirus (LVs) targeting ventral α-motoneuronal pools. At 2–3 weeks after lentivirus delivery animals were treated systemically with tiagabine (4, 10, 20 or 40 mg/kg or vehicle) and the degree of spasticity response measured. In a separate experiment the expression of GAD65 gene after spinal parenchymal delivery of GAD65-lentivirus in naive minipigs was studied. Spastic SD rats receiving spinal injections of the GAD65 gene and treated with systemic tiagabine showed potent and tiagabine-dose-dependent alleviation of spasticity. Neither treatment alone (i.e., GAD65-LVs injection only or tiagabine treatment only) had any significant antispasticity effect nor had any detectable side effect. Measured antispasticity effect correlated with increase in spinal parenchymal GABA synthesis and was restricted to spinal segments overexpressing GAD65 gene. Conclusions/Significance These data show that treatment with orally bioavailable GABA-mimetic drugs if combined with spinal-segment-specific GAD65 gene overexpression can represent a novel

  7. The Analysis of TRICARE Navy Obstetric Delivery Costs within Continental United States Military Treatment Facilities

    DTIC Science & Technology

    2009-12-01

    1 A baby born vaginally is called a birth, while a baby born by cesarean section is called a...MTFs DESCRIPTION DRG CESAREAN SECTION W CC 370 CESAREAN SECTION W/O CC 371 VAGINAL DELIVERY W COMPLICATING DIAGNOSES 372 VAGINAL DELIVERY W/O...with complicated vaginal deliveries and cesarean sections , there was a large variation in costs associated with complicated deliveries. Thus, for

  8. Functionalized gold nanoparticles for topical delivery of methotrexate for the possible treatment of psoriasis.

    PubMed

    Bessar, Hagar; Venditti, Iole; Benassi, Luisa; Vaschieri, Cristina; Azzoni, Paola; Pellacani, Giovanni; Magnoni, Cristina; Botti, Elisabetta; Casagrande, Viviana; Federici, Massimo; Costanzo, Antonio; Fontana, Laura; Testa, Giovanna; Mostafa, Fawzia Farag; Ibrahim, Samia Ali; Russo, Maria Vittoria; Fratoddi, Ilaria

    2016-05-01

    Gold nanoparticles (AuNPs) represent an effective choice for topical drug delivery systems thanks to their small size, general non-toxicity, ease of functionalization and high surface to volume ratio. Even if systemic, methotrexate still plays an important role in psoriasis treatment: its topical use shows insufficient percutaneus penetration owing to limited passive diffusion, high molecular weight and dissociation at physiological pH. The aim of our study was to design a new drug delivery nanocarrier for Methotrexate and to improve its solubility, stability and biodistribution. AuNPs were on purpose prepared with a hydrophilic stabilizing layer, in order to improve the colloidal stability in water. Water-soluble gold nanoparticles functionalized by sodium 3-mercapto-1-propansulfonate (Au-3MPS) were prepared and loaded with methotrexate (MTX). The loading efficiency of MTX on Au-3MPS was assessed in the range 70-80%, with a fast release (80% in one hour). The release was studied up to 24h reaching the value of 95%. The Au-3MPS@MTX conjugate was fully characterized by spectroscopic techniques (UV-vis, FTIR) and DLS. Preliminary toxicity tests in the presence of keratinocytes monolayers allowed to assess that the used Au-3MPS are not toxic. The conjugate was then topically used on C57BL/6 mouse normal skin in order to trace the absorption behavior. STEM images clearly revealed the distribution of gold nanoparticles inside the cells. In vitro studies showed that Methotrexate conjugated with Au-3MPS is much more efficient than Methotrexate alone. Moreover, DL50, based on MTT analysis, is 20 folds reduced at 48 h, by the presence of nanoparticles conjugation. UV-vis spectra for in vivo tracing of the conjugate on bare mouse skin after 24h of application, show increased delivery of Methotrexate in the epidermis and dermis using Au-3MPS@MTX conjugate, compared to MTX alone. Moreover we observed absence of the Au-3MPS in the dermis and in the epidermis, suggesting that

  9. Assessing the quality of proton PBS treatment delivery using machine log files: comprehensive analysis of clinical treatments delivered at PSI Gantry 2

    NASA Astrophysics Data System (ADS)

    Scandurra, D.; Albertini, F.; van der Meer, R.; Meier, G.; Weber, D. C.; Bolsi, A.; Lomax, A.

    2016-02-01

    Pencil beam scanning (PBS) proton therapy requires the delivery of many thousand proton beams, each modulated for position, energy and monitor units, to provide a highly conformal patient treatment. The quality of the treatment is dependent on the delivery accuracy of each beam and at each fraction. In this work we describe the use of treatment log files, which are a record of the machine parameters for a given field delivery on a given fraction, to investigate the integrity of treatment delivery compared to the nominal planned dose. The dosimetry-relevant log file parameters are used to reconstruct the 3D dose distribution on the patient anatomy, using a TPS-independent dose calculation system. The analysis was performed for patients treated at Paul Scherrer Institute on Gantry 2, both for individual fields and per series (or plan), and delivery quality was assessed by determining the percentage of voxels in the log file dose distribution within  +/-  1% of the nominal dose. It was seen that, for all series delivered, the mean pass rate is 96.4%. Furthermore, this work establishes a correlation between the delivery quality of a field and the beam position accuracy. This correlation is evident for all delivered fields regardless of individual patient or plan characteristics. We have also detailed further usefulness of log file analysis within our clinical workflow. In summary, we have highlighted that the integrity of PBS treatment delivery is dependent on daily machine performance and is specifically highly correlated with the accuracy of beam position. We believe this information will be useful for driving machine performance improvements in the PBS field.

  10. Assessing the quality of proton PBS treatment delivery using machine log files: comprehensive analysis of clinical treatments delivered at PSI Gantry 2.

    PubMed

    Scandurra, D; Albertini, F; van der Meer, R; Meier, G; Weber, D C; Bolsi, A; Lomax, A

    2016-02-07

    Pencil beam scanning (PBS) proton therapy requires the delivery of many thousand proton beams, each modulated for position, energy and monitor units, to provide a highly conformal patient treatment. The quality of the treatment is dependent on the delivery accuracy of each beam and at each fraction. In this work we describe the use of treatment log files, which are a record of the machine parameters for a given field delivery on a given fraction, to investigate the integrity of treatment delivery compared to the nominal planned dose. The dosimetry-relevant log file parameters are used to reconstruct the 3D dose distribution on the patient anatomy, using a TPS-independent dose calculation system. The analysis was performed for patients treated at Paul Scherrer Institute on Gantry 2, both for individual fields and per series (or plan), and delivery quality was assessed by determining the percentage of voxels in the log file dose distribution within  +/-  1% of the nominal dose. It was seen that, for all series delivered, the mean pass rate is 96.4%. Furthermore, this work establishes a correlation between the delivery quality of a field and the beam position accuracy. This correlation is evident for all delivered fields regardless of individual patient or plan characteristics. We have also detailed further usefulness of log file analysis within our clinical workflow. In summary, we have highlighted that the integrity of PBS treatment delivery is dependent on daily machine performance and is specifically highly correlated with the accuracy of beam position. We believe this information will be useful for driving machine performance improvements in the PBS field.

  11. Applicability and safety of dual-frequency ultrasonic treatment for the transdermal delivery of drugs

    PubMed Central

    Schoellhammer, Carl M.; Srinivasan, Sharanya; Barman, Ross; Mo, Stacy H.; Polat, Baris E.; Langer, Robert; Blankschtein, Daniel

    2016-01-01

    Low-frequency ultrasound presents an attractive method for transdermal drug delivery. The controlled, yet nonspecific nature of enhancement broadens the range of therapeutics that can be delivered, while minimizing necessary reformulation efforts for differing compounds. Long and inconsistent treatment times, however, have partially limited the attractiveness of this method. Building on recent advances made in this area, the simultaneous use of low- and high-frequency ultrasound is explored in a physiologically relevant experimental setup to enable the translation of this treatment to testing in vivo. Dual-frequency ultrasound, utilizing 20 kHz and 1 MHz wavelengths simultaneously, was found to significantly enhance the size of localized transport regions (LTRs) in both in vitro and in vivo models while decreasing the necessary treatment time compared to 20 kHz alone. Additionally, LTRs generated by treatment with 20 kHz + 1 MHz were found to be more permeable than those generated with 20 kHz alone. This was further corroborated with pore-size estimates utilizing hindered-transport theory, in which the pores in skin treated with 20 kHz + 1 MHz were calculated to be significantly larger than the pores in skin treated with 20 kHz alone. This demonstrates for the first time that LTRs generated with 20 kHz + 1 MHz are also more permeable than those generated with 20 kHz alone, which could broaden the range of therapeutics and doses administered transdermally. With regard to safety, treatment with 20 kHz + 1 MHz both in vitro and in vivo appeared to result in no greater skin disruption than that observed in skin treated with 20 kHz alone, an FDA-approved modality. This study demonstrates that dual-frequency ultrasound is more efficient and effective than single-frequency ultrasound and is well-tolerated in vivo. PMID:25662228

  12. Applicability and safety of dual-frequency ultrasonic treatment for the transdermal delivery of drugs.

    PubMed

    Schoellhammer, Carl M; Srinivasan, Sharanya; Barman, Ross; Mo, Stacy H; Polat, Baris E; Langer, Robert; Blankschtein, Daniel

    2015-03-28

    Low-frequency ultrasound presents an attractive method for transdermal drug delivery. The controlled, yet non-specific nature of enhancement broadens the range of therapeutics that can be delivered, while minimizing necessary reformulation efforts for differing compounds. Long and inconsistent treatment times, however, have partially limited the attractiveness of this method. Building on recent advances made in this area, the simultaneous use of low- and high-frequency ultrasound is explored in a physiologically relevant experimental setup to enable the translation of this treatment to testing in vivo. Dual-frequency ultrasound, utilizing 20kHz and 1MHz wavelengths simultaneously, was found to significantly enhance the size of localized transport regions (LTRs) in both in vitro and in vivo models while decreasing the necessary treatment time compared to 20kHz alone. Additionally, LTRs generated by treatment with 20kHz+1MHz were found to be more permeable than those generated with 20kHz alone. This was further corroborated with pore-size estimates utilizing hindered-transport theory, in which the pores in skin treated with 20kHz+1MHz were calculated to be significantly larger than the pores in skin treated with 20kHz alone. This demonstrates for the first time that LTRs generated with 20kHz+1MHz are also more permeable than those generated with 20kHz alone, which could broaden the range of therapeutics and doses administered transdermally. With regard to safety, treatment with 20kHz+1MHz both in vitro and in vivo appeared to result in no greater skin disruption than that observed in skin treated with 20kHz alone, an FDA-approved modality. This study demonstrates that dual-frequency ultrasound is more efficient and effective than single-frequency ultrasound and is well-tolerated in vivo.

  13. Noninvasive, Targeted, and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson’s Disease

    NASA Astrophysics Data System (ADS)

    Fan, Ching-Hsiang; Ting, Chien-Yu; Lin, Chung-Yin; Chan, Hong-Lin; Chang, Yuan-Chih; Chen, You-Yin; Liu, Hao-Li; Yeh, Chih-Kuang

    2016-01-01

    Glial cell line-derived neurotrophic factor (GDNF) supports the growth and survival of dopaminergic neurons. CNS gene delivery currently relies on invasive intracerebral injection to transit the blood-brain barrier. Non-viral gene delivery via systematic transvascular route is an attractive alternative because it is non-invasive, but a high-yield and targeted gene-expressed method is still lacking. In this study, we propose a novel non-viral gene delivery approach to achieve targeted gene transfection. Cationic microbubbles as gene carriers were developed to allow the stable formation of a bubble-GDNF gene complex, and transcranial focused ultrasound (FUS) exposure concurrently interacting with the bubble-gene complex allowed transient gene permeation and induced local GDNF expression. We demonstrate that the focused ultrasound-triggered GDNFp-loaded cationic microbubbles platform can achieve non-viral targeted gene delivery via a noninvasive administration route, outperform intracerebral injection in terms of targeted GDNF delivery of high-titer GDNF genes, and has a neuroprotection effect in Parkinson’s disease (PD) animal models to successfully block PD syndrome progression and to restore behavioral function. This study explores the potential of using FUS and bubble-gene complexes to achieve noninvasive and targeted gene delivery for the treatment of neurodegenerative disease.

  14. Noninvasive, Targeted, and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson's Disease.

    PubMed

    Fan, Ching-Hsiang; Ting, Chien-Yu; Lin, Chung-Yin; Chan, Hong-Lin; Chang, Yuan-Chih; Chen, You-Yin; Liu, Hao-Li; Yeh, Chih-Kuang

    2016-01-20

    Glial cell line-derived neurotrophic factor (GDNF) supports the growth and survival of dopaminergic neurons. CNS gene delivery currently relies on invasive intracerebral injection to transit the blood-brain barrier. Non-viral gene delivery via systematic transvascular route is an attractive alternative because it is non-invasive, but a high-yield and targeted gene-expressed method is still lacking. In this study, we propose a novel non-viral gene delivery approach to achieve targeted gene transfection. Cationic microbubbles as gene carriers were developed to allow the stable formation of a bubble-GDNF gene complex, and transcranial focused ultrasound (FUS) exposure concurrently interacting with the bubble-gene complex allowed transient gene permeation and induced local GDNF expression. We demonstrate that the focused ultrasound-triggered GDNFp-loaded cationic microbubbles platform can achieve non-viral targeted gene delivery via a noninvasive administration route, outperform intracerebral injection in terms of targeted GDNF delivery of high-titer GDNF genes, and has a neuroprotection effect in Parkinson's disease (PD) animal models to successfully block PD syndrome progression and to restore behavioral function. This study explores the potential of using FUS and bubble-gene complexes to achieve noninvasive and targeted gene delivery for the treatment of neurodegenerative disease.

  15. Noninvasive, Targeted, and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson’s Disease

    PubMed Central

    Fan, Ching-Hsiang; Ting, Chien-Yu; Lin, Chung‐Yin; Chan, Hong-Lin; Chang, Yuan-Chih; Chen, You-Yin; Liu, Hao-Li; Yeh, Chih-Kuang

    2016-01-01

    Glial cell line-derived neurotrophic factor (GDNF) supports the growth and survival of dopaminergic neurons. CNS gene delivery currently relies on invasive intracerebral injection to transit the blood-brain barrier. Non-viral gene delivery via systematic transvascular route is an attractive alternative because it is non-invasive, but a high-yield and targeted gene-expressed method is still lacking. In this study, we propose a novel non-viral gene delivery approach to achieve targeted gene transfection. Cationic microbubbles as gene carriers were developed to allow the stable formation of a bubble-GDNF gene complex, and transcranial focused ultrasound (FUS) exposure concurrently interacting with the bubble-gene complex allowed transient gene permeation and induced local GDNF expression. We demonstrate that the focused ultrasound-triggered GDNFp-loaded cationic microbubbles platform can achieve non-viral targeted gene delivery via a noninvasive administration route, outperform intracerebral injection in terms of targeted GDNF delivery of high-titer GDNF genes, and has a neuroprotection effect in Parkinson’s disease (PD) animal models to successfully block PD syndrome progression and to restore behavioral function. This study explores the potential of using FUS and bubble-gene complexes to achieve noninvasive and targeted gene delivery for the treatment of neurodegenerative disease. PMID:26786201

  16. Development of a rectal nicotine delivery system for the treatment of ulcerative colitis.

    PubMed

    Dash, A K; Gong, Z; Miller, D W; Huai-Yan, H; Laforet, J

    1999-11-10

    The aims of this investigation were: i. to develop a rectal nicotine delivery system with bioadhesives for the treatment of ulcerative colitis and ii. to evaluate nicotine transport and cytotoxicity of the delivery system using Caco-2 cell culture systems. Rectal nicotine suppository formulations were prepared in semi-synthetic glyceride bases (Suppocire AM and AI, Gattefosse Inc.) by fusion method. The in vitro release of nicotine was carried out in modified USP dissolution apparatus 1. Differential scanning calorimetry (DSC) and powder X-ray diffraction were used to study the polymorphic changes if any in the formulations. An LC method was used for the assay of nicotine. The effect of bioadhesives (glyceryl monooleate (GMO), and Carbopol) on the nicotine flux was evaluated using Caco-2 cell permeability studies and Caco-2 cell viability was determined using the MTT toxicity assay. In vitro release studies indicated that the low melting AI base was superior to that of the AM base. Presence of GMO in the formulation enhanced the release of nicotine whereas Carbopol showed an opposite effect. The enhanced release of nicotine in the presence of GMO was found to be partly due to the melting point lowering effect of this compound. Caco-2 cell absorption studies showed that there was a decrease in the flux of nicotine in the presence of both the bioadhesives. The flux of the fluorescein marker which is used to study the integrity of the cell monolayers was found to be slightly higher only in the presence of 10% (w/w) Carbopol. Nicotine, Carbopol, and GMO do not have any cytotoxic effect on these cell monolayers within the concentration range used in the formulations. Rectal nicotine formulations containing bioadhesives were developed and characterized. Both in vitro release and cell culture studies have indicated that one can manipulate the nicotine release from these rectal delivery systems by incorporation of various bioadhesives or the use of different bases in the

  17. Targeted delivery of siRNA to macrophages for anti-inflammatory treatment.

    PubMed

    Kim, Sang-Soo; Ye, Chunting; Kumar, Priti; Chiu, Isaac; Subramanya, Sandesh; Wu, Haoquan; Shankar, Premlata; Manjunath, N

    2010-05-01

    Inflammation mediated by tumor necrosis factor-alpha (TNF-alpha) and the associated neuronal apoptosis characterizes a number of neurologic disorders. Macrophages and microglial cells are believed to be the major source of TNF-alpha in the central nervous system (CNS). Here, we show that suppression of TNF-alpha by targeted delivery of small interfering RNA (siRNA) to macrophage/microglial cells dramatically reduces lipopolysaccharide (LPS)-induced neuroinflammation and neuronal apoptosis in vivo. Because macrophage/microglia express the nicotinic acetylcholine receptor (AchR) on their surface, we used a short AchR-binding peptide derived from the rabies virus glycoprotein (RVG) as a targeting ligand. This peptide was fused to nona-D-arginine residues (RVG-9dR) to enable siRNA binding. RVG-9dR was able to deliver siRNA to induce gene silencing in macrophages and microglia cells from wild type, but not AchR-deficient mice, confirming targeting specificity. Treatment with anti-TNF-alpha siRNA complexed to RVG-9dR achieved efficient silencing of LPS-induced TNF-alpha production by primary macrophages and microglia cells in vitro. Moreover, intravenous injection with RVG-9dR-complexed siRNA in mice reduced the LPS-induced TNF-alpha levels in blood as well as in the brain, leading to a significant reduction in neuronal apoptosis. These results demonstrate that RVG-9dR provides a tool for siRNA delivery to macrophages and microglia and that suppression of TNF-alpha can potentially be used to suppress neuroinflammation in vivo.

  18. Development of a novel injectable drug delivery system for subconjunctival glaucoma treatment.

    PubMed

    Voss, Karsten; Falke, Karen; Bernsdorf, Arne; Grabow, Niels; Kastner, Christian; Sternberg, Katrin; Minrath, Ingo; Eickner, Thomas; Wree, Andreas; Schmitz, Klaus-Peter; Guthoff, Rudolf; Witt, Martin; Hovakimyan, Marina

    2015-09-28

    In this study we present the development of an injectable polymeric drug delivery system for subconjunctival treatment of primary open angle glaucoma. The system consists of hyaluronic acid sodium salt (HA), which is commonly used in ophthalmology in anterior segment surgery, and an isocyanate-functionalized 1,2-ethylene glycol bis(dilactic acid) (ELA-NCO). The polymer mixtures with different ratios of HA to ELA-NCO (1/1, 1/4, and 1/10 (v/v)) were investigated for biocompatibility, degradation behavior and applicability as a sustained release system. For the latter, the lipophilic latanoprost ester pro-drug (LA) was incorporated into the HA/ELA-NCO system. In vitro, a sustained LA release over a period of about 60days was achieved. In cell culture experiments, the HA/ELA-NCO (1/1, (v/v)) system was proven to be biocompatible for human and rabbit Tenon's fibroblasts. Examination of in vitro degradation behavior revealed a total mass loss of more than 60% during the observation period of 26weeks. In vivo, LA was continuously released for 152days into rabbit aqueous humor and serum. Histological investigations revealed a marked leuko-lymphocytic infiltration soon after subconjunctival injection. Thereafter, the initial tissue reaction declined concomitantly with a continuous degradation of the polymer, which was completed after 10months. Our study demonstrates the suitability of the polymer resulting from the reaction of HA with ELA-NCO as an injectable local drug delivery system for glaucoma therapy, combining biocompatibility and biodegradability with prolonged drug release.

  19. Nanoethosomal transdermal delivery of vardenafil for treatment of erectile dysfunction: optimization, characterization, and in vivo evaluation

    PubMed Central

    Fahmy, Usama A

    2015-01-01

    Vesicular drug delivery systems have recently gained attention as a way of improving dosing accuracy for drugs with poor transdermal permeation. The current study focuses on utilization of the natural biocompatible vesicles to formulate vardenafil nanoethosomes (VRD-NE), for the enhancement of their transdermal permeation and bioavailability. Fifteen formulations were prepared by thin-layer evaporation technique according to Box–Behnken design to optimize formulation variables. The effects of lipid composition, sonication time, and ethanol concentration on particle size and encapsulation efficiency were studied. The diffusion of vardenafil (VRD) from the prepared nanoethosomes specified by the design was carried out using automated Franz diffusion cell apparatus. The optimized formula was investigated for in vivo pharmacokinetic parameters compared with oral VRD suspension. Confocal laser scanning microscopy images were used to confirm enhanced diffusion release of VRD in rat skin. The results showed that the optimized formula produced nanoethosomes with an average size of 128 nm and an entrapment efficiency of 76.23%. VRD-NE provided a significant improvement in permeation with an enhancement ratio of 3.05-fold for a film made with optimally formulated VRD-NE compared with a film made with VRD powder. The transdermal bioavailability of VRD from the nanoethosome film was approximately twofold higher than the oral bioavailability from an aqueous suspension. VRD-NE thus provide a promising transdermal drug delivery system. As a result, management of impotence for a longer duration could be achieved with a reduced dosage rate that improves patient tolerability and compliance for the treatment of erectile dysfunction. PMID:26604700

  20. Photothermal treatment of glioma; an in vitro study of macrophage-mediated delivery of gold nanoshells.

    PubMed

    Baek, Seung-Kuk; Makkouk, Amani Riad; Krasieva, Tatiana; Sun, Chung-Ho; Madsen, Steen J; Hirschberg, Henry

    2011-09-01

    One of the major factors that limits the treatment effectiveness for gliomas is the presence of the blood-brain barrier (BBB) which protects infiltrating glioma cells from the effects of anti-cancer agents. Circulating monocytes/macrophages (Ma) have a natural ability to traverse the intact and compromised BBB and loaded with anti cancer agents could be used as vectors to target tumors and surrounding tumor infiltrated tissue. Nanoshells (NS) are composed of a dielectric core (silica) coated with an ultrathin gold layer which converts absorbed near-infrared light (NIR) to heat with an extremely high efficacy and stability. We have investigated the effects of exposure to laser NIR on multicell human glioma spheroids infiltrated with empty (containing no nanoshells) or nanoshell loaded macrophages. Our results demonstrated that; (1) macrophages could efficiently take up bare or coated (PEGylated) gold NS: (2) NS loaded macrophages infiltrated into glioma spheroids to the same or, in some cases, to a greater degree than empty Ma; (3) NIR laser irradiation of spheroids incorporating NS loaded macrophages resulted in complete growth inhibition in an irradiance dependent manner, and (4) spheroids infiltrated with empty macrophages had growth curves identical to untreated control cultures. The results of this study provide proof of concept for the use of macrophages as a delivery vector of NS into gliomas for photothermal ablation and open the possibility of developing such regimens for patient treatment.

  1. Developments on drug delivery systems for the treatment of mycobacterial infections.

    PubMed

    Gaspar, M M; Cruz, A; Fraga, A G; Castro, A G; Cruz, M E M; Pedrosa, J

    2008-01-01

    The clinical management of tuberculosis and other mycobacterial diseases with antimycobacterial chemotherapy remains a difficult task. The classical treatment protocols are long-lasting; the drugs reach mycobacteria-infected macrophages in low amounts and/or do not persist long enough to develop the desired antimycobacterial effect; and the available agents induce severe toxic effects. Nanotechnology has provided a huge improvement to pharmacology through the designing of drug delivery systems able to target phagocytic cells infected by intracellular pathogens, such as mycobacteria. Liposomes and nanoparticles of polymeric nature represent two of the most efficient drug carrier systems that after in vivo administration are endocytosed by phagocytic cells and then release the carried agents into these cells. This article reviews the relevant publications describing the effectiveness of the association of antimycobacterial agents with liposomes or nanoparticles for the treatment of mycobacterioses, particularly for Mycobacterium tuberculosis and M. avium infections. The increased therapeutic index of antimycobacterial drugs; the reduction of dosing frequency; and the improvement of solubility of hydrophobic agents, allowing the administration of higher doses, have been demonstrated in experimental infections. These advantages may lead to new therapeutic protocols that will improve patient compliance and, consequently, lead to a more successful control of mycobacterial infections. The potential therapeutic advantages resulting from the use of non-invasive administration routes for nanoparticulate systems are also discussed.

  2. Innovative Technology for the Assisted Delivery of Intensive Voice Treatment (LSVT[R]LOUD) for Parkinson Disease

    ERIC Educational Resources Information Center

    Halpern, Angela E.; Ramig, Lorraine O.; Matos, Carlos E. C.; Petska-Cable, Jill A.; Spielman, Jennifer L.; Pogoda, Janice M.; Gilley, Phillip M.; Sapir, Shimon; Bennett, John K.; McFarland, David H.

    2012-01-01

    Purpose: To assess the feasibility and effectiveness of a newly developed assistive technology system, Lee Silverman Voice Treatment Companion (LSVT[R] Companion[TM], hereafter referred to as "Companion"), to support the delivery of LSVT[R]LOUD, an efficacious speech intervention for individuals with Parkinson disease (PD). Method: Sixteen…

  3. Local delivery system of doxycycline hyclate based on ε-caprolactone copolymers for periodontitis treatment.

    PubMed

    Kopytynska-Kasperczyk, Anna; Dobrzynski, Piotr; Pastusiak, Małgorzata; Jarzabek, Bozena; Prochwicz, Wojciech

    2015-08-01

    The aim of the study was to evaluate kinetics of doxycycline hyclate release from polymeric bioresorbable implants and to examine suitability of this system for local treatment of periodontitis. Selected trimethylene carbonate/ϵ-caprolactone (TMC/CL) and glycolide/caprolactone (GL/CL) copolymers were synthesized and used as carriers in the form of small elastic rings with 5 wt% and 10 wt% doxycycline hyclate content, or in the form of flakes obtained through electro-spinning technique. The release of the drug under in vitro conditions has been tested. The study has shown that equimolar TMC/CL copolymer loaded with 10 wt% of doxycycline hyclate appears to be the most suitable copolymer for assumed system. The drug release proceeds mainly by diffusion of medium into the polymeric matrix and then the drug is washed out. Daily validation of doxycycline doses released by the system should ensure accurate course of the therapy.

  4. Articulating feedstock delivery device

    SciTech Connect

    Jordan, Kevin

    2013-11-05

    A fully articulable feedstock delivery device that is designed to operate at pressure and temperature extremes. The device incorporates an articulating ball assembly which allows for more accurate delivery of the feedstock to a target location. The device is suitable for a variety of applications including, but not limited to, delivery of feedstock to a high-pressure reaction chamber or process zone.

  5. Types of Nasal Delivery Drugs and Medications in Iranian Traditional Medicine to Treatment of Headache

    PubMed Central

    Ghorbanifar, Zahra; Delavar Kasmaei, Hosein; Minaei, Bagher; Rezaeizadeh, Hossein; Zayeri, Farid

    2014-01-01

    Context: Headache is a common symptom throughout the world. The main purpose of patient-centered approaches is the utilization of useful and simple treatment. Nowadays, there is a rising propensity toward herbal remedies. Nasal route is one of the ancient and topical prescriptions used in headache. In Iranian traditional medicine, physicians such as Avicenna were prescribing herbal drugs through the nose to treat a variety of central nervous system diseases like headache. In this review paper, authors have attempted to introduce different types of nasal administrations which were used in Iranian traditional medicine for the treatment of headaches. Evidence Acquisition: Initially, we studied two different types of Canon and separated all herbs used in the treatment of headache. Next, all plants were classified according to the method of prescription. Then, we pick out all the plants which were nasally utilized in the treatment of headache and divided them based on the method of administration. In order to find scientific names of herbs, we used two different botany references. Moreover, we conducted various researches in scientific databases with the aim of finding results concerning the analgesic and antinociceptive effects of herbs. Throughout the research, key terms were “analgesic” and “antinociceptive “with the scientific names of all herbs separately. The databases searched included PubMed, Scopus, Cochrane library and SID. Results: 35 plants were prescribed for the treatment of headaches, which were all nasally used. These plants took either the form of powder, liquid or gas (steam). They were divided in to six categories according to the method of prescription. The Percentage of usage for each method was as follows: 62% Saoot (nasal drop), 25% Shamoom (smell), 17% Inkabab (vapor), 11% Nafookh (snuff), 11% Nashooq (inhaling) and 2% Bokhoor (smoke). Conclusions: Medications that are used via nasal delivery have greater effect than oral medications

  6. Increasing Rates of Tobacco Treatment Delivery in Primary Care Practice: Evaluation of the Ottawa Model for Smoking Cessation

    PubMed Central

    Papadakis, Sophia; Cole, Adam G.; Reid, Robert D.; Coja, Mustafa; Aitken, Debbie; Mullen, Kerri-Anne; Gharib, Marie; Pipe, Andrew L.

    2016-01-01

    PURPOSE We report on the effectiveness of the Ottawa Model for Smoking Cessation (OMSC), a multicomponent knowledge translation intervention, in increasing the rate at which primary care providers delivered smoking cessation interventions using the 3 A’s model—Ask, Advise, and Act, and examine clinic-, provider-and patient-level determinants of 3 A’s delivery. METHODS We examined the effect of the knowledge translation intervention in 32 primary care practices in Ontario, Canada, by assessing a cross-sectional sample of patients before the implementation of the OMSC and a second cross-sectional sample following implementation. We used 3-level modeling (clinic, clinician, patient) to examine the main effects and predictors of 3 A’s delivery. RESULTS Four hundred eighty-one primary care clinicians and more than 3,500 tobacco users contributed data to the evaluation. Rates of delivery of the 3 A’s increased significantly following program implementation (Ask: 55.3% vs 71.3%, P <.001; Advise: 45.5% vs 63.6%, P <.001; Act: 35.4% vs 54.4%, P <.001). The adjusted odds ratios (AOR) for the delivery of 3 A’s between the pre- and post-assessments were AOR = 1.94; (95% CI, 1.61–2.34) for Ask, AOR = 1.92; (95% CI, 1.60–2.29) for Advise, and AOR = 2.03; (95% CI, 1.71–2.42) for Act. The quality of program implementation and the reason for clinic visit were associated with increased rates of 3 A’s delivery. CONCLUSIONS Implementation of the OMSC was associated with increased rates of smoking cessation treatment delivery. High quality implementation of the OMSC program was associated with increased rates of 3 A’s delivery. PMID:27184994

  7. WE-EF-BRA-03: Catheter- Free Ablation with External Photon Radiation: Treatment Planning, Delivery Considerations, and Correlation of Effects with Delivered Dose

    SciTech Connect

    Deisher, A; Anderson, S; Cusma, J; Herman, M; Johnson, S; Lehmann, H; Packer, D; Parker, K; Song, L; Takami, M; Kruse, J

    2015-06-15

    Purpose: To plan, target, and calculate delivered dose in atrioventricular node (AVN) ablation with volume-modulated arc therapy (VMAT) in an intact porcine model. Methods: Seven pigs underwent AVN irradiation, with prescription doses ranging between 25 and 55Gy in a single fraction. Cardiac CT scans were acquired at expiration. Two physicians contoured AVN targets on 10 phases, providing estimates of target motion and inter-physician variability. Treatment planning was conducted on a static phase-averaged CT. The volume designated to receive prescription dose covered the full extent of AVN cardiac motion, expanded by 4mm for setup uncertainty. Optimization limited doses to risk structures according to single-fraction tumor treatment protocols. Orthogonal kV images were used to align bony anatomy at time of treatment. Localization was further refined with respiratory-gated cone-beam CT, and range of cardiac motion was verified under fluoroscopy. Beam delivery was respiratory-gated for expiration with a mean efficiency of 60%. Deformable registration of the 10 cardiac CT phases was used to calculate actual delivered dose for comparison to electro-anatomical and visually evident lesions. Results: The mean [minimum,maximum] amplitude of AVN cardiac motion was LR 2.9 [1.7,3.9]mm, AP 6.6 [4.4,10.4]mm, and SI 5.6 [2.0,9.9]mm. Incorporating cardiac motion into the dose calculation showed the volume receiving full dose was 40–80% of the volume indicated on the static planning image, although the contoured AVN target received full dose in all animals. Initial results suggest the dimensions of the electro-anatomical lesion are correlated with the 40Gy isodose volume. Conclusion: Image-guidance techniques allow for accurate and precise delivery of VMAT for catheter-free arrhythmia ablation. An arsenal of advanced radiation planning, dose optimization, and image-guided delivery techniques was employed to assess and mitigate effects of cardiac and respiratory motion

  8. Ethosomes: a novel delivery system for antifungal drugs in the treatment of topical fungal diseases.

    PubMed

    Bhalaria, M K; Naik, Sachin; Misra, A N

    2009-05-01

    Aim of this work was to prepare and characterize fluconazole (FLZ) encapsulated ethosomes, incorporate it in suitable dermatological base, and asses its comparative clinical efficacy in the treatment of Candidiasis patients against liposomal gel, marketed product and hydroethanolic solution of the drug. Drug encapsulated ethosomes and liposomes were prepared and optimized by "Hot" method technique and lipid film hydration technique. Vesicular carriers were characterized for % entrapment efficiency, particle size and shape, in vitro drug diffusion study, mean % reduction in dimension of Candidiasis lesion and stability study by using suitable analytical technique. Vesicle size and drug entrapment efficiency of the optimized ethosomes and liposomes were found to be 144 +/- 6.8 nm and 82.68% and 216 +/- 9.2 nm and 68.22% respectively. Microscopic examinations suggest ethosomes to be multilamellar spherical vesicles with a smooth surface. The differential scanning calorimetry results suggest high fluidity of the ethosomes than liposomes. In vitro drug diffusion studies demonstrated that % drug diffused from ethosomes was nearly twice than liposomes and three times higher than the hydroethanolic solution across rat skin. From the clinical evaluation, the developed novel delivery system demonstrated enhanced antifungal activity compared to liposomal formulation, marketed formulation and hydroethanolic solution of the drug.

  9. A Novel Vehicle for Enhanced Drug Delivery Across the Human Nail for the Treatment of Onychomycosis.

    PubMed

    Turner, Rob; Weaver, Sean; Caserta, Francesco; Brown, Marc B

    2016-01-01

    The aim of this study was to use in vitro nail models to investigate the potential of a novel base formulation (Recura) containing either fluconazole or miconazole for the treatment of onychomycosis in comparison to two commercial comparators (Jublia and a Penlac generic). Initially, a modified Franz cell was used, where sections of human nail served as the barrier through which drug penetrated into an agar-filled chamber infected with dermatophytes. A second study was performed using a novel infected nail model where dermatophytes grew into human nail and adenosine triphosphate levels were used as biological marker for antimicrobial activity. The novel enhancing system Recura increased the permeation of both existing drugs through human nail sections mounted in a modified Franz cell. Furthermore, the infected nail model also confirmed that the system also enhanced the permeation through infected nail resulting in a decrease in adenosine triphosphate levels superior (P ≤ 0.05) to Penlac generic and equivalent (P > 0.05) to the commercial comparator Jublia. This study demonstrated that with the use of a novel permeation-enhancing formulation base, Recura enhances delivery of miconazole and fluconazole when applied ungually such that the efficacy was equivalent or superior to commercial comparators. Such a topically applied system has the possibility of overcoming the systemic side effects of antifungals when taken orally.

  10. A new era of cancer treatment: carbon nanotubes as drug delivery tools.

    PubMed

    Madani, Seyed Yazdan; Naderi, Naghmeh; Dissanayake, Oshani; Tan, Aaron; Seifalian, Alexander M

    2011-01-01

    Cancer is a generic term that encompasses a group of diseases characterized by an uncontrolled proliferation of cells. There are over 200 different types of cancer, each of which gains its nomenclature according to the type of tissue the cell originates in. Many patients who succumb to cancer do not die as a result of the primary tumor, but because of the systemic effects of metastases on other regions away from the original site. One of the aims of cancer therapy is to prevent the metastatic process as early as possible. There are currently many therapies in clinical use, and recent advances in biotechnology lend credence to the potential of nanotechnology in the fight against cancer. Nanomaterials such as carbon nanotubes (CNTs), quantum dots, and dendrimers have unique properties that can be exploited for diagnostic purposes, thermal ablation, and drug delivery in cancer. CNTs are tubular materials with nanometer-sized diameters and axial symmetry, giving them unique properties that can be exploited in the diagnosis and treatment of cancer. In addition, CNTs have the potential to deliver drugs directly to targeted cells and tissues. Alongside the rapid advances in the development of nanotechnology-based materials, elucidating the toxicity of nanoparticles is also imperative. Hence, in this review, we seek to explore the biomedical applications of CNTs, with particular emphasis on their use as therapeutic platforms in oncology.

  11. Characterization of corrosion scale formed on stainless steel delivery pipe for reclaimed water treatment.

    PubMed

    Cui, Yong; Liu, Shuming; Smith, Kate; Yu, Kanghua; Hu, Hongying; Jiang, Wei; Li, Yuhong

    2016-01-01

    To reveal corrosion behavior of stainless steel delivery pipe used in reclaimed water treatment, this research focused on the morphological, mineralogical and chemical characteristics of stainless steel corrosion scale and corroded passive film. Corrosion scale and coupon samples were taken from a type 304 pipe delivering reclaimed water to a clear well in service for more than 12 years. Stainless steel corrosion scales and four representative pipe coupons were investigated using mineralogy and material science research methods. The results showed corrosion scale was predominantly composed of goethite, lepidocrocite, hematite, magnetite, ferrous oxide, siderite, chrome green and chromite, the same as that of corroded pipe coupons. Hence, corrosion scale can be identified as podiform chromite deposit. The loss of chromium in passive film is a critical phenomenon when stainless steel passive film is damaged by localized corrosion. This may provide key insights toward improving a better comprehension of the formation of stainless steel corrosion scale and the process of localized corrosion. The localized corrosion behavior of stainless steel is directly connected with reclaimed water quality parameters such as residual chlorine, DO, Cl(-) and SO4(2-). In particular, when a certain amount of residual chlorine in reclaimed water is present as an oxidant, ferric iron is the main chemical state of iron minerals.

  12. Monocytic delivery of therapeutic oxygen bubbles for dual-modality treatment of tumor hypoxia.

    PubMed

    Huang, Wen-Chia; Shen, Ming-Yin; Chen, Hsin-Hung; Lin, Sung-Chyr; Chiang, Wen-Hsuan; Wu, Pei-Hsuan; Chang, Chien-Wen; Chiang, Chi-Shiun; Chiu, Hsin-Cheng

    2015-12-28

    Photodynamic therapy (PDT) is a powerful technique photochemically tailored for activating apoptosis of malignant cells. Although PDT has shown promise in several clinical applications, malignant cells in hypoxic regions are often resistant to PDT due to the transport limitation of therapeutics and the oxygen-dependent nature of PDT. Herein, we present an innovative strategy for overcoming the limits of PDT in tumor hypoxia using bone marrow-derived monocytes as cellular vehicles for co-transport of oxygen and red light activatable photosensitizer, chlorin e6 (Ce6). Superparamagnetic iron oxide nanoparticle/Ce6/oxygen-loaded polymer bubbles were prepared and internalized into tumortropic monocytes. These functional bubbles were found harmless to cellular hosts without external triggers. Nevertheless, the therapeutic monocytes exhibited a superior performance in inhibiting tumor growth on Tramp-C1 tumor-bearing mice (C57BL/6J) upon the treatments of tumors with high frequency magnetic field and red light laser (660 nm). Histological examinations of the tumor sections confirmed the successful cellular transport of therapeutic payloads to tumor hypoxia and the pronounced antitumor effect elicited by combined hyperthermia/photodynamic therapy along with the additional oxygen supply. This work demonstrates that this oxygen/therapeutic co-delivery via tumortropic monocytes toward tumor hypoxia is promising for improving PDT efficacy.

  13. Predictive Factors for Delivery within 7 Days after Successful 48-Hour Treatment of Threatened Preterm Labor

    PubMed Central

    Roos, Carolien; Schuit, Ewoud; Scheepers, Hubertina C. J.; Bloemenkamp, Kitty W. M.; Bolte, Antoinette C.; Duvekot, Hans J. J.; van Eyck, Jim; Kok, Joke H.; Kwee, Anneke; Merién, Ashley E. R.; Opmeer, Brent C.; Oudijk, Martijn A.; van Pampus, Mariëlle G.; Papatsonis, Dimitri N. M.; Porath, Martina M.; Sollie, Krystyna M.; Spaanderman, Marc E. A.; Vijgen, Sylvia M. C.; Willekes, Christine; Lotgering, Fred K.; van der Post, Joris A. M.; Mol, Ben Willem J.

    2015-01-01

    Objective The aim of this study was to assess which characteristics and results of vaginal examination are predictive for delivery within 7 days, in women with threatened preterm labor after initial treatment. Study Design A secondary analysis of a randomized controlled trial on maintenance nifedipine includes women who remained undelivered after threatened preterm labor for 48 hours. We developed one model for women with premature prelabor rupture of membranes (PPROM) and one without PPROM. The predictors were identified by backward selection. We assessed calibration and discrimination and used bootstrapping techniques to correct for potential overfitting. Results For women with PPROM (model 1), nulliparity, history of preterm birth, and vaginal bleeding were included in the multivariable analysis. For women without PPROM (model 2), maternal age, vaginal bleeding, cervical length, and fetal fibronectin (fFN) status were in the multivariable analysis. Discriminative capability was moderate to good (c-statistic 0.68; 95% confidence interval [CI] 0.60–0.77 for model 1 and 0.89; 95% CI, 0.84–0.93 for model 2). Conclusion PPROM and vaginal bleeding in the current pregnancy are relevant predictive factors in all women, as are maternal age, cervical length, and fFN in women without PPROM and nulliparity, history of preterm birth in women with PPROM. PMID:26495173

  14. Evaluation of polycaprolactone matrices for the intravaginal delivery of metronidazole in the treatment of bacterial vaginosis.

    PubMed

    Pathak, Meenakshi; Turner, Mark; Palmer, Cheryn; Coombes, Allan G A

    2014-09-01

    Microporous, poly (ɛ-caprolactone) (PCL) matrices loaded with the antibacterial, metronidazole were produced by rapidly cooling suspensions of drug powder in PCL solutions in acetone. Drug incorporation in the matrices increased from 2.0% to 10.6% w/w on raising the drug loading of the PCL solution from 5% to 20% w/w measured with respect to the PCL content. Drug loading efficiencies of 40-53% were obtained. Rapid 'burst release' of 35-55% of the metronidazole content was recorded over 24 h when matrices were immersed in simulated vaginal fluid (SVF), due to the presence of large amounts of drug on matrix surface as revealed by Raman microscopy. Gradual release of around 80% of the drug content occurred over the following 12 days. Metronidazole released from PCL matrices in SVF retained antimicrobial activity against Gardnerella vaginalis in vitro at levels up to 97% compared to the free drug. Basic modelling predicted that the concentrations of metronidazole released into vaginal fluid in vivo from a PCL matrix in the form of an intravaginal ring would exceed the minimum inhibitory concentration of metronidazole against G. vaginalis. These findings recommend further investigation of PCL matrices as intravaginal devices for controlled delivery of metronidazole in the treatment and prevention of bacterial vaginosis.

  15. Herpes simplex virus vector-mediated gene delivery for the treatment of lower urinary tract pain

    PubMed Central

    Goins, WF; Goss, JR; Chancellor, MB; de Groat, WC; Glorioso, JC; Yoshimura, N

    2009-01-01

    Interstitial cystitis (IC)/painful bladder syndrome (PBS) is a painful debilitating chronic visceral pain disorder of unknown etiology that affects an estimated 1 million people in the, United States alone. It is characterized by inflammation of the bladder that results in chronic pelvic pain associated with bladder symptoms of urinary frequency and urgency. Regardless of the etiology, IC/PBS involves either increased and/or abnormal activity in afferent nociceptive sensory neurons. Pain-related symptoms in patients with IC/PBS are often very difficult to treat. Both medical and surgical therapies have had limited clinical utility in this debilitating disease and numerous drug treatments, such as heparin, dimethylsulfoxide and amitriptyline, have proven to be palliative at best, and in some IC/PBS patients provide no relief whatsoever. Although opiate narcotics have been employed to help alleviate IC/PBS pain, this strategy is fraught with problems as systemic narcotic administration causes multiple unwanted side effects including mental status change and constipation. Moreover, chronic systemic narcotic use leads to dependency and need for dose escalation due to tolerance: therefore, new therapies are desperately needed to treat refractory IC/PBS. This has led our group to develop a gene therapy strategy that could potentially alleviate chronic pelvic pain using the herpes simplex virus-directed delivery of analgesic proteins to the bladder. PMID:19242523

  16. Nanodroplet-Vaporization-Assisted Sonoporation for Highly Effective Delivery of Photothermal Treatment

    NASA Astrophysics Data System (ADS)

    Liu, Wei-Wen; Liu, Shu-Wei; Liou, Yu-Ren; Wu, Yu-Hsun; Yang, Ya-Chuen; Wang, Churng-Ren Chris; Li, Pai-Chi

    2016-04-01

    Sonoporation refers to the use of ultrasound and acoustic cavitation to temporarily enhance the permeability of cellular membranes so as to enhance the delivery efficiency of therapeutic agents into cells. Microbubble-based ultrasound contrast agents are often used to facilitate these cavitation effects. This study used nanodroplets to significantly enhance the effectiveness of sonoporation relative to using conventional microbubbles. Significant enhancements were demonstrated both in vitro and in vivo by using gold nanorods encapsulated in nanodroplets for implementing plasmonic photothermal therapy. Combined excitation by ultrasound and laser radiation is used to trigger the gold nanodroplets to induce a liquid-to-gas phase change, which induces cavitation effects that are three-to-fivefold stronger than when using conventional microbubbles. Enhanced cavitation also leads to significant enhancement of the sonoporation effects. Our in vivo results show that nanodroplet-vaporization-assisted sonoporation can increase the treatment temperature by more than 10 °C above that achieved by microbubble-based sonoporation.

  17. The therapeutic potential of vaginal drug delivery in the treatment of cervical cancer.

    PubMed

    McConville, Christopher

    2015-01-01

    Cervical cancer is usually treated by surgery, with the more advanced cancers requiring adjuvant chemo or radiotherapy. Its location makes it easily accessible through the vagina for the localized delivery of chemotherapeutic drugs. Localized delivery has the advantage of direct delivery to the site of action resulting in a lower dose being required and a reduction in systemic side effects. This approach would be advantageous in fertility-sparing surgery, where by localized delivery could be used to reduce tumor size allowing for a much smaller tumor to be removed, reducing the risk of preterm birth. Furthermore, localized delivery could be used after surgery to reduce the risk of recurrence, which is significantly higher in fertility-sparing surgery compared with standard surgery.

  18. Development of nanoantibiotic delivery system using cockle shell-derived aragonite nanoparticles for treatment of osteomyelitis

    PubMed Central

    Saidykhan, Lamin; Abu Bakar, Md Zuki Bin; Rukayadi, Yaya; Kura, Aminu Umar; Latifah, Saiful Yazan

    2016-01-01

    A local antibiotic delivery system (LADS) with biodegradable drug vehicles is recognized as the most effective therapeutic approach for the treatment of osteomyelitis. However, the design of a biodegradable LADS with high therapeutic efficacy is too costly and demanding. In this research, a low-cost, facile method was used to design vancomycin-loaded aragonite nanoparticles (VANPs) with the aim of understanding its potency in developing a nanoantibiotic bone implant for the treatment of osteomyelitis. The aragonite nanoparticles (ANPs) were synthesized from cockle shells by a hydrothermal approach using a zwitterionic surfactant. VANPs were prepared using antibiotic ratios of several nanoparticles, and the formulation (1:4) with the highest drug-loading efficiency (54.05%) was used for physicochemical, in vitro drug release, and biological evaluation. Physiochemical characterization of VANP was performed by using transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray powder diffraction, and Zetasizer. No significant differences were observed between VANP and ANP in terms of size and morphology as both samples were cubic shaped with sizes of approximately 35 nm. The Fourier transform infrared spectroscopy of VANP indicated a weak noncovalent interaction between ANP and vancomycin, while the zeta potential values were slightly increased from −19.4±3.3 to −21.2±5.7 mV after vancomycin loading. VANP displayed 120 hours (5 days) release profile of vancomycin that exhibited high antibacterial effect against methicillin-resistant Staphylococcus aureus ATCC 29213. The cell proliferation assay showed 80% cell viability of human fetal osteoblast cell line 1.19 treated with the highest concentration of VANP (250 µg/mL), indicating good biocompatibility of VANP. In summary, VANP is a potential formulation for the development of an LADS against osteomyelitis with optimal antibacterial efficacy, good bone resorbability, and biocompatibility. PMID

  19. A direct nitinol stent delivery technique for endovascular treatment: a sheath-less stenting technique.

    PubMed

    Shintani, Yoshiaki; Kawasaki, Tomohiro; Fujimura, Takashi; Ishida, Kouichirou; Higuchi, Takanori; Kajiwara, Masataka; Fukuoka, Ryota; Orita, Yoshiya; Umeji, Kyoko; Koga, Hisashi; Koga, Nobuhiko

    2015-04-01

    Access site problems often cause serious complications in endovascular treatment. The aim of this study is to investigate whether a sheath-less nitinol stenting technique leads to reduce access site complications. This study was a single-center retrospective analysis of a prospectively maintained database. The study enrolled consecutive 98 patients with 111 lesions undergoing provisional stenting for de novo iliac artery or femoro-popliteal artery stenosis between August 2010 and November 2011. The patients were divided into two groups, a conventional procedure group and a sheath-less procedure group. The outcomes of this study were peri-procedural access site complications, initial success rate, procedure time, hemostatic time and bed-rest time. Forty-four lesions in 39 patients that treated using the sheath-less nitinol stent delivery technique were compared with 67 lesions in 59 patients treated using the conventional procedure. All procedures were successful. The incidence of pseudoaneurysm was significantly lower in the sheath-less procedure group than in the conventional procedure group (p = 0.043). However, there were no significant differences in any other complications. No significant difference was observed in the procedural time (p = 0.309). However, hemostatic time and bed-rest time were significantly shorter in the sheath-less procedure than in the conventional procedure (p < 0.0001). A sheath-less stenting technique reduced the access site incidence of pseudoaneurysm and did not increase other access site complications. Besides, this technique shortened hemostatic time and bed-rest time. The sheath-less stenting technique is considered to be a useful method for endovascular treatment.

  20. Development of nanoantibiotic delivery system using cockle shell-derived aragonite nanoparticles for treatment of osteomyelitis.

    PubMed

    Saidykhan, Lamin; Abu Bakar, Md Zuki Bin; Rukayadi, Yaya; Kura, Aminu Umar; Latifah, Saiful Yazan

    2016-01-01

    A local antibiotic delivery system (LADS) with biodegradable drug vehicles is recognized as the most effective therapeutic approach for the treatment of osteomyelitis. However, the design of a biodegradable LADS with high therapeutic efficacy is too costly and demanding. In this research, a low-cost, facile method was used to design vancomycin-loaded aragonite nanoparticles (VANPs) with the aim of understanding its potency in developing a nanoantibiotic bone implant for the treatment of osteomyelitis. The aragonite nanoparticles (ANPs) were synthesized from cockle shells by a hydrothermal approach using a zwitterionic surfactant. VANPs were prepared using antibiotic ratios of several nanoparticles, and the formulation (1:4) with the highest drug-loading efficiency (54.05%) was used for physicochemical, in vitro drug release, and biological evaluation. Physiochemical characterization of VANP was performed by using transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray powder diffraction, and Zetasizer. No significant differences were observed between VANP and ANP in terms of size and morphology as both samples were cubic shaped with sizes of approximately 35 nm. The Fourier transform infrared spectroscopy of VANP indicated a weak noncovalent interaction between ANP and vancomycin, while the zeta potential values were slightly increased from -19.4±3.3 to -21.2±5.7 mV after vancomycin loading. VANP displayed 120 hours (5 days) release profile of vancomycin that exhibited high antibacterial effect against methicillin-resistant Staphylococcus aureus ATCC 29213. The cell proliferation assay showed 80% cell viability of human fetal osteoblast cell line 1.19 treated with the highest concentration of VANP (250 µg/mL), indicating good biocompatibility of VANP. In summary, VANP is a potential formulation for the development of an LADS against osteomyelitis with optimal antibacterial efficacy, good bone resorbability, and biocompatibility.

  1. Biomimetic nanoparticles for siRNA delivery in the treatment of leukaemia.

    PubMed

    Guo, Jianfeng; Cahill, Mary R; McKenna, Sharon L; O'Driscoll, Caitriona M

    2014-12-01

    Leukaemia is a bone marrow cancer occurring in acute and chronic subtypes. Acute leukaemia is a rapidly fatal cancer potentially causing death within a few weeks, if untreated. Leukaemia arises as a result of disruption to haematopoietic precursors, caused either by acquired gene fusions, gene mutations or inappropriate expression of the relevant oncogenes. Current treatment options have made significant progress, but the 5 year survival for acute leukaemia remains under 10% in elderly patients, and less than 50% for some types of acute leukaemia in younger adults. For chronic leukaemias longer survival is generally expected and for chronic myeloid leukaemia patients on tyrosine kinase inhibitors the median survival is not yet reached and is expected to exceed 10 years. Chemotherapy and haematopoietic stem cell transplantation (HSCT) for acute leukaemia provide the mainstay of therapy for patients under 65 and both carry significant morbidity and mortality. Alternative and superior therapeutic strategies for acute leukaemias are urgently required. Recent molecular-based knowledge of recurring chromosome rearrangements, in particular translocations and inversions, has resulted in significant advances in understanding the molecular pathogenesis of leukaemia. Identification of a number of unique fusion genes has facilitated the development of highly specific small interfering RNAs (siRNA). Although delivery of siRNA using multifunctional nanoparticles has been investigated to treat solid cancers, the application of this approach to blood cancers is at an early stage. This review describes current treatments for leukaemia and highlights the potential of leukaemic fusion genes as therapeutic targets for RNA interference (RNAi). In addition, the design of biomimetic nanoparticles which are capable of responding to the physiological environment of leukaemia and their potential to advance RNAi therapeutics to the clinic will be critically evaluated.

  2. Commissioning and quality assurance for the treatment delivery components of the AccuBoost system.

    PubMed

    Iftimia, Ileana; Talmadge, Mike; Ladd, Ron; Halvorsen, Per

    2015-03-08

    The objective for this work was to develop a commissioning methodology for the treatment delivery components of the AccuBoost system, as well as to establish a routine quality assurance program and appropriate guidance for clinical use based on the commissioning results. Various tests were developed: 1) assessment of the accuracy of the displayed separation value; 2) validation of the dwell positions within each applicator; 3) assessment of the accuracy and precision of the applicator localization system; 4) assessment of the combined dose profile of two opposed applicators to confirm that they are coaxial; 5) measurement of the absolute dose delivered with each applicator to confirm acceptable agreement with dose based on Monte Carlo modeling; 6) measurements of the skin-to-center dose ratio using optically stimulated luminescence dosimeters; and 7) assessment of the mammopad cushion's effect on the center dose. We found that the difference between the measured and the actual paddle separation is < 0.1 cm for the separation range of 3 cm to 7.5 cm. Radiochromic film measurements demonstrated that the number of dwell positions inside the applicators agree with the values from the vendor, for each applicator type and size. The shift needed for a good applicator-grid alignment was within 0.2 cm. The dry-run test using film demonstrated that the shift of the dosimetric center is within 0.15 cm. Dose measurements in water converted to polystyrene agreed within 5.0% with the Monte Carlo data in polystyrene for the same applicator type, size, and depth. A solid water-to-water (phantom) factor was obtained for each applicator, and all future annual quality assurance tests will be performed in solid water using an average value of 1.07 for the solid water-to-water factor. The skin-to-center dose ratio measurements support the Monte Carlo-based values within 5.0% agreement. For the treatment separation range of 4 cm to 8cm, the change in center dose would be < 1.0% for all

  3. Validation of Pinnacle treatment planning system for use with Novalis delivery unit.

    PubMed

    Faygelman, Vladimir; Hunt, Dylan; Walker, Luke; Mueller, Richard; Demarco, Mary Lou; Dilling, Thomas; Stevens, Craig; Zhang, Geoffrey

    2010-06-15

    For an institution that already owns the licenses, it is economically advantageous and technically feasible to use Pinnacle TPS (Philips Radiation Oncology Systems, Fitchburg, WI) with the BrainLab Novalis delivery system (BrainLAB A.G., Heimstetten, Germany). This takes advantage of the improved accuracy of the convolution algorithm in the presence of heterogeneities compared with the pencil beam calculation, which is particularly significant for lung SBRT treatments. The reference patient positioning DRRs still have to be generated by the BrainLab software from the CT images and isocenter coordinates transferred from Pinnacle. We validated this process with the end-to-end hidden target test, which showed an isocenter positioning error within one standard deviation from the previously established mean value. The Novalis treatment table attenuation is substantial (up to 6.2% for a beam directed straight up and up to 8.4% for oblique incidence) and has to be accounted for in calculations. A simple single-contour treatment table model was developed, resulting in mean differences between the measured and calculated attenuation factors of 0.0%-0.2%, depending on the field size. The maximum difference for a single incidence angle is 1.1%. The BrainLab micro-MLC (mMLC) leaf tip, although not geometrically round, can be represented in Pinnacle by an arch with satisfactory dosimetric accuracy. Subsequently, step-and-shoot (direct machine parameter optimization) IMRT dosimetric agreement is excellent. VMAT (called "SmartArc" in Pinnacle) treatments with constant gantry speed and dose rate are feasible without any modifications to the accelerator. Due to the 3 mm-wide mMLC leaves, the use of a 2 mm calculation grid is recommended. When dual arcs are used for the more complex cases, the overall dosimetric agreement for the SmartArc plans compares favorably with the previously reported results for other implementations of VMAT: gamma(3%,3mm) for absolute dose obtained with the

  4. Depot delivery of dexamethasone and cediranib for the treatment of brain tumor associated edema in an intracranial rat glioma model.

    PubMed

    Ong, Qunya; Hochberg, Fred H; Cima, Michael J

    2015-11-10

    Treatments of brain tumor associated edema with systemically delivered dexamethasone, the standard of care, and cediranib, a novel anti-edema agent, are associated with systemic toxicities in brain tumor patients. A tunable, reservoir-based drug delivery device was developed to investigate the effects of delivering dexamethasone and cediranib locally in the brain in an intracranial 9L gliosarcoma rat model. Reproducible, sustained releases of both dexamethasone and solid dispersion of cediranib in polyvinylpyrrolidone (AZD/PVP) from these devices were achieved. The water-soluble AZD/PVP, which exhibited similar bioactivity as cediranib, was developed to enhance the release of cediranib from the device. Local and systemic administration of both dexamethasone and cediranib was equally efficacious in alleviating edema but had no effect on tumor growth. Edema reduction led to modest but significant improvement in survival. Local delivery of dexamethasone prevented dexamethasone-induced weight loss, an adverse effect seen in animals treated with systemic dexamethasone. Local deliveries of dexamethasone and cediranib via these devices used only 2.36% and 0.21% of the systemic doses respectively, but achieved similar efficacy as systemic drug deliveries without the side effects associated with systemic administration. Other therapeutic agents targeting brain tumor can be delivered locally in the brain to provide similar improved treatment outcomes.

  5. 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.

  6. Interval From Imaging to Treatment Delivery in the Radiation Surgery Age: How Long Is Too Long?

    SciTech Connect

    Seymour, Zachary A.; Fogh, Shannon E.; Westcott, Sarah K.; Braunstein, Steve; Larson, David A.; Barani, Igor J.; Nakamura, Jean; Sneed, Penny K.

    2015-09-01

    Purpose: The purpose of this study was to evaluate workflow and patient outcomes related to frameless stereotactic radiation surgery (SRS) for brain metastases. Methods and Materials: We reviewed all treatment demographics, clinical outcomes, and workflow timing, including time from magnetic resonance imaging (MRI), computed tomography (CT) simulation, insurance authorization, and consultation to the start of SRS for brain metastases. Results: A total of 82 patients with 151 brain metastases treated with SRS were evaluated. The median times from consultation, insurance authorization, CT simulation, and MRI for treatment planning were 15, 7, 6, and 11 days to SRS. Local freedom from progression (LFFP) was lower in metastases with MRI ≥14 days before treatment (P=.0003, log rank). The 6- and 12-month LFFP rate were 95% and 75% for metastasis with interval of <14 days from MRI to treatment compared to 56% and 34% for metastases with MRI ≥14 days before treatment. On multivariate analysis, LFFP remained significantly lower for lesions with MRI ≥14 days at SRS (P=.002, Cox proportional hazards; hazard ratio: 3.4, 95% confidence interval: 1.6-7.3). Conclusions: Delay from MRI to SRS treatment delivery for brain metastases appears to reduce local control. Future studies should monitor the timing from imaging acquisition to treatment delivery. Our experience suggests that the time from MRI to treatment should be <14 days.

  7. Intranasal delivery of rotigotine to the brain with lactoferrin-modified PEG-PLGA nanoparticles for Parkinson's disease treatment.

    PubMed

    Bi, Chenchen; Wang, Aiping; Chu, Yongchao; Liu, Sha; Mu, Hongjie; Liu, Wanhui; Wu, Zimei; Sun, Kaoxiang; Li, Youxin

    Sustainable and safe delivery of brain-targeted drugs is highly important for successful therapy in Parkinson's disease (PD). This study was designed to formulate biodegradable poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NPs), which were surface-modified with lactoferrin (Lf), for efficient intranasal delivery of rotigotine to the brain for the treatment of PD. Rotigotine NPs were prepared by nanoprecipitation, and the effect of various independent process variables on the resulting properties of NPs was investigated by a Box-Behnken experimental design. The physicochemical and pharmaceutical properties of the NPs and Lf-NPs were characterized, and the release kinetics suggested that both NPs and Lf-NPs provided continuous, slow release of rotigotine for 48 h. Neither rotigotine NPs nor Lf-NPs reduced the viability of 16HBE and SH-SY5Y cells; in contrast, free rotigotine was cytotoxic. Qualitative and quantitative cellular uptake studies demonstrated that accumulation of Lf-NPs was greater than that of NPs in 16HBE and SH-SY5Y cells. Following intranasal administration, brain delivery of rotigotine was much more effective with Lf-NPs than with NPs. The brain distribution of rotigotine was heterogeneous, with a higher concentration in the striatum, the primary region affected in PD. This strongly suggested that Lf-NPs enable the targeted delivery of rotigotine for the treatment of PD. Taken together, these results demonstrated that Lf-NPs have potential as a carrier for nose-to-brain delivery of rotigotine for the treatment of PD.

  8. Delivery of local therapeutics to the brain: working toward advancing treatment for malignant gliomas.

    PubMed

    Chaichana, Kaisorn L; Pinheiro, Leon; Brem, Henry

    2015-03-01

    Malignant gliomas, including glioblastoma and anaplastic astrocytomas, are characterized by their propensity to invade surrounding brain parenchyma, making curative resection difficult. These tumors typically recur within two centimeters of the resection cavity even after gross total removal. As a result, there has been an emphasis on developing therapeutics aimed at achieving local disease control. In this review, we will summarize the current developments in the delivery of local therapeutics, namely direct injection, convection-enhanced delivery and implantation of drug-loaded polymers, as well as the application of these therapeutics in future methods including microchip drug delivery and local gene therapy.

  9. Treatment planning system and dose delivery accuracy in extracranial stereotactic radiotherapy using Elekta body frame

    NASA Astrophysics Data System (ADS)

    Dawod, Tamer; Bremer, Michael; Karstens, Johann H.; Werner, Martin

    2010-01-01

    The purpose of this study was to measure the photon beam transmission through the Elekta Stereotactic Body Frame (ESBF) and treatment couch, to determine the dose calculations accuracy of the MasterPlan Treatment Planning System (TPS) using Pencil Beam (PBA) and Collapsed Cone (CCA) algorithms during the use of Elekta Stereotactic Body Frame (ESBF), and to demonstrate a simple calculation method to put this transmission into account during the treatment planning dose calculations. The dose was measured at the center of an in-house custom-built inhomogeneous PMMA thorax phantom with and without ‘the frame + treatment couch’. The phantom was CT-imaged inside the ESBF and planned with multiple 3D-CRT fields using PBA and CCA for photon beams of energies 6 MV and 10 MV. There were two treatment plans for dose calculations. In the first plan, the ‘frame + couch’ were included in the body contour and, therefore, included in the TPS dose calculations. In the second plan, the ‘frame + couch’ were not included in the body contour and, therefore, not included in the calculations. Transmission of the ‘frame + couch’ was determined by the ratio of the dose measurements with the ‘frame + couch’ to the measurements without them. To validate the accuracy of the calculation model, plans with and without the ‘frame + couch’ surrounding the phantoms were compared with their corresponding measurements. The transmission of the ‘frame + couch’ varies from 90.23-97.54% depending on the energy, field size, the angle of the beams and whether the beams also intercept them. The validation accuracy of the Pencil Beam (PBA) and Collapsed Cone (CCA) algorithms were within 5.33% and 4.04% respectively for the individual measurements for all gantry angles under this study. The results showed that both PBA and CCA algorithms can calculate the dose to the target within 4.25% and 1.95% of the average measured value. The attenuation caused by the ESBF and couch must be

  10. Numerical optimization of targeted delivery of charged nanoparticles to the ostiomeatal complex for treatment of rhinosinusitis

    PubMed Central

    Xi, Jinxiang; Yuan, Jiayao Eddie; Si, Xiuhua April; Hasbany, James

    2015-01-01

    Background Despite the prevalence of rhinosinusitis that affects 10%–15% of the population, current inhalation therapy shows limited efficacy. Standard devices deliver <5% of the drugs to the sinuses due to the complexity of nose structure, secluded location of the sinus, poor ventilation, and lack of control of particle motions inside the nasal cavity. Methods An electric-guided delivery system was developed to guide charged particles to the ostiomeatal complex (OMC). Its performance was numerically assessed in an MRI-based nose–sinus model. Key design variables related to the delivery device, drug particles, and patient breathing were determined using sensitivity analysis. A two-stage optimization of design variables was conducted to obtain the best performance of the delivery system using the Nelder-Mead algorithm. Results and discussion The OMC delivery system exhibited high sensitivity to the applied electric field and electrostatic charges carried by the particles. Through the synthesis of electric guidance and point drug release, the new delivery system eliminated particle deposition in the nasal valve and turbinate regions and significantly enhanced the OMC doses. An OMC delivery efficiency of 72.4% was obtained with the optimized design, which is one order of magnitude higher than the standard nasal devices. Moreover, optimization is imperative to achieve a sound delivery protocol because of the large number of design variables. The OMC dose increased from 45.0% in the baseline model to 72.4% in the optimized system. The optimization framework developed in this study can be easily adapted for the delivery of drugs to other sites in the nose such as the ethmoid sinus and olfactory region. PMID:26257521

  11. Chronomodulated drug delivery system of urapidil for the treatment of hypertension

    PubMed Central

    Chaudhary, Sona S.; Patel, Hetal K.; Parejiya, Punit B.; Shelat, Pragna K.

    2015-01-01

    Introduction: Hypertension is a disease which shows circadian rhythm in the pattern of two peaks, one in the evening at about 7pm and other in the early morning between 4 am to 8 am. Conventional therapies are incapable to target those time points when actually the symptoms get worsened. To achieve drug release at two time points, chronomodulated delivery system may offer greater benefits. Materials and methods: The chronomodulated system comprised of dual approach; immediate release granules (IRG) and pulsatile release mini-tablets (PRM) filled in the hard gelatin capsule. The mini-tablets were coated using Eudragit S-100 which provided the lag time. To achieve the desired release, various parameters like coating duration and coat thickness were studied. The immediate release granules were evaluated for micromeritical properties and drug release, while mini-tablets were evaluated for various parameters such as hardness, thickness, friability, weight variation, drug content, and disintegration time and in-vitro drug release. Compatibility of drug-excipient was checked by fourier transform infrared spectroscopy and Differential scanning calorimetry studies and pellets morphology was done by Scanning electron microscopy studies. Results: The in-vitro release profile suggested that immediate release granules gives drug release within 20 min at the time of evening attack while the programmed pulsatile release was achieved from coated mini-tablets after a lag time of 9hrs, which was consistent with the demand of drug during early morning hour attack. Pellets found to be spherical in shape with smooth surface. Moreover compatibility studies illustrated no deleterious reaction between drug and polymers used in the study. Conclusions: The dual approach of developed chronomodulated formulation found to be satisfactory in the treatment of hypertension. PMID:25838996

  12. Greatly improved neuroprotective efficiency of citicoline by stereotactic delivery in treatment of ischemic injury.

    PubMed

    Xu, Fangjingwei; Hongbin Han; Yan, Junhao; Chen, He; He, Qingyuan; Xu, Weiguo; Zhu, Ning; Zhang, Hong; Zhou, Fugen; Lee, Kejia

    2011-01-01

    Limited penetration of neuroprotective drug citicoline into the central nervous system (CNS) by systemic administration led to poor efficiency. A novel method of stereotactic drug delivery was explored to make citicoline bypass the blood brain barrier (BBB) and take effect by direct contact with ischemic neurons. A permanent middle cerebral artery occlusion (pMCAO) model of rats was prepared. To get the optimal conditions for citicoline administration by the novel stereotactic delivery pathway, magnetic resonance imaging (MRI) tracer method was used, and a dose-dependent effect was given. Examinations of MRI, behavior evaluation, infarct volume assessment and histological staining were performed to evaluate the outcome. This MRI-guided stereotactic delivery of citicoline resulted in a notable reduction (>80%) in infarct size and a delayed ischemic injury in cortex 12 hours after onset of acute ischemia when compared with the systematic delivery. The improved neuroprotective efficiency was realized by a full distribution of citicoline in most of middle cerebral artery (MCA) territory and an adequate drug reaction in the involved areas of the brain. Brain lesions of treated rats by stereotactic delivery of citicoline were well predicted in the lateral ventricle and thalamus due to a limited drug deposition by MRI tracer method. Our study realized an improved neuroprotective efficiency of citicoline by stereotactic delivery, and an optimal therapeutic effect of this administration pathway can be achieved under MRI guidance.

  13. Enhanced Therapeutic Epidermal Growth Factor Receptor (EGFR) Antibody Delivery via Pulsed Ultrasound with Targeting Microbubbles for Glioma Treatment.

    PubMed

    Liao, Ai-Ho; Chou, Hsin-Yi; Hsieh, Yi-Lei; Hsu, Sheng-Chieh; Wei, Kuo-Chen; Liu, Hao-Li

    Pulsed-mode ultrasound (pUS) in combination with intravenously (IV) administered microbubbles (MBs) can enhance local drug delivery by temporarily enhancing capillary permeability. This study evaluates the use of epidermal growth factor receptor (EGFR)-targeting MBs after pUS treatment to enhance the effects of therapeutic-EGFR antibody delivery to glioma tumor cells in mice. Three animal groups were compared: (1) IV-injected non-targeting MBs, (2) IV-injected targeting MBs, and (3) IV-injected targeting MBs combined with pUS treatment. All animals were analyzed using high-frequency small-animal US imaging. The mean halftime of circulating targeting MBs was significantly increased from 3.13 min of targeting bubble alone to 5.86 min by targeting MBs combined with pUS treatment, compared to 2.34 min for non-targeting MBs. Compared to targeting bubble administration alone, pUS exposure prior to injection of targeting MBs was also significantly better at suppressing tumor growth when monitored for up to 35 days (p < 0.05). The final relative tumor volumes were 2664, 700, and 188 mm(3) for non-targeting MBs, targeting MBs, and targeting MBs combined with pUS treatment, respectively. pUS treatment prolonged the mean circulatory halftime of targeting MBs and enhanced the anti-tumor effect of EGFR antibodies in a human glioma model in mice. Targeting MBs combined with pUS treatment thus has potential for enhanced therapeutic antibody delivery for facilitating anti-glioma treatment.

  14. Simultaneous delivery of cytotoxic and biologic therapeutics using nanophotoactivatable liposomes enhances treatment efficacy in a mouse model of pancreatic cancer.

    PubMed

    Tangutoori, Shifalika; Spring, Bryan Q; Mai, Zhiming; Palanisami, Akilan; Mensah, Lawrence B; Hasan, Tayyaba

    2016-01-01

    A lack of intracellular delivery systems has limited the use of biologics such as monoclonal antibodies (mAb) that abrogate molecular signaling pathways activated to promote escape from cancer treatment. We hypothesized that intracellular co-delivery of the photocytotoxic chromophore benzoporphyrin derivative monoacid A (BPD) and the anti-VEGF mAb bevacizumab in a nanophotoactivatable liposome (nanoPAL) might enhance the efficacy of photodynamic therapy (PDT) combined with suppression of VEGF-mediated signaling pathways. As a proof-of-concept we found that nanoPAL-PDT induced enhanced extra- and intracellular bevacizumab delivery and enhanced acute cytotoxicity in vitro. In an in vivo subcutaneous mouse model of pancreatic ductal adenocarcinoma, nanoPAL-PDT achieved significantly enhanced tumor reduction. We attribute this to the optimal incorporation of insoluble BPD into the lipid bilayer, enhancing photocytotoxicity, and the simultaneous spatiotemporal delivery of bevacizumab, ensuring efficient neutralization of the rapid but transient burst of VEGF following PDT. From the Clinical Editor: Most patients with pancreatic ductal adenocarcinoma (PDAC) by the time present the disease it is very advanced, which unavoidably translates to poor survival. For these patients, use of traditional chemotherapy often becomes ineffective due to tumor resistance to drugs. Photodynamic therapy (PDT) can be an effective modality against chemo-resistant cancers. In this article, the authors investigated the co-delivery of a photocytotoxic agent and anti-VEGF mAb using liposomes. This combination was shown to results in enhanced tumor killing. This method should be applicable to other combination of treatments.

  15. Clinical application of in vivo treatment delivery verification based on PET/CT imaging of positron activity induced at high energy photon therapy

    NASA Astrophysics Data System (ADS)

    Janek Strååt, Sara; Andreassen, Björn; Jonsson, Cathrine; Noz, Marilyn E.; Maguire, Gerald Q., Jr.; Näfstadius, Peder; Näslund, Ingemar; Schoenahl, Frederic; Brahme, Anders

    2013-08-01

    The purpose of this study was to investigate in vivo verification of radiation treatment with high energy photon beams using PET/CT to image the induced positron activity. The measurements of the positron activation induced in a preoperative rectal cancer patient and a prostate cancer patient following 50 MV photon treatments are presented. A total dose of 5 and 8 Gy, respectively, were delivered to the tumors. Imaging was performed with a 64-slice PET/CT scanner for 30 min, starting 7 min after the end of the treatment. The CT volume from the PET/CT and the treatment planning CT were coregistered by matching anatomical reference points in the patient. The treatment delivery was imaged in vivo based on the distribution of the induced positron emitters produced by photonuclear reactions in tissue mapped on to the associated dose distribution of the treatment plan. The results showed that spatial distribution of induced activity in both patients agreed well with the delivered beam portals of the treatment plans in the entrance subcutaneous fat regions but less so in blood and oxygen rich soft tissues. For the preoperative rectal cancer patient however, a 2 ± (0.5) cm misalignment was observed in the cranial-caudal direction of the patient between the induced activity distribution and treatment plan, indicating a beam patient setup error. No misalignment of this kind was seen in the prostate cancer patient. However, due to a fast patient setup error in the PET/CT scanner a slight mis-position of the patient in the PET/CT was observed in all three planes, resulting in a deformed activity distribution compared to the treatment plan. The present study indicates that the induced positron emitters by high energy photon beams can be measured quite accurately using PET imaging of subcutaneous fat to allow portal verification of the delivered treatment beams. Measurement of the induced activity in the patient 7 min after receiving 5 Gy involved count rates which were about

  16. SU-E-T-268: Differences in Treatment Plan Quality and Delivery Between Two Commercial Treatment Planning Systems for Volumetric Arc-Based Radiation Therapy

    SciTech Connect

    Chen, S; Zhang, H; Zhang, B; D’Souza, W

    2015-06-15

    Purpose: To clinically evaluate the differences in volumetric modulated arc therapy (VMAT) treatment plan and delivery between two commercial treatment planning systems. Methods: Two commercial VMAT treatment planning systems with different VMAT optimization algorithms and delivery approaches were evaluated. This study included 16 clinical VMAT plans performed with the first system: 2 spine, 4 head and neck (HN), 2 brain, 4 pancreas, and 4 pelvis plans. These 16 plans were then re-optimized with the same number of arcs using the second treatment planning system. Planning goals were invariant between the two systems. Gantry speed, dose rate modulation, MLC modulation, plan quality, number of monitor units (MUs), VMAT quality assurance (QA) results, and treatment delivery time were compared between the 2 systems. VMAT QA results were performed using Mapcheck2 and analyzed with gamma analysis (3mm/3% and 2mm/2%). Results: Similar plan quality was achieved with each VMAT optimization algorithm, and the difference in delivery time was minimal. Algorithm 1 achieved planning goals by highly modulating the MLC (total distance traveled by leaves (TL) = 193 cm average over control points per plan), while maintaining a relatively constant dose rate (dose-rate change <100 MU/min). Algorithm 2 involved less MLC modulation (TL = 143 cm per plan), but greater dose-rate modulation (range = 0-600 MU/min). The average number of MUs was 20% less for algorithm 2 (ratio of MUs for algorithms 2 and 1 ranged from 0.5-1). VMAT QA results were similar for all disease sites except HN plans. For HN plans, the average gamma passing rates were 88.5% (2mm/2%) and 96.9% (3mm/3%) for algorithm 1 and 97.9% (2mm/2%) and 99.6% (3mm/3%) for algorithm 2. Conclusion: Both VMAT optimization algorithms achieved comparable plan quality; however, fewer MUs were needed and QA results were more robust for Algorithm 2, which more highly modulated dose rate.

  17. In Vitro and In Vivo Evaluation of a Hydrogel Reservoir as a Continuous Drug Delivery System for Inner Ear Treatment

    PubMed Central

    Hessler, Roland; Stöver, Timo; Esser, Karl-Heinz; Möller, Martin; Lenarz, Thomas; Jolly, Claude; Groll, Jürgen; Scheper, Verena

    2014-01-01

    Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear. PMID:25105670

  18. In vitro and in vivo evaluation of a hydrogel reservoir as a continuous drug delivery system for inner ear treatment.

    PubMed

    Hütten, Mareike; Dhanasingh, Anandhan; Hessler, Roland; Stöver, Timo; Esser, Karl-Heinz; Möller, Martin; Lenarz, Thomas; Jolly, Claude; Groll, Jürgen; Scheper, Verena

    2014-01-01

    Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear.

  19. Design and construction of a DNA origami drug delivery system based on MPT64 antibody aptamer for tuberculosis treatment

    PubMed Central

    Ranjbar, Reza; Hafezi-Moghadam, Mohammad Sadegh

    2016-01-01

    Introduction With all of the developments on infectious diseases, tuberculosis (TB) remains a cause of death among people. One of the most promising assembly techniques in nano-technology is “scaffolded DNA origami” to design and construct a nano-scale drug delivery system. Because of the global health problems of tuberculosis, the development of potent new anti-tuberculosis drug delivery system without cross-resistance with known anti-mycobacterial agents is urgently needed. The aim of this study was to design a nano-scale drug delivery system for TB treatment using the DNA origami method Methods In this study, we presented an experimental research on a DNA drug delivery system for treating Tuberculosis. TEM images were visualized with an FEI Tecnai T12 BioTWIN at 120 kV. The model was designed by caDNAno software and computational prediction of the 3D solution shape and its flexibility was calculated with a CanDo server. Results Synthesizing the product was imaged using transmission electron microscopy after negative-staining by uranyl formate. Conclusion We constructed a multilayer 3D DNA nanostructure system by designing square lattice geometry with the scaffolded-DNA-origami method. With changes in the lock and key sequences, we recommend that this system be used for other infectious diseases to target the pathogenic bacteria. PMID:27053991

  20. SU-E-T-127: Application of TG-119 for Evaluation of Proton Spot Scanning Based Planning and Treatment Delivery

    SciTech Connect

    Saini, J; Cao, N; Wong, T; Bowen, S; Bloch, C

    2015-06-15

    Purpose: The clinical test cases presented in AAPM TG-119 are used to evaluate the accuracy of treatment planning and delivery through spot scanning proton beams. Methods: An IBA spot scanning delivery system has been commissioned to be used with the RayStation treatment planning system. Various test cases provided in TG-119 were used for planning and delivery verification. The CT dataset and structures as provided by TG-119 were imported into a mock patient. The plans were optimized using the multi field optimization (MFO) to achieve the desired goals. The planner was given the flexibility to achieve the given dose-volume goals by creating appropriate objectives and constraints. Beams were delivered to a phantom and measurements were performed at multiple depths using the MatrixxPT detector array. The analyses were performed on beam by beam basis and quantified using the gamma index. A tolerance of 3%/3 mm in 2D was used for gamma index analysis along with dose threshold of 10%. Results: The clinical goals for targets and critical structures were met or improved for all cases except the C-Shape target with difficult constraints. The minimum gamma index using the 3%/3mm as a criterion is 93.3% for one of the planes measured for C-Shape target. Using 2%/2mm as a criterion, the minimum gamma index drops to 70%. Only Prostate target has all the planes above >90% pass using the 2%/2mm criterion. Conclusion: The overall accuracy of the treatment planning and delivery is deemed clinically acceptable. The test cases with highly modulated beams can have steep gradients in the dose profiles that can reduce the gamma index pass rate. Gamma analysis based on 3D data may be needed for routine use of 2%/2mm criterion. In addition, improvements in modelling of spot profiles in dose engine may be required for further improving the gamma index pass rate.

  1. Motion management during IMAT treatment of mobile lung tumors—A comparison of MLC tracking and gated delivery

    PubMed Central

    Falk, Marianne; Pommer, Tobias; Keall, Paul; Korreman, Stine; Persson, Gitte; Poulsen, Per; Munck af Rosenschöld, Per

    2014-01-01

    Purpose: To compare real-time dynamic multileaf collimator (MLC) tracking, respiratory amplitude and phase gating, and no compensation for intrafraction motion management during intensity modulated arc therapy (IMAT). Methods: Motion management with MLC tracking and gating was evaluated for four lung cancer patients. The IMAT plans were delivered to a dosimetric phantom mounted onto a 3D motion phantom performing patient-specific lung tumor motion. The MLC tracking system was guided by an optical system that used stereoscopic infrared (IR) cameras and five spherical reflecting markers attached to the dosimetric phantom. The gated delivery used a duty cycle of 35% and collected position data using an IR camera and two reflecting markers attached to a marker block. Results: The average gamma index failure rate (2% and 2 mm criteria) was <0.01% with amplitude gating for all patients, and <0.1% with phase gating and <3.7% with MLC tracking for three of the four patients. One of the patients had an average failure rate of 15.1% with phase gating and 18.3% with MLC tracking. With no motion compensation, the average gamma index failure rate ranged from 7.1% to 46.9% for the different patients. Evaluation of the dosimetric error contributions showed that the gated delivery mainly had errors in target localization, while MLC tracking also had contributions from MLC leaf fitting and leaf adjustment. The average treatment time was about three times longer with gating compared to delivery with MLC tracking (that did not prolong the treatment time) or no motion compensation. For two of the patients, the different motion compensation techniques allowed for approximately the same margin reduction but for two of the patients, gating enabled a larger reduction of the margins than MLC tracking. Conclusions: Both gating and MLC tracking reduced the effects of the target movements, although the gated delivery showed a better dosimetric accuracy and enabled a larger reduction of the

  2. Spatial Modeling of Drug Delivery Routes for Treatment of Disseminated Ovarian Cancer.

    PubMed

    Winner, Kimberly R Kanigel; Steinkamp, Mara P; Lee, Rebecca J; Swat, Maciej; Muller, Carolyn Y; Moses, Melanie E; Jiang, Yi; Wilson, Bridget S

    2016-03-15

    In ovarian cancer, metastasis is typically confined to the peritoneum. Surgical removal of the primary tumor and macroscopic secondary tumors is a common practice, but more effective strategies are needed to target microscopic spheroids persisting in the peritoneal fluid after debulking surgery. To treat this residual disease, therapeutic agents can be administered by either intravenous or intraperitoneal infusion. Here, we describe the use of a cellular Potts model to compare tumor penetration of two classes of drugs (cisplatin and pertuzumab) when delivered by these two alternative routes. The model considers the primary route when the drug is administered either intravenously or intraperitoneally, as well as the subsequent exchange into the other delivery volume as a secondary route. By accounting for these dynamics, the model revealed that intraperitoneal infusion is the markedly superior route for delivery of both small-molecule and antibody therapies into microscopic, avascular tumors typical of patients with ascites. Small tumors attached to peritoneal organs, with vascularity ranging from 2% to 10%, also show enhanced drug delivery via the intraperitoneal route, even though tumor vessels can act as sinks during the dissemination of small molecules. Furthermore, we assessed the ability of the antibody to enter the tumor by in silico and in vivo methods and suggest that optimization of antibody delivery is an important criterion underlying the efficacy of these and other biologics. The use of both delivery routes may provide the best total coverage of tumors, depending on their size and vascularity.

  3. The occasional case against broad dissemination and implementation: retaining a role for specialty care in the delivery of psychological treatments.

    PubMed

    Comer, Jonathan S; Barlow, David H

    2014-01-01

    Mental illness imposes a staggering public health burden in the United States. Although the past 40 years have witnessed tremendous advances in the identification of evidence-based practices (EBPs) in psychological treatments, gaps persist between treatment in experimental settings and services available in the community. In response, considerable attention and large financial commitments have focused in recent years on broad dissemination and implementation efforts designed to improve the quality of psychological services delivered by a variety of generalist practitioners across practice settings. Increasingly, under the influence of the Patient Protection and Affordable Care Act, it is envisioned that these generalists will practice in integrated primary care settings. These advances hold enormous potential, and yet, given the tremendous diversity of mental health problems and human suffering, broad dissemination and implementation efforts to generalists alone may not be sufficient to adequately address the burden of mental illness. Some EBPs may prove too complex for universal dissemination, and the time and expense required for quality dissemination and implementation preclude large-scale training in the treatment of low base rate disorders. As dissemination and implementation efforts work to ensure a quality generalist mental health care workforce, herein we highlight the vital need for available specialty care in the delivery of psychological treatments. Given traditional barriers that interfere with the accessibility of specialty care, we propose the transformative potential of a specialty behavioral telehealth care workforce, transacting with the generalist practitioner workforce to collectively ensure the highest quality and timely delivery of needed treatments to affected individuals.

  4. Treatment Planning and Delivery of External Beam Radiotherapy for Pediatric Sarcoma: The St. Jude Children's Research Hospital Experience

    SciTech Connect

    Hua Chiaho Gray, Jonathan M.; Merchant, Thomas E.; Kun, Larry E.; Krasin, Matthew J.

    2008-04-01

    Purpose: To describe and review the radiotherapy (RT) treatment planning and delivery techniques used for pediatric sarcoma patients at St. Jude Children's Research Hospital. The treatment characteristics serve as a baseline for future comparison with developing treatment modalities. Patients and Methods: Since January 2003, we have prospectively treated pediatric and young-adult patients with soft-tissue and bone sarcomas on an institutional Phase II protocol evaluating local control and RT-related treatment effects from external-beam RT (conformal or intensity-modulated RT; 83.4%), low-dose-rate brachytherapy (8.3%), or both (8.3%). Here we describe the treatment dosimetry and delivery parameters of the initial 72 patients (median, 11.6 years; range, 1.4-21.6 years). Results: Cumulative doses from all RT modalities ranged from 41.4 to 70.2 Gy (median, 50.4 Gy). Median D{sub 95} and V{sub 95} of the planning target volume of external-beam RT plans were, respectively, 93.4% of the prescribed dose and 94.6% of the target volume for the primary phase and 97.8% and 99.2% for the cone-down/boost phase. The dose-volume histogram statistics for 27 critical organs varied greatly. The spinal cord in 13 of 36 patients received dose >45 Gy (up to 52 Gy in 1 cc) because of tumor proximity. Conclusions: Planning and delivery of complex multifield external beam RT is feasible in pediatric patients with sarcomas. Improvements on conformity and dose gradients are still desired in many cases with sensitive adjacent critical structures. Long-term follow-up will determine the risk of local failure and the benefit of normal tissue avoidance for this population.

  5. SU-E-T-370: Evaluating Plan Quality and Dose Delivery Accuracy of Tomotherapy SBRT Treatments for Lung Cancer

    SciTech Connect

    Blake, S; Thwaites, D; Hansen, C; Deshpande, S; Phan, P; Franji, I; Holloway, L

    2015-06-15

    Purpose: This study evaluated the plan quality and dose delivery accuracy of stereotactic body radiotherapy (SBRT) helical Tomotherapy (HT) treatments for lung cancer. Results were compared with those previously reported by our group for flattening filter (FF) and flattening filter free (FFF) VMAT treatments. This work forms part of an ongoing multicentre and multisystem planning and dosimetry audit on FFF beams for lung SBRT. Methods: CT datasets and DICOM RT structures delineating the target volume and organs at risk for 6 lung cancer patients were selected. Treatment plans were generated using the HT treatment planning system. Tumour locations were classified as near rib, near bronchial tree or in free lung with prescribed doses of 48Gy/4fr, 50Gy/5fr and 54Gy/3fr respectively. Dose constraints were specified by a modified RTOG0915 protocol used for an Australian SBRT phase II trial. Plan quality was evaluated using mean PTV dose, PTV volume receiving 100% of the prescribed dose (V100%), target conformity (CI=VD100%/VPTV) and low dose spillage (LDS=VD50%/VPTV). Planned dose distributions were compared to those measured using an ArcCheck phantom. Delivery accuracy was evaluated using a gamma-index pass rate of 95% with 3% (of max dose) and 3mm criteria. Results: Treatment plans for all patients were clinically acceptable in terms of quality and accuracy of dose delivery. The following DVH metrics are reported as averages (SD) of all plans investigated: mean PTV dose was 115.3(2.4)% of prescription, V100% was 98.8(0.9)%, CI was 1.14(0.03) and LDS was 5.02(0.37). The plans had an average gamma-index passing rate of 99.3(1.3)%. Conclusion: The results reported in this study for HT agree within 1 SD to those previously published by our group for VMAT FF and FFF lung SBRT treatments. This suggests that HT delivers lung SBRT treatments of comparable quality and delivery accuracy as VMAT using both FF and FFF beams.

  6. Effective combination treatment of lung cancer cells by single vehicular delivery of siRNA and different anticancer drugs.

    PubMed

    Li, Jinming; Wang, Yuanyuan; Xue, Shanshan; Sun, Jinghua; Zhang, Wei; Hu, Ping; Ji, Liangnian; Mao, Zongwan

    In recent years, lung cancer has become one of the fastest growing cancers in the world. Thus, the development of efficient combination therapy to treat lung cancer has attracted significant attention in the cancer therapy field. In this article, we developed a single vehicle drug delivery system, based on quantum dot (QD) nanoparticles, to deliver small interfering RNA (siRNA; target Bcl-2) and different anticancer drugs (carboplatin, paclitaxel, and doxorubicin) simultaneously for treating A549 lung cancer cells efficiently by combination therapy. The QD nanoparticles were conjugated with l-arginine (l-Arg) and different kinds of hydroxypropyl-cyclodextrins (HP-α-CDs, HP-β-CDs, and HP-γ-CDs) on the surface to form the delivery nanocarriers (QD nanocarriers). They were able to not only bind and transport the siRNA through electrostatic interactions with l-Arg residues but also accommodate various disparate anticancer drugs using different HP-CD modifications. Compared with free drug treatments, the use of QD nanocarriers to deliver Bcl-2 siRNA and different anticancer drugs simultaneously exerted a threefold to fourfold increase in cytotoxicity in A549 cells, which greatly improved the treatment efficacy through combined action. Furthermore, the QD nanocarriers could be used as a probe for real-time imaging of the drug delivery and release because of their strong fluorescence properties. These findings indicate that multifunctional QD nanocarriers hold great promise as a powerful tool for combination therapy for lung cancer.

  7. α-Galactosidase delivery using 30Kc19-human serum albumin nanoparticles for effective treatment of Fabry disease.

    PubMed

    Lee, Hong Jai; Park, Hee Ho; Sohn, Youngsoo; Ryu, Jina; Park, Ju Hyun; Rhee, Won Jong; Park, Tai Hyun

    2016-12-01

    Fabry disease is a genetic lysosomal storage disease caused by deficiency of α-galactosidase, the enzyme-degrading neutral glycosphingolipid that is transported to lysosome. Glycosphingolipid accumulation by this disease causes multi-organ dysfunction and premature death of the patient. Currently, enzyme replacement therapy (ERT) using recombinant α-galactosidase is the only treatment available for Fabry disease. To maximize the efficacy of treatment, enhancement of cellular delivery and enzyme stability is a challenge in ERT using α-galactosidase. In this study, protein nanoparticles using human serum albumin (HSA) and 30Kc19 protein, originating from silkworm, were used to enhance the delivery and intracellular α-galactosidase stability. 30Kc19-HSA nanoparticles loaded with the α-galactosidase were formed by desolvation method. 30Kc19-HSA nanoparticles had a uniform spherical shape and were well dispersed in cell culture media. 30Kc19-HSA nanoparticles had negligible toxicity to human cells. The nanoparticles exhibited enhanced cellular uptake and intracellular stability of delivered α-galactosidase in human foreskin fibroblast. Additionally, they showed enhanced globotriaosylceramide degradation in Fabry patients' fibroblasts. It is expected that 30Kc19-HSA protein nanoparticles could be used as an effective tool for efficient delivery and enhanced stability of drugs.

  8. Effective combination treatment of lung cancer cells by single vehicular delivery of siRNA and different anticancer drugs

    PubMed Central

    Li, Jinming; Wang, Yuanyuan; Xue, Shanshan; Sun, Jinghua; Zhang, Wei; Hu, Ping; Ji, Liangnian; Mao, Zongwan

    2016-01-01

    In recent years, lung cancer has become one of the fastest growing cancers in the world. Thus, the development of efficient combination therapy to treat lung cancer has attracted significant attention in the cancer therapy field. In this article, we developed a single vehicle drug delivery system, based on quantum dot (QD) nanoparticles, to deliver small interfering RNA (siRNA; target Bcl-2) and different anticancer drugs (carboplatin, paclitaxel, and doxorubicin) simultaneously for treating A549 lung cancer cells efficiently by combination therapy. The QD nanoparticles were conjugated with l-arginine (l-Arg) and different kinds of hydroxypropyl-cyclodextrins (HP-α-CDs, HP-β-CDs, and HP-γ-CDs) on the surface to form the delivery nanocarriers (QD nanocarriers). They were able to not only bind and transport the siRNA through electrostatic interactions with l-Arg residues but also accommodate various disparate anticancer drugs using different HP-CD modifications. Compared with free drug treatments, the use of QD nanocarriers to deliver Bcl-2 siRNA and different anticancer drugs simultaneously exerted a threefold to fourfold increase in cytotoxicity in A549 cells, which greatly improved the treatment efficacy through combined action. Furthermore, the QD nanocarriers could be used as a probe for real-time imaging of the drug delivery and release because of their strong fluorescence properties. These findings indicate that multifunctional QD nanocarriers hold great promise as a powerful tool for combination therapy for lung cancer. PMID:27695321

  9. Drug delivery system design and development for boron neutron capture therapy on cancer treatment.

    PubMed

    Sherlock Huang, Lin-Chiang; Hsieh, Wen-Yuan; Chen, Jiun-Yu; Huang, Su-Chin; Chen, Jen-Kun; Hsu, Ming-Hua

    2014-06-01

    We have already synthesized a boron-containing polymeric micellar drug delivery system for boron neutron capture therapy (BNCT). The synthesized diblock copolymer, boron-terminated copolymers (Bpin-PLA-PEOz), consisted of biodegradable poly(D,l-lactide) (PLA) block and water-soluble polyelectrolyte poly(2-ethyl-2-oxazoline) (PEOz) block, and a cap of pinacol boronate ester (Bpin). In this study, we have demonstrated that synthesized Bpin-PLA-PEOz micelle has great potential to be boron drug delivery system with preliminary evaluation of biocompatibility and boron content.

  10. Pregnancy and the Patient with Inflammatory Bowel Disease: Fertility, Treatment, Delivery, and Complications.

    PubMed

    McConnell, Ryan A; Mahadevan, Uma

    2016-06-01

    For many women with inflammatory bowel disease (IBD), the illness coincides with their childbearing years. IBD increases the risk of pregnancy complications and adverse pregnancy outcomes. The multidisciplinary care team should emphasize the importance of medication adherence to achieve preconception disease control and maintain corticosteroid-free remission throughout pregnancy. Medication adjustments to reduce fetal exposure may be considered on an individualized basis in quiescent disease; however, any benefits of such adjustments remain theoretic and there is risk of worsening disease activity. Mode of delivery is determined by obstetric indications, except for women with active perianal disease who should consider cesarean delivery.

  11. Evaluating Outcomes in Patients with Overactive Bladder within an Integrated Healthcare Delivery System Using a Treatment Patterns Analyzer

    PubMed Central

    Ng, Daniel B.; McCart, Melissa; Klein, Christopher; Campbell, Chelsey; Schoenhaus, Robert; Berner, Todd

    2016-01-01

    Background Overactive bladder (OAB) is a relatively common disease that has been linked to a variety of comorbidities, reductions in quality of life, and increased healthcare costs. Antimuscarinic agents are the standard of care among pharmacologic treatments for OAB, but these drugs are linked to high levels of anticholinergic burden, especially in the elderly. Objective To demonstrate how efficient data analysis can be used to identify gaps in care as a result of improvement strategies for OAB within an integrated healthcare delivery system setting. Methods We developed an OAB treatment patterns analyzer, a clinical outcomes software analysis program, to identify gaps in care, high anticholinergic burden, and potential quality improvement initiatives. Deidentified pharmacy and medical claims data from an integrated delivery network were imported into the OAB treatment patterns analyzer. Patients with a diagnosis of OAB who were continuously enrolled in the network between January 1, 2009, and December 31, 2013, were identified and were imported into the analyzer. The analyzer used National Drug Code; International Classification of Diseases, Ninth Edition, Clinical Modification; Current Procedural Terminology; and UB-92 codes to measure treatment patterns, comorbid conditions, anticholinergic burden, concomitant use with anticholinesterases, costs, and healthcare resource utilization. Results Of 157,710 members in the integrated delivery network population, 7309 patients met the study eligibility criteria. Of patients taking medications for OAB, 85% were nonadherent and 73% discontinued treatment within 1 year. Among 1147 patients in the integrated healthcare delivery system who were using medications for OAB, 39 (3.4%) patients were concomitantly taking anticholinesterase drugs and an antimuscarinic agent. The per-month plan-paid cost per member was $318.67. Of all the patients with OAB within the population, the rates of all-cause office visits, emergency

  12. Functional Analysis and Treatment of Rumination Using Fixed-Time Delivery of a Flavor Spray

    ERIC Educational Resources Information Center

    Wilder, David A.; Register, Martisa; Register, Stanley; Bajagic, Vedrana; Neidert, Pamela L.

    2009-01-01

    A functional analysis suggested that rumination exhibited by an adult with autism was maintained by automatic reinforcement. Next, a preference assessment with three flavor sprays (i.e., flavored sprays used by dieters) showed that apple pie spray was most preferred. Finally, the effects of fixed-time delivery of the apple pie spray on levels of…

  13. 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.

  14. Stem cell-mediated delivery of therapies in the treatment of glioma.

    PubMed

    Frosina, G

    2011-06-01

    High grade gliomas can be seldom controlled, due to the infiltrative nature of these tumors and the presence of cell populations resistant to radio- and chemotherapy. Current research aims to develop novel therapeutic approaches to track and eliminate the disseminated glioma-driving cells. Selected delivery of therapeutic agents taking advantage of the tropism of normal stem cells for glioma cells might be one.

  15. Efficient siRNA delivery system using carboxilated single-wall carbon nanotubes in cancer treatment.

    PubMed

    Neagoe, Ioana Berindan; Braicu, Cornelia; Matea, Cristian; Bele, Constantin; Florin, Graur; Gabriel, Katona; Veronica, Chedea; Irimie, Alexandru

    2012-08-01

    Several functionalized carbon nanotubes have been designed and tested for the purpose of nucleic acid delivery. In this study, the capacity of SWNTC-COOH for siRNA deliverey were investigated delivery in parallel with an efficient commercial system. Hep2G cells were reverse-transfected with 50 nM siRNA (p53 siRNA, TNF-alphasiRNA, VEGFsiRNA) using the siPORT NeoFX (Ambion) transfection agent in paralel with SWNTC-COOH, functionalised with siRNA. The highest level of gene inhibition was observed in the cases treated with p53 siRNA gene; in the case of transfection with siPort, the NeoFX value was 33.8%, while in the case of SWNTC-COOH as delivery system for p53 siRNA was 37.5%. The gene silencing capacity for VEGF was 53.7%, respectively for TNF-alpha 56.7% for siPORT NeoFX delivery systems versus 47.7% (VEGF) and 46.5% (TNF-alpha) for SWNTC-COOH delivery system. SWNTC-COOH we have been showed to have to be an efficient carrier system. The results from the inhibition of gene expresion for both transfection systems were confirmed at protein level. Overall, the lowest mRNA expression was confirmed at protein level, especially in the case of p53 siRNA and TNF-alpha siRNA transfection. Less efficient reduction protein expressions were observed in the case of VEGF siRNA, for both transfection systems at 24 h; only at 48 h, there was a statistically significant reduction of VEGF protein expression. SWCNT-COOH determined an efficient delivery of siRNA. SWNTC-COOH, combined with suitable tumor markers like p53 siRNA, TNFalpha siRNA or VEGF siRNA can be used for the efficient delivery of siRNA.

  16. Targeted drug delivery nanosystems based on copolymer poly(lactide)-tocopheryl polyethylene glycol succinate for cancer treatment

    NASA Astrophysics Data System (ADS)

    Thu Ha, Phuong; Nguyen, Hoai Nam; Doan Do, Hai; Thong Phan, Quoc; Nguyet Tran Thi, Minh; Phuc Nguyen, Xuan; Nhung Hoang Thi, My; Huong Le, Mai; Nguyen, Linh Toan; Quang Bui, Thuc; Hieu Phan, Van

    2016-03-01

    Along with the development of nanotechnology, drug delivery nanosystems (DDNSs) have attracted a great deal of concern among scientists over the world, especially in cancer treatment. DDNSs not only improve water solubility of anticancer drugs but also increase therapeutic efficacy and minimize the side effects of treatment methods through targeting mechanisms including passive and active targeting. Passive targeting is based on the nano-size of drug delivery systems while active targeting is based on the specific bindings between targeting ligands attached on the drug delivery systems and the unique receptors on the cancer cell surface. In this article we present some of our results in the synthesis and testing of DDNSs prepared from copolymer poly(lactide)-tocopheryl polyethylene glycol succinate (PLA-TPGS), which carry anticancer drugs including curcumin, paclitaxel and doxorubicin. In order to increase the targeting effect to cancer cells, active targeting ligand folate was attached to the DDNSs. The results showed copolymer PLA-TPGS to be an excellent carrier for loading hydrophobic drugs (curcumin and paclitaxel). The fabricated DDNSs had a very small size (50-100 nm) and enhanced the cellular uptake and cytotoxicity of drugs. Most notably, folate-decorated paclitaxel-loaded copolymer PLA-TPGS nanoparticles (Fol/PTX/PLA-TPGS NPs) were tested on tumor-bearing nude mice. During the treatment time, Fol/PTX/PLA-TPGS NPs always exhibited the best tumor growth inhibition compared to free paclitaxel and paclitaxel-loaded copolymer PLA-TPGS nanoparticles. All results evidenced the promising potential of copolymer PLA-TPGS in fabricating targeted DDNSs for cancer treatment.

  17. SU-F-BRE-10: Methods to Simulate and Measure the Attenuation for Modeling a Couch Top with Rails for FFF Treatment Delivery On the Varian Edge Linac

    SciTech Connect

    Gulam, M; Gardner, S; Zhao, B; Snyder, K; Song, K; Li, H; Gordon, J; Wen, N; Chetty, I; Kearns, W

    2014-06-15

    Purpose: To measure attenuation for modelling of the KVue Couchtop for 6X and 10X FFF SRS/SBRT treatment Methods: Treatment planning simulation studies were done using 6X FFF beams to estimate the dosimetric impact of KVue couchtops (including the Q-Fix IGRT [carbon fiber] and Calypso [nonconductive Kevlar material]) with a structure model obtained from a research workstation (Eclipse, advanced planning interface (API) v13). Prior to installation on the Varian Edge linac, the couchtop along with (Kevlar) rails were CT scanned with the rails at various positions. An additional scan with the couchtop 15cm above the CT table top was obtained with 20cm solid water to facilitate precised/indexed data acquisition. Measurements for attenuation were obtained for field sizes of 2, 4 and 10 cm{sup 2} at 42 gantry angles including 6 pairs of opposing fields and other angles for oblique delivery where the beams traversed the couchtop and or rails. The delivery was fully automated with xml scripts running in developer mode. The results were then used to determine an accurate structure model for AAA (Eclipse v11) planning of IMRT and RapidArc delivery. Results: The planning simulation relative dose attenuation for oblique entry was not significantly different than the Exact IGRT or BrainLab iBeam couch except that the rails added 6% additional attenuation. The relative attenuation measurements for PA, PA (rails: inner position), oblique, oblique (rails: outer position), oblique (rails: inner position) were: −2.0%, −2.5%, −15.6%, −2.5%, −5.0% for 6X FFF and −1.4%, −1.5%, −12.2%, − 2.5%, −5.0% for 10X FFF with slight decrease in attenuation versus field size. A Couch structure model (with HU values) was developed. Calculation compared to measurement showed good agreement except for oblique (rails: outer position) where differences approached a magnitude of 6%. Conclusion: A model of the couch structures has been developed accounting for attenuation for FFF

  18. Shortening Delivery Times of Intensity Modulated Proton Therapy by Reducing Proton Energy Layers During Treatment Plan Optimization

    SciTech Connect

    Water, Steven van de; Kooy, Hanne M.; Heijmen, Ben J.M.; Hoogeman, Mischa S.

    2015-06-01

    Purpose: To shorten delivery times of intensity modulated proton therapy by reducing the number of energy layers in the treatment plan. Methods and Materials: We have developed an energy layer reduction method, which was implemented into our in-house-developed multicriteria treatment planning system “Erasmus-iCycle.” The method consisted of 2 components: (1) minimizing the logarithm of the total spot weight per energy layer; and (2) iteratively excluding low-weighted energy layers. The method was benchmarked by comparing a robust “time-efficient plan” (with energy layer reduction) with a robust “standard clinical plan” (without energy layer reduction) for 5 oropharyngeal cases and 5 prostate cases. Both plans of each patient had equal robust plan quality, because the worst-case dose parameters of the standard clinical plan were used as dose constraints for the time-efficient plan. Worst-case robust optimization was performed, accounting for setup errors of 3 mm and range errors of 3% + 1 mm. We evaluated the number of energy layers and the expected delivery time per fraction, assuming 30 seconds per beam direction, 10 ms per spot, and 400 Giga-protons per minute. The energy switching time was varied from 0.1 to 5 seconds. Results: The number of energy layers was on average reduced by 45% (range, 30%-56%) for the oropharyngeal cases and by 28% (range, 25%-32%) for the prostate cases. When assuming 1, 2, or 5 seconds energy switching time, the average delivery time was shortened from 3.9 to 3.0 minutes (25%), 6.0 to 4.2 minutes (32%), or 12.3 to 7.7 minutes (38%) for the oropharyngeal cases, and from 3.4 to 2.9 minutes (16%), 5.2 to 4.2 minutes (20%), or 10.6 to 8.0 minutes (24%) for the prostate cases. Conclusions: Delivery times of intensity modulated proton therapy can be reduced substantially without compromising robust plan quality. Shorter delivery times are likely to reduce treatment uncertainties and costs.

  19. Investigating the Temporal Effects of Respiratory-Gated and Intensity-Modulated Radiotherapy Treatment Delivery on In Vitro Survival: An Experimental and Theoretical Study

    SciTech Connect

    Keall, Paul J. Chang, Michael; Benedict, Stanley; Thames, Howard; Vedam, S. Sastry; Lin, Peck-Sun

    2008-08-01

    Purpose: To experimentally and theoretically investigate the temporal effects of respiratory-gated and intensity-modulated radiotherapy (IMRT) treatment delivery on in vitro survival. Methods and Materials: Experiments were designed to isolate the effects of periodic irradiation (gating), partial tumor irradiation (IMRT), and extended treatment time (gating and IMRT). V79 Chinese hamster lung fibroblast cells were irradiated to 2 Gy with four delivery methods and a clonogenic assay performed. Theoretical incomplete repair model calculations were performed using the incomplete repair model. Results: Treatment times ranged from 1.67 min (conformal radiotherapy, CRT) to 15 min (gated IMRT). Survival fraction calculations ranged from 68.2% for CRT to 68.7% for gated IMRT. For the same treatment time (5 min), gated delivery alone and IMRT delivery alone both had a calculated survival fraction of 68.3%. The experimental values ranged from 65.7% {+-} 1.0% to 67.3% {+-} 1.3%, indicating no significant difference between the experimental observations and theoretical calculations. Conclusion: The theoretical results predicted that of the three temporal effects of radiation delivery caused by gating and IMRT, extended treatment time was the dominant effect. Care should be taken clinically to ensure that the use of gated IMRT does not significantly increase treatment times, by evaluating appropriate respiratory gating duty cycles and IMRT delivery complexity.

  20. Ocular delivery of macromolecules

    PubMed Central

    Kim, Yoo-Chun; Chiang, Bryce; Wu, Xianggen; Prausnitz, Mark R.

    2014-01-01

    Biopharmaceuticals are making increasing impact on medicine, including treatment of indications in the eye. Macromolecular drugs are typically given by physician-administered invasive delivery methods, because non--invasive ocular delivery methods, such as eye drops, and systemic delivery, have low bioavailability and/or poor ocular targeting. There is a need to improve delivery of biopharmaceuticals to enable less-invasive delivery routes, less-frequent dosing through controlled-release drug delivery and improved drug targeting within the eye to increase efficacy and reduce side effects. This review discusses the barriers to drug delivery via various ophthalmic routes of administration in the context of macromolecule delivery and discusses efforts to develop controlled-release systems for delivery of biopharmaceuticals to the eye. The growing number of macromolecular therapies in the eye needs improved drug delivery methods that increase drug efficacy, safety and patient compliance. PMID:24998941

  1. Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging

    PubMed Central

    2010-01-01

    Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as

  2. Long-term epidural block treatment in patients with early threatening preterm delivery and vaginal fetal engagement.

    PubMed

    Arabin, Birgit; Kuizenga, Karel; van Zoeren, Diny; Zveren, Diny V; Eyck, Jim V

    2008-01-01

    We report on an exceptional therapy with epidural anesthesia and tunnelling of the peridural catheter over a time period of 2-14 days in patients with threatening early preterm labor, intact membranes and vaginal engagement of the infants (4 singleton, 8 twin and 2 triplet pregnancies). A combination of bupivacaine (0.125%) and fentanyl (2 microg/mL) was used up to a maximum of 20 mL/h during the treatment period. Long-term follow-up of the infants was normal in 19/20 infants. The advantages, such as prolongation of pregnancy without maternal pain and disadvantages such as the risk of fetal and maternal infection and of sudden delivery are discussed. The online version of the Journal (see http://dx.doi.org/10.1515/jpm.2008.081_supp-1) allows video illustrations of a triplet pregnancy, in which the first triplet was born after one week of epidural anesthesia and the pregnancy continued under epidural anesthesia for the remaining two triplets staying with intact membranes in the vagina (delayed interval delivery) for six more days. The results of this pilot series suggest that prolongation of these pregnancies under epidural anesthesia might be an option in exceptional cases when viability is questionable or when corticosteroid therapy is desired before final delivery. Further evaluation of this strategy is needed but only in tertiary centers with 24-h presence of qualified obstetric and neonatal care and intensive surveillance.

  3. Lipopolyplex for Therapeutic Gene Delivery and Its Application for the Treatment of Parkinson’s Disease

    PubMed Central

    Chen, Wei; Li, Hui; Liu, Zhenguo; Yuan, Weien

    2016-01-01

    Lipopolyplex is a core-shell structure composed of nucleic acid, polycation and lipid. As a non-viral gene delivery vector, lipopolyplex combining the advantages of polyplex and lipoplex has shown superior colloidal stability, reduced cytotoxicity, extremely high gene transfection efficiency. Following intravenous administration, there are many strategies based on lipopolyplex to overcome the complex biological barriers in systemic gene delivery including condensation of nucleic acids into nanoparticles, long circulation, cell targeting, endosomal escape, release to cytoplasm and entry into cell nucleus. Parkinson’s disease (PD) is the second most common neurodegenerative disorder and severely influences the patients’ life quality. Current gene therapy clinical trials for PD employing viral vectors didn’t achieve satisfactory efficacy. However, lipopolyplex may become a promising alternative approach owing to its stability in blood, ability to cross the blood-brain barrier (BBB) and specific targeting to diseased brain cells. PMID:27092073

  4. Nanoscaled boron-containing delivery systems and therapeutic agents for cancer treatment.

    PubMed

    Wang, Jing; Wu, Wei; Jiang, Xiqun

    2015-01-01

    Significant efforts have recently been made to develop nanoscaled boron-containing delivery systems for improving drug delivery in cancer therapy. On one hand, borate ester chemistry has shown importance in ligand-mediated tumor targeting owing to the recognition ability of boronic acid to polyol residues in cell membranes. In particular, the phenylboronic acid-functionalized nanocarriers for specific targeting to sialic acid groups which are overexpressed on tumor cells have made great achievements. On the other hand, nanoscaled boron neutron capture therapy agents show growing potential in efficiently transporting boron to tumor. The current review outlines the recent developments in the application of borate ester chemistry in tumor targeting by nanoparticles, then summarizes recent work on the development of boron-based nanomaterials as boron neutron capture therapy agents.

  5. Lipopolyplex for Therapeutic Gene Delivery and Its Application for the Treatment of Parkinson's Disease.

    PubMed

    Chen, Wei; Li, Hui; Liu, Zhenguo; Yuan, Weien

    2016-01-01

    Lipopolyplex is a core-shell structure composed of nucleic acid, polycation and lipid. As a non-viral gene delivery vector, lipopolyplex combining the advantages of polyplex and lipoplex has shown superior colloidal stability, reduced cytotoxicity, extremely high gene transfection efficiency. Following intravenous administration, there are many strategies based on lipopolyplex to overcome the complex biological barriers in systemic gene delivery including condensation of nucleic acids into nanoparticles, long circulation, cell targeting, endosomal escape, release to cytoplasm and entry into cell nucleus. Parkinson's disease (PD) is the second most common neurodegenerative disorder and severely influences the patients' life quality. Current gene therapy clinical trials for PD employing viral vectors didn't achieve satisfactory efficacy. However, lipopolyplex may become a promising alternative approach owing to its stability in blood, ability to cross the blood-brain barrier (BBB) and specific targeting to diseased brain cells.

  6. Messenger RNA delivery of a cartilage-anabolic transcription factor as a disease-modifying strategy for osteoarthritis treatment

    PubMed Central

    Aini, Hailati; Itaka, Keiji; Fujisawa, Ayano; Uchida, Hirokuni; Uchida, Satoshi; Fukushima, Shigeto; Kataoka, Kazunori; Saito, Taku; Chung, Ung-il; Ohba, Shinsuke

    2016-01-01

    Osteoarthritis (OA) is a chronic degenerative joint disease and a major health problem in the elderly population. No disease-modifying osteoarthritis drug (DMOAD) has been made available for clinical use. Here we present a disease-modifying strategy for OA, focusing on messenger RNA (mRNA) delivery of a therapeutic transcription factor using polyethylene glycol (PEG)-polyamino acid block copolymer-based polyplex nanomicelles. When polyplex nanomicelles carrying the cartilage-anabolic, runt-related transcription factor (RUNX) 1 mRNA were injected into mouse OA knee joints, OA progression was significantly suppressed compared with the non-treatment control. Expressions of cartilage-anabolic markers and proliferation were augmented in articular chondrocytes of the RUNX1-injected knees. Thus, this study provides a proof of concept of the treatment of degenerative diseases such as OA by the in situ mRNA delivery of therapeutic transcription factors; the presented approach will directly connect basic findings on disease-protective or tissue-regenerating factors to disease treatment. PMID:26728350

  7. Inhalable Antimicrobials for Treatment of Bacterial Biofilm-Associated Sinusitis in Cystic Fibrosis Patients: Challenges and Drug Delivery Approaches

    PubMed Central

    Kłodzińska, Sylvia Natalie; Priemel, Petra Alexandra; Rades, Thomas; Mørck Nielsen, Hanne

    2016-01-01

    Bacterial biofilm-associated chronic sinusitis in cystic fibrosis (CF) patients caused by Pseudomonas aeruginosa infections and the lack of available treatments for such infections constitute a critical aspect of CF disease management. Currently, inhalation therapies to combat P. aeruginosa infections in CF patients are focused mainly on the delivery of antimicrobials to the lower respiratory tract, disregarding the sinuses. However, the sinuses constitute a reservoir for P. aeruginosa growth, leading to re-infection of the lungs, even after clearing an initial lung infection. Eradication of P. aeruginosa from the respiratory tract after a first infection has been shown to delay chronic pulmonary infection with the bacteria for up to two years. The challenges with providing a suitable treatment for bacterial sinusitis include: (i) identifying a suitable antimicrobial compound; (ii) selecting a suitable device to deliver the drug to the sinuses and nasal cavities; and (iii) applying a formulation design, which will mediate delivery of a high dose of the antimicrobial directly to the site of infection. This review highlights currently available inhalable antimicrobial formulations for treatment and management of biofilm infections caused by P. aeruginosa and discusses critical issues related to novel antimicrobial drug formulation design approaches. PMID:27735846

  8. Patient Satisfaction with Methadone Maintenance Treatment in Vietnam: A Comparison of Different Integrative-Service Delivery Models

    PubMed Central

    Tran, Bach Xuan; Nguyen, Long Hoang; Phan, Huong Thu Thi; Latkin, Carl A.

    2015-01-01

    Background Patient satisfaction is an important component of quality in healthcare delivery. To inform the expansion of Methadone Maintenance Treatment (MMT) services in Vietnam, we examined the satisfaction of patients with regards to different services delivery models and identified its associated factors. Methods We interviewed 1,016 MMT patients at 5 clinics in Hanoi and Nam Dinh province. The modified SATIS instrument, a 10-item scale, was used to measure three dimensions: “Services quality and convenience”, “Health workers’ capacity and responsiveness” and “Inter-professional care”. Results The average score was high across three SATIS dimensions. However, only one third of patients completely satisfied with general health services and treatment outcomes. Older age, higher education, having any problem in self-care and anxiety/depression were negatively associated with patient’s satisfaction. Meanwhile, patients receiving MMT at clinics, where more comprehensive HIV and general health care services were available, were more likely to report a complete satisfaction. Conclusion Patients were highly satisfied with MMT services in Vietnam. However, treatment for drug users should go beyond methadone maintenance to address complicated health demands of drug users. Integrating MMT with comprehensive HIV and general health services together with improving the capacity of health workers and efficiency of services organisation to provide interconnected health care for drug users are critical for improving the outcomes of the MMT program. PMID:26556036

  9. Messenger RNA delivery of a cartilage-anabolic transcription factor as a disease-modifying strategy for osteoarthritis treatment.

    PubMed

    Aini, Hailati; Itaka, Keiji; Fujisawa, Ayano; Uchida, Hirokuni; Uchida, Satoshi; Fukushima, Shigeto; Kataoka, Kazunori; Saito, Taku; Chung, Ung-il; Ohba, Shinsuke

    2016-01-05

    Osteoarthritis (OA) is a chronic degenerative joint disease and a major health problem in the elderly population. No disease-modifying osteoarthritis drug (DMOAD) has been made available for clinical use. Here we present a disease-modifying strategy for OA, focusing on messenger RNA (mRNA) delivery of a therapeutic transcription factor using polyethylene glycol (PEG)-polyamino acid block copolymer-based polyplex nanomicelles. When polyplex nanomicelles carrying the cartilage-anabolic, runt-related transcription factor (RUNX) 1 mRNA were injected into mouse OA knee joints, OA progression was significantly suppressed compared with the non-treatment control. Expressions of cartilage-anabolic markers and proliferation were augmented in articular chondrocytes of the RUNX1-injected knees. Thus, this study provides a proof of concept of the treatment of degenerative diseases such as OA by the in situ mRNA delivery of therapeutic transcription factors; the presented approach will directly connect basic findings on disease-protective or tissue-regenerating factors to disease treatment.

  10. Investigation of Pitch and Jaw Width to Decrease Delivery Time of Helical Tomotherapy Treatments for Head and Neck Cancer

    SciTech Connect

    Moldovan, Monica; Fontenot, Jonas D.; Gibbons, John P.; Lee, Tae Kyu; Rosen, Isaac I.; Fields, Robert S.; Hogstrom, Kenneth R.

    2011-01-01

    Helical tomotherapy plans using a combination of pitch and jaw width settings were developed for 3 patients previously treated for head and neck cancer. Three jaw widths (5, 2.5, and 1 cm) and 4 pitches (0.86, 0.43, 0.287, and 0.215) were used with a (maximum) modulation factor setting of 4. Twelve plans were generated for each patient using an identical optimization procedure (e.g., number of iterations, objective weights, and penalties, etc.), based on recommendations from TomoTherapy (Madison, WI). The plans were compared using isodose plots, dose volume histograms, dose homogeneity indexes, conformity indexes, radiobiological models, and treatment times. Smaller pitches and jaw widths showed better target dose homogeneity and sparing of normal tissue, as expected. However, the treatment time increased inversely proportional to the jaw width, resulting in delivery times of 24 {+-} 1.9 min for the 1-cm jaw width. Although treatment plans produced with the 2.5-cm jaw were dosimetrically superior to plans produced with the 5-cm jaw, subsequent calculations of tumor control probabilities and normal tissue complication probabilities suggest that these differences may not be radiobiologically meaningful. Because treatment plans produced with the 5-cm jaw can be delivered in approximately half the time of plans produced with the 2.5-cm jaw (5.1 {+-} 0.6 min vs. 9.5 {+-} 1.1 min), use of the 5-cm jaw in routine treatment planning may be a viable approach to decreasing treatment delivery times from helical tomotherapy units.

  11. Theoretical Approaches to Lentiviral Mediated Neurotrophin Delivery in Potential Treatments of Parkinson’s Disease

    PubMed Central

    Qudrat, Anam; Unni, Netra

    2016-01-01

    Parkinson’s disease is a late-onset neurodegenerative disease, characterized by both motor and non-motor symptoms. Motor symptoms include postural instability, rigidity, and tremor, while non-motor symptoms include anxiety, dementia, and depression. In this integrative review, we discuss PD disease pathophysiology in detail and introduce how neurotrophic growth factor delivery via a retroviral-based system can be used as efficacious tools for targeted gene therapy. PMID:27354847

  12. 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

  13. Prostate intrafraction motion evaluation using kV fluoroscopy during treatment delivery: A feasibility and accuracy study

    SciTech Connect

    Adamson, Justus; Wu Qiuwen

    2008-05-15

    Margin reduction for prostate radiotherapy is limited by uncertainty in prostate localization during treatment. We investigated the feasibility and accuracy of measuring prostate intrafraction motion using kV fluoroscopy performed simultaneously with radiotherapy. Three gold coils used for target localization were implanted into the patient's prostate gland before undergoing hypofractionated online image-guided step-and-shoot intensity modulated radiation therapy (IMRT) on an Elekta Synergy linear accelerator. At each fraction, the patient was aligned using a cone-beam computed tomography (CBCT), after which the IMRT treatment delivery and fluoroscopy were performed simultaneously. In addition, a post-treatment CBCT was acquired with the patient still on the table. To measure the intrafraction motion, we developed an algorithm to register the fluoroscopy images to a reference image derived from the post-treatment CBCT, and we estimated coil motion in three-dimensional (3D) space by combining information from registrations at different gantry angles. We also detected the MV beam turning on and off using MV scatter incident in the same fluoroscopy images, and used this information to synchronize our intrafraction evaluation with the treatment delivery. In addition, we assessed the following: the method to synchronize with treatment delivery, the dose from kV imaging, the accuracy of the localization, and the error propagated into the 3D localization from motion between fluoroscopy acquisitions. With 0.16 mAs/frame and a bowtie filter implemented, the coils could be localized with the gantry at both 0 deg. and 270 deg. with the MV beam off, and at 270 deg. with the MV beam on when multiple fluoroscopy frames were averaged. The localization in two-dimensions for phantom and patient measurements was performed with submillimeter accuracy. After backprojection into 3D the patient localization error was (-0.04{+-}0.30) mm, (0.09{+-}0.36) mm, and (0.03{+-}0.68) mm in the

  14. Prostate intrafraction motion evaluation using kV fluoroscopy during treatment delivery: A feasibility and accuracy study

    PubMed Central

    Adamson, Justus; Wu, Qiuwen

    2008-01-01

    Margin reduction for prostate radiotherapy is limited by uncertainty in prostate localization during treatment. We investigated the feasibility and accuracy of measuring prostate intrafraction motion using kV fluoroscopy performed simultaneously with radiotherapy. Three gold coils used for target localization were implanted into the patient’s prostate gland before undergoing hypofractionated online image-guided step-and-shoot intensity modulated radiation therapy (IMRT) on an Elekta Synergy linear accelerator. At each fraction, the patient was aligned using a cone-beam computed tomography (CBCT), after which the IMRT treatment delivery and fluoroscopy were performed simultaneously. In addition, a post-treatment CBCT was acquired with the patient still on the table. To measure the intrafraction motion, we developed an algorithm to register the fluoroscopy images to a reference image derived from the post-treatment CBCT, and we estimated coil motion in three-dimensional (3D) space by combining information from registrations at different gantry angles. We also detected the MV beam turning on and off using MV scatter incident in the same fluoroscopy images, and used this information to synchronize our intrafraction evaluation with the treatment delivery. In addition, we assessed the following: the method to synchronize with treatment delivery, the dose from kV imaging, the accuracy of the localization, and the error propagated into the 3D localization from motion between fluoroscopy acquisitions. With 0.16 mAs∕frame and a bowtie filter implemented, the coils could be localized with the gantry at both 0° and 270° with the MV beam off, and at 270° with the MV beam on when multiple fluoroscopy frames were averaged. The localization in two-dimensions for phantom and patient measurements was performed with submillimeter accuracy. After backprojection into 3D the patient localization error was (−0.04±0.30) mm, (0.09±0.36) mm, and (0.03±0.68) mm in the right

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

    PubMed

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

    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

  16. The VACS Index Accurately Predicts Mortality and Treatment Response among Multi-Drug Resistant HIV Infected Patients Participating in the Options in Management with Antiretrovirals (OPTIMA) Study

    PubMed Central

    Brown, Sheldon T.; Tate, Janet P.; Kyriakides, Tassos C.; Kirkwood, Katherine A.; Holodniy, Mark; Goulet, Joseph L.; Angus, Brian J.; Cameron, D. William; Justice, Amy C.

    2014-01-01

    Objectives The VACS Index is highly predictive of all-cause mortality among HIV infected individuals within the first few years of combination antiretroviral therapy (cART). However, its accuracy among highly treatment experienced individuals and its responsiveness to treatment interventions have yet to be evaluated. We compared the accuracy and responsiveness of the VACS Index with a Restricted Index of age and traditional HIV biomarkers among patients enrolled in the OPTIMA study. Methods Using data from 324/339 (96%) patients in OPTIMA, we evaluated associations between indices and mortality using Kaplan-Meier estimates, proportional hazards models, Harrel’s C-statistic and net reclassification improvement (NRI). We also determined the association between study interventions and risk scores over time, and change in score and mortality. Results Both the Restricted Index (c = 0.70) and VACS Index (c = 0.74) predicted mortality from baseline, but discrimination was improved with the VACS Index (NRI = 23%). Change in score from baseline to 48 weeks was more strongly associated with survival for the VACS Index than the Restricted Index with respective hazard ratios of 0.26 (95% CI 0.14–0.49) and 0.39(95% CI 0.22–0.70) among the 25% most improved scores, and 2.08 (95% CI 1.27–3.38) and 1.51 (95%CI 0.90–2.53) for the 25% least improved scores. Conclusions The VACS Index predicts all-cause mortality more accurately among multi-drug resistant, treatment experienced individuals and is more responsive to changes in risk associated with treatment intervention than an index restricted to age and HIV biomarkers. The VACS Index holds promise as an intermediate outcome for intervention research. PMID:24667813

  17. Local immunotherapy via delivery of interleukin-10 and transforming growth factor β antagonist for treatment of chronic kidney disease.

    PubMed

    Rodell, Christopher B; Rai, Reena; Faubel, Sarah; Burdick, Jason A; Soranno, Danielle E

    2015-05-28

    Obstructive nephropathy is the leading cause of kidney disease in children. The tissue injury resulting from initial dilation precipitates a deleterious cascade of macrophage infiltration, apoptosis, and fibrosis to produce a resultant dysfunctional tissue. We propose to abate this tissue remodeling process through immunotherapy administered via the local and sustained delivery of interleukin-10 (IL-10; anti-inflammatory) and anti-transforming growth factor β (anti-TGFβ; anti-fibrotic). Shear-thinning, injectable hyaluronic acid (HA) hydrogels were formed through supramolecular guest-host interactions and used to contain IL-10, anti-TGFβ, or both molecules together. Degradation assays demonstrated that diffusive molecule release was associated with concurrent hydrogel erosion and was sustained for up to 3weeks in vitro. Erosion was likewise monitored in vivo by non-invasive optical imaging, where gel localization to the affected tissue was observed with near complete clearance by day 18. Hydrogels were applied to a murine model of chronic kidney disease, with subcapsular hydrogel injections acting as a delivery depot. Quantitative histological analysis (days 7, 21, and 35) was used to evaluate treatment efficacy. Notably, results demonstrated reduced macrophage infiltration beyond day 7 in treatment groups and reduced apoptosis at day 21, relative to untreated unilateral ureteral obstruction disease model. Fibrosis was reduced at the 35day timepoint in groups treated with IL-10 or anti-TGFβ alone, but not with the combination therapy. Rather, dual delivery of IL-10 and anti-TGFβ resulted in a paradoxical hastening of fibrosis, warranting further investigation. Localized immunotherapy is a novel approach to treat kidney disease and shows promise as a translatable therapy.

  18. Pulmonary delivery of an ultra-fine oxytocin dry powder formulation: potential for treatment of postpartum haemorrhage in developing countries.

    PubMed

    Prankerd, Richard J; Nguyen, Tri-Hung; Ibrahim, Jibriil P; Bischof, Robert J; Nassta, Gemma C; Olerile, Livesey D; Russell, Adrian S; Meiser, Felix; Parkington, Helena C; Coleman, Harold A; Morton, David A V; McIntosh, Michelle P

    2013-01-01

    Oxytocin is recommended by the World Health Organisation as the most effective uterotonic for the prevention and treatment of postpartum haemorrhage. The requirement for parenteral administration by trained healthcare providers and the need for the drug solution to be maintained under cold-chain storage limit the use of oxytocin in the developing world. In this study, a spray-dried ultrafine formulation of oxytocin was developed with an optimal particle size diameter (1-5 µm) to facilitate aerosolised delivery via the lungs. A powder formulation of oxytocin, using mannitol, glycine and leucine as carriers, was prepared with a volume-based median particle diameter of 1.9 µm. Oxytocin content in the formulation was assayed using high-performance liquid chromatography-mass spectroscopy and was found to be unchanged after spray-drying. Ex vivo contractility studies utilising human and ovine uterine tissue indicated no difference in the bioactivity of oxytocin before and after spray-drying. Uterine electromyographic (EMG) activity in postpartum ewes following pulmonary (in vivo) administration of oxytocin closely mimicked that observed immediately postpartum (0-12 h following normal vaginal delivery of the lamb). In comparison to the intramuscular injection, pulmonary administration of an oxytocin dry powder formulation to postpartum ewes resulted in generally similar EMG responses, however a more rapid onset of uterine EMG activity was observed following pulmonary administration (129 ± 18 s) than intramuscular injection (275 ± 22 s). This is the first study to demonstrate the potential for oxytocin to elicit uterine activity after systemic absorption as an aerosolised powder from the lungs. Aerosolised oxytocin has the potential to provide a stable and easy to administer delivery system for effective prevention and treatment of postpartum haemorrhage in resource-poor settings in the developing world.

  19. Focused ultrasound induced blood-brain barrier disruption to enhance chemotherapeutic drugs (BCNU) delivery for glioblastoma treatment

    NASA Astrophysics Data System (ADS)

    Liu, Hao-Li; Hua, Mu-Yi; Chen, Pin-Yuan; Huang, Chiung-Yin; Wang, Jiun-Jie; Wei, Kuo-Chen

    2010-03-01

    Focused ultrasound has been recently found to capable of temporally and reversibly disrupt local blood-brain barrier (BBB) and opens new frontier in delivering varies type of drugs into brain for central nerve system (CNS) disorder treatment. In this study, we aim to investigate the feasibility of delivering 1, 3-bits (2-chloroethyl) -1-nitrosourea (BCNU) to treat glioblastoma in animal models and evaluate whether this approach would gain treatment efficacy. Under the presence of microbubbles administration, a 400-kHz focused ultrasound was employed to deliver burst-tone ultrasonic energy stimulation to disrupt BBB in animal brains transcranially, and in-vivo monitored by magnetic-resonance imaging (MRI). C6-glioma cells were cultured and implanted into Sprague-Dawley rats as the brain-tumor model. BCNU deposited in brain was quantified by using high-performance liquid chromatography (HPLC), and brain tissues were examined histologically. MRI was employed to longitudinal evaluate the brain tumor treatment including the analysis of tumor progression and animal survival. We confirmed that the focused ultrasound, under the secure ultrasonic energy level, can significantly enhance the BCNU penetration through BBB over 300% than control without cause hemorrhage. Apparent improvement of treatment efficacy achieved by combining focused ultrasound with BCNU delivery, including significant suppression of tumor growth and a prolonged animal survival. This study highly support that this treatment strategy could be clinically-relevant and may help to provide another potential strategy in increasing local chemotherapeutic drugs for brain-tumor treatment.

  20. The potentials of nanotechnology-based drug delivery system for treatment of ovarian cancer.

    PubMed

    Gidwani, Bina; Vyas, Amber

    2015-01-01

    Ovarian cancer is one of the leading causes for death of women. Every year the percentage of mortality rate is increasing day by day. Various chemotherapeutic agents are used to increase the survival rate of patients with ovarian cancer, but the available conventional dosage forms/marketed preparations are associated with several limitations. The use of nanotechnology in drug delivery contributes to their small size (10-100 nm), which improves the circulation and enables superior accumulation of therapeutic drugs at the tumor sites. In future, the use of nanotechnology will enable passive targeting and further improvements can be made using targeting moieties.

  1. Heart rate variability biofeedback: Theoretical basis, delivery, and its potential for the treatment of substance use disorders

    PubMed Central

    Eddie, David; Vaschillo, Evgeny; Vaschillo, Bronya; Lehrer, Paul

    2016-01-01

    Heart rate variability biofeedback (HRV BFB) is a biobehavioural clinical intervention that is gaining growing empirical support for the treatment of a number of psychological disorders, several of which are highly comorbid with substance use disorders (SUDs). The present article reviews the autonomic nervous system bases of two key processes implicated in the formation and maintenance of addictive pathology—affect dysregulation and craving—and asks if HRV BFB may be an effective intervention to ameliorate autonomic nervous system dysregulation in these processes, and as such, prove to be an effective intervention for SUDs. A detailed description of HRV BFB and its delivery is provided. Preliminary evidence suggests HRV BFB may be an effective addendum to current first-line SUD treatments, though no firm conclusions can be drawn at this time; more research is needed. PMID:28077937

  2. Enhanced Topical Delivery of Tetrandrine by Ethosomes for Treatment of Arthritis

    PubMed Central

    Fan, Chao; Li, Xinru; Zhou, Yanxia; Zhao, Yong; Ma, Shujin; Li, Wenjing; Liu, Yan; Li, Guiling

    2013-01-01

    The purpose of this work was to explore the feasibility of ethosomes for improving the antiarthritic efficacy of tetrandrine by topical application. It was found that tetrandrine was a weak base (pKa = 7.06) with pH-dependent partition coefficient. The spherical-shaped ethosomes were prepared by pH gradient loading method. Ex vivo permeation and deposition behavior demonstrated that the drug flux across rat skin and deposition of the drug in rat skin for ethosomes was 2.1- and 1.7-fold higher than that of liposomes, respectively. Confocal laser scanning microscopy confirmed that ethosomes could enhance the topical delivery of the drug in terms of depth and quantity compared with liposomes. The ethosomes were shown to generate substantial enhancement of therapeutic efficacy of tetrandrine on Freund's complete adjuvant-induced arthritis with regard to liposomes. These results indicated that ethosomes would be a promising carrier for topical delivery of tetrandrine into and across the skin. PMID:24062995

  3. Enhanced topical delivery of tetrandrine by ethosomes for treatment of arthritis.

    PubMed

    Fan, Chao; Li, Xinru; Zhou, Yanxia; Zhao, Yong; Ma, Shujin; Li, Wenjing; Liu, Yan; Li, Guiling

    2013-01-01

    The purpose of this work was to explore the feasibility of ethosomes for improving the antiarthritic efficacy of tetrandrine by topical application. It was found that tetrandrine was a weak base (pK(a) = 7.06) with pH-dependent partition coefficient. The spherical-shaped ethosomes were prepared by pH gradient loading method. Ex vivo permeation and deposition behavior demonstrated that the drug flux across rat skin and deposition of the drug in rat skin for ethosomes was 2.1- and 1.7-fold higher than that of liposomes, respectively. Confocal laser scanning microscopy confirmed that ethosomes could enhance the topical delivery of the drug in terms of depth and quantity compared with liposomes. The ethosomes were shown to generate substantial enhancement of therapeutic efficacy of tetrandrine on Freund's complete adjuvant-induced arthritis with regard to liposomes. These results indicated that ethosomes would be a promising carrier for topical delivery of tetrandrine into and across the skin.

  4. 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).

  5. Brain delivery of buspirone hydrochloride chitosan nanoparticles for the treatment of general anxiety disorder.

    PubMed

    Bari, Naimat Kalim; Fazil, Mohammad; Hassan, Md Quamrul; Haider, Md Rafi; Gaba, Bharti; Narang, Jasjeet K; Baboota, Sanjula; Ali, Javed

    2015-11-01

    The present work discusses the preparation, characterization and in vivo evaluation of thiolated chitosan nanoparticles (TCS-NPs) of buspirone hydrochloride (BUH) for brain delivery through intranasal route. TCS NPs were prepared by ionic gelation method and characterized for various parameters. The NPs formed were having particle size of 226.7±2.52nm with PDI 0.483±0.031. Drug entrapment efficiency (EE) and loading capacity (LC) were found to be 81.13±2.8 and 49.67±5.5%. The cumulative percentage drug permeation through nasal mucosa was 76.21%. Bioadhesion study carried out on porcine mucin and showed a bioadhesion efficiency of 90.218±0.134%. Nose-to-brain delivery of placebo NPs was investigated by confocal laser scanning microscopy (CLSM) technique using rhodamine-123 as a marker. The brain concentration achieved after intranasal administration of TCS-NPs was 797.46±35.76ng/ml with tmax 120min which was significantly higher than achieved after intravenous administration on BUH solution 384.15±13.42ng/ml and tmax of 120min and intranasal administration of BUH solution 417.77±19.24ng/ml and tmax 60min.

  6. Reversibly crosslinked nanocarriers for on-demand drug delivery in cancer treatment

    PubMed Central

    Shao, Yu; Huang, Wenzhe; Shi, Changying; Atkinson, Sean T; Luo, Juntao

    2013-01-01

    Polymer micelles have proven to be one of the most versatile nanocarriers for anticancer drug delivery. However, the in vitro and in vivo stability of micelles remains a challenge due to the dynamic nature of these self-assembled systems, which leads to premature drug release and nonspecific biodistribution in vivo. Recently, reversibly crosslinked micelles have been developed to provide solutions to stabilize nanocarriers in blood circulation. Increased stability allows nanoparticles to accumulate at tumor sites efficiently via passive and/or active tumor targeting, while cleavage of the micelle crosslinkages, through internal or external stimuli, facilitates on-demand drug release. In this review, various crosslinking chemistries as well as the choices for reversible linkages in these nanocarriers will be introduced. Then, the development of reversibly crosslinked micelles for on-demand drug release in response to single or dual stimuli in the tumor microenvironment is discussed, for example, acidic pH, reducing microenvironment, enzymatic microenvironment, photoirradiation and the administration of competitive reagents postmicelle delivery. PMID:23323559

  7. Local in vitro delivery of rapamycin from electrospun PEO/PDLLA nanofibers for glioblastoma treatment.

    PubMed

    Wang, Benlin; Li, Haoyuan; Yao, Qingyu; Zhang, Yulin; Zhu, Xiaodong; Xia, Tongliang; Wang, Jian; Li, Gang; Li, Xingang; Ni, Shilei

    2016-10-01

    Rapamycin, a mammalian target of rapamycin inhibitor and anti-proliferative agent, is used to treat glioma and other malignancies, but its effectiveness is limited by the fact that it cannot be delivered in a targeted manner to the site of the tumor. To address this issue, we fabricated a mesh via electrospinning using two biodegradable materials, poly(lactic acid) (PLA) and polyethylene oxide (PEO) as a carrier for rapamycin delivery to the tumor. Nanofiber diameter decreased with increasing PLA concentration in the mixed solution. Scanning electron microscopy analysis revealed the smooth and uniform surface morphology of hybrid fibers. Fourier transform infrared spectroscopy analysis demonstrated that rapamycin was encapsulated in the polymer solution; encapsulation efficiency was high and stable over the range of drug concentrations from 0.5-2wt%. A correlation was observed between sustained release of the drug in vitro and cytotoxicity in cultured glioma cells. These results indicate that the PEO/poly(d,l-lactic acid) nanofiber mesh can be used as a targeted delivery system for rapamycin that can limit side effects and prevent locoregional recurrence following surgical resection of glioma.

  8. Three dimensional transient multifield analysis of a piezoelectric micropump for drug delivery system for treatment of hemodynamic dysfunctions.

    PubMed

    Nisar, Asim; Afzulpurkar, Nitin; Tuantranont, Adisorn; Mahaisavariya, Banchong

    2008-12-01

    In this paper, we present design of a transdermal drug delivery system for treatment of cardiovascular or hemodynamic disorders such as hypertension. The system comprises of integrated control electronics and microelectromechanical system devices such as micropump, micro blood pressure sensor and microneedle array. The objective is to overcome the limitations of oral therapy such as variable absorption profile and the need for frequent dosing, by fabricating a safe, reliable and cost effective transdermal drug delivery system to dispense various pharmacological agents through the skin for treatment of hemodynamic dysfunction such as hypertension. Moreover, design optimization of a piezoelectrically actuated valveless micropump is presented for the drug delivery system. Because of the complexity in analysis of piezoelectric micropump, which involves structural and fluid field couplings in a complicated geometrical arrangement, finite element (FE) numerical simulation rather than an analytical system has been used. The behavior of the piezoelectric actuator with biocompatible polydimethylsiloxane membrane is first studied by conducting piezoelectric analysis. Then the performance of the valveless micropump is analyzed by building a three dimensional electric-solid-fluid model of the micropump. The effect of geometrical dimensions on micropump characteristics and efficiency of nozzle/diffuser elements of a valveless micropump is investigated in the transient analysis using multiple code coupling method. The deformation results of the membrane using multifield code coupling analysis are in good agreement with analytical as well as results of single code coupling analysis of a piezoelectric micropump. The analysis predicts that to enhance the performance of the micropump, diffuser geometrical dimensions such as diffuser length, diffuser neck width and diffuser angle need to be optimized. Micropump flow rate is not strongly affected at low excitation frequencies from 10

  9. SU-E-P-27: Efficient Process for AccuBoost Planning and Treatment Delivery to Minimize Patient Compression Time

    SciTech Connect

    Iftimia, I; Talmadge, M; Halvorsen, P

    2015-06-15

    Purpose: To implement an efficient and robust process for AccuBoost planning and treatment delivery that can be safely performed by a single Physicist while minimizing patient’s total session time. Methods: Following a thorough commissioning and validation process, templates were created in the brachytherapy planning system for each AccuBoost applicator. Tables of individual and total nominal dwell times for each applicator as a function of separation were generated to streamline planning while an Excel-based nomogram provided by the vendor functions as a secondary verification of the treatment parameters. Tables of surface dose as a function of separation and applicator, along with concise guidance documents for applicator selection, are readily available during the planning process. The entire process is described in a set of detailed Standard Operating Procedures which, in addition to the items described above, include a verbal time-out between the primary planner and the individual performing the secondary verification as well as direct visual confirmation of applicator placement using an articulated mirror. Prior to treatment initiation, a final time-out is conducted with the Radiation Oncologist. Chart documentation is finalized after the patient is released from compression following completion of the treatment. Results: With the aforementioned procedures, it has been possible to consistently limit the time required to prepare each treatment such that the patient is typically under compression for less than 10 minutes per orientation prior to the initiation of the treatment, which is particularly important for APBI cases. This process can be overseen by a single physicist assisted by a dosimetrist and has been optimized during the past 16 months, with 180 treatment sessions safely completed to date. Conclusion: This work demonstrates the implementation of an efficient and robust process for real-time-planned AccuBoost treatments that effectively minimizes

  10. Treatment of Breast Tumors using Pulsed HIFU for Delivery and Activation of Sonosensitizers

    DTIC Science & Technology

    2009-08-01

    done. Using similar treatment parameters in vivo necessitated the use of ultrasound contrast agents to initiate cavitation . When this was done, we...ablation for breast cancer treatment. 15. SUBJECT TERMS high intensity focused ultrasound , sonodynamic, cavitation , free radicals, chemotherapy...40 W (abou 8.6 MPa peak negative pressure). Targeting and cavitation monitoring was via ultrasonic b-mode imaging. After the ultrasound treatment

  11. A column generation approach for evaluating delivery efficiencies of collimator technologies in IMRT treatment planning

    NASA Astrophysics Data System (ADS)

    Gören, M.; Taşkın, Z. C.

    2015-03-01

    Collimator systems used in Intensity Modulated Radiation Therapy can form different geometric aperture shapes depending on their physical capabilities. We compare the efficiency of using regular, rotating and dual multileaf collimator (MLC) systems under different combinations of consecutiveness, interdigitation and rectangular constraints. We also create a virtual freeform collimator, which can form any possible segment shape by opening or closing each bixel independently, to provide a basis for comparison. We formulate the problem of minimizing beam-on time as a large-scale linear programming problem. To deal with its dimensionality, we propose a column generation approach. We demonstrate the efficacy of our approach on a set of clinical problem instances. Our results indicate that the dual MLC under consecutiveness constraint yields very similar beam-on time to a virtual freeform collimator. Our approach also provides a ranking between other collimator technologies in terms of their delivery efficiencies.

  12. Improvement of drug delivery by hyperthermia treatment using magnetic cubic cobalt ferrite nanoparticles

    NASA Astrophysics Data System (ADS)

    Dey, Chaitali; Baishya, Kaushik; Ghosh, Arup; Goswami, Madhuri Mandal; Ghosh, Ajay; Mandal, Kalyan

    2017-04-01

    In this study, we report a novel synthesis method, characterization and application of a new class of ferromagnetic cubic cobalt ferrite magnetic nanoparticles (MNPs) for hyperthermia therapy and temperature triggered drug release. The MNPs are characterized by XRD, TEM, FESEM, AC magnetic hysteresis and VSM. These MNPs were coated with folic acid and loaded with an anticancer drug. The drug release studies were done at two different temperatures (37 °C and 44 °C) with progress of time. It was found that higher release of drug took place at elevated temperature (44 °C). We have developed a temperature sensitive drug delivery system which releases the heat sensitive drug selectively as the particles are heated up under AC magnetic field and controlled release is possible by changing the external AC magnetic field.

  13. Intensity-modulated arc therapy to improve radiation dose delivery in the treatment of abdominal neuroblastoma.

    PubMed

    Gains, Jennifer E; Stacey, Christopher; Rosenberg, Ivan; Mandeville, Henry C; Chang, Yen-Ch'ing; D'Souza, Derek; Moroz, Veronica; Wheatley, Keith; Gaze, Mark N

    2013-03-01

    The standard European radiotherapy technique for children with neuroblastoma is a conventional parallel opposed pair. This frequently results in compromise on planning target volume coverage to stay within normal tissue tolerances. This study investigates the use of an intensity-modulated arc therapy (IMAT) technique to improve dose distribution and allow better protocol compliance. Among 20 previously treated patients, ten had received the full prescribed dose with conventional planning (protocol compliant) and ten had a compromise on planning target volume coverage (protocol noncompliant). All patients were replanned with IMAT. Dosimetric parameters of the conventional radiotherapy and IMAT were compared. The dose received by 98% of the planning target volume, homogeneity and conformity indices were all improved with IMAT (p < 0.001). IMAT would have enabled delivery of the full protocol dose in eight out of ten protocol-noncompliant patients. IMAT may improve outcomes through improved protocol compliance and better dose distributions.

  14. Evaluation of unnatural cyclic amino acids as boron delivery agents for treatment of melanomas and gliomas.

    PubMed

    Barth, Rolf F; Kabalka, George W; Yang, Weilian; Huo, Tianyao; Nakkula, Robin J; Shaikh, Aarif L; Haider, Syed A; Chandra, Subhash

    2014-06-01

    Unnatural cyclic amino acids (UNAAs) are a new class of boron delivery agents that are in a pre-clinical stage of evaluation. In the present study, the biodistribution of racemic forms of the cis- and trans-isomers of the boronated UNAA 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC) and 1-amino-3-boronocycloheptanecarboxylic acid (ABCHC) were evaluted in B16 melanoma bearing mice and this was compared to l-p-boronophenylalanine (BPA). Boron concentrations were determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES) at 2.5h following intraperitoneal (i.p.) injection of the test agents at a concentration equivalent to 24mg/B/kg. While all compounds attained comparable tumor boron concentrations, the tumor/blood (T/Bl) boron concentration ratios were far superior for both cis-ABCPC and cis-ABCHC compared to BPA (T/Bl=16.4, and 15.1 vs. 5.4). Secondary ion mass spectrometry (SIMS) imaging revealed that the cis-ABCPC delivered boron to the nuclei, as well as the cytoplasm of B16 cells. Next, a biodistribution study of cis-ABCPC and BPA was carried out in F98 glioma bearing rats following i.p. administration. Both compounds attained comparable tumor boron concentrations but the tumor/brain (T/Br) boron ratio was superior for cis-ABCPC compared to BPA (6 vs. 3.3). Since UNAAs are water soluble and cannot be metabolized by tumor cells, they could be potentially more effective boron delivery agents than BPA. Our data suggest that further studies are warranted to evaluate these compounds prior to the initiation of clinical studies.

  15. Nanoparticle-mediated miR200-b delivery for the treatment of diabetic retinopathy

    PubMed Central

    Mitra, Rajendra Narayan; Nichols, Chance A.; Guo, Junjing; Makkia, Rasha; Cooper, Mark J.; Naash, Muna I.; Han, Zongchao

    2017-01-01

    We recently reported that the Ins2Akita mouse is a good model for late-onset diabetic retinopathy. Here, we investigated the effect of miR200-b, a potential anti-angiogenic factor, on VEGF receptor 2 (VEGFR-2) expression and to determine the underlying angiogenic response in mouse endothelial cells, and in retinas from aged Ins2Akita mice. MiR200-b and its native flanking sequences were amplified and cloned into a pCAG-eGFP vector directed by the ubiquitous CAG promoter (namely pCAG-miR200-b-IRES-eGFP). The plasmid was compacted by CK30PEG10K into DNA nanoparticles (NPs) for in vivo delivery. Murine endothelial cell line, SVEC4-10, was first transfected with the plasmid. The mRNA levels of VEGF and VEGFR-2 were quantified by qRT-PCR and showed significant reduction in message expression compared with lipofectamine-transfected cells. Transfection of miR200-b suppressed the migration of SVEC4-10 cells. There was a significant inverse correlation between the level of expression of miR200-b and VEGFR-2. Intravitreal injection of miR200-b DNA NPs significantly reduced protein levels of VEGFR-2 as revealed by western blot and markedly suppressed angiogenesis as evaluated by fundus imaging in aged Ins2Akita mice even after 3 months of post-injection. These findings suggest that NP-mediated miR200-b delivery has negatively regulated VEGFR-2 expression in vivo. PMID:27297781

  16. Effects of Verbal and Written Performance Feedback on Treatment Adherence: Practical Application of Two Delivery Formats

    ERIC Educational Resources Information Center

    Kaufman, Dahlia; Codding, Robin S.; Markus, Keith A.; Tryon, Georgiana Shick; Kyse, Eden Nagler

    2013-01-01

    Verbal and written performance feedback for improving preschool and kindergarten teachers' treatment integrity of behavior plans was compared using a combined multiple-baseline and multiple-treatment design across teacher-student dyads with order counterbalanced as within-series conditions. Supplemental generalized least square regression analyses…

  17. Efficacy of transdermal magnesium ascorbyl phosphate delivery after ultrasound treatment with microbubbles in gel-type surrounding medium in mice.

    PubMed

    Liao, Ai-Ho; Lu, Ying-Jui; Hung, Chi-Ray; Yang, Meng-Yu

    2016-04-01

    Liquid microemulsions appropriate for topical application were obtained by increasing their viscosity through the addition of thickening agents. The present study first assessed the usefulness of ultrasound (US) plus US contrast agent, microbubbles (MBs), in agarose gel for enhancing transdermal drug delivery. The effect of US plus MBs in agarose gel on the penetration of the skin by magnesium ascorbyl phosphate (MAP) was explored both in vitro and in vivo. In the in vitro experiments, the stability of MBs was investigated by examining the penetration of MAP by the model drug, Evans blue, in two media: an agarose phantom and pig skin. The penetration depth in the agarose phantom and pig skin increased by 40% and 195%, respectively, when treated with US plus MBs in 0.1% agarose solution combined with MAP (UMB1), and by 48% and 206%, respectively, when treated with US plus MBs in 0.15% agarose solution and MAP (UMB2). The skin-whitening effects in C57BL/6J mice in the UMB1 and UMB2 groups over a 4-week experimental period were significantly increased by 63% and 70%, respectively, in the fourth week. The findings of this study suggest that the survival of MBs with US is affected by the viscosity of the surrounding medium, and that in mice, treatment with US plus MBs in a suitable agarose gel can increase skin permeability and enhance transdermal MAP delivery.

  18. On-demand drug delivery from self-assembled nanofibrous gels: a new approach for treatment of proteolytic disease.

    PubMed

    Vemula, Praveen Kumar; Boilard, Eric; Syed, Abdullah; Campbell, Nathaniel R; Muluneh, Melaku; Weitz, David A; Lee, David M; Karp, Jeffrey M

    2011-05-01

    Local delivery of drugs offers the potential for high local drug concentration while minimizing systemic toxicity, which is often observed with oral dosing. However, local depots are typically administered less frequently and include an initial burst followed by a continuous release. To maximize efficiency of therapy, it is critical to ensure that drug is only released when needed. One of the hallmarks of rheumatoid arthritis, for example, is its variable disease activity consisting of exacerbations of inflammation punctuated by periods of remission. This presents significant challenges for matching localized drug delivery with disease activity. An optimal system would be nontoxic and only release drugs during the period of exacerbation, self-titrating in response to the level of inflammation. We report the development of an injectable self-assembled nanofibrous hydrogel, from a generally recognized as safe material, which is capable of encapsulation and release of agents in response to specific enzymes that are significantly upregulated in a diseased state including matrix metalloproteinases (MMP-2 and MMP-9) and esterases. We show that these self-assembled nanofibrous gels can withstand shear forces that may be experienced in dynamic environments such as joints, can remain stable following injection into healthy joints of mice, and can disassemble in vitro to release encapsulated agents in response to synovial fluid from arthritic patients. This novel approach represents a next-generation therapeutic strategy for localized treatment of proteolytic diseases.

  19. Design, fabrication and analysis of silicon hollow microneedles for transdermal drug delivery system for treatment of hemodynamic dysfunctions.

    PubMed

    Ashraf, M W; Tayyaba, S; Nisar, A; Afzulpurkar, N; Bodhale, D W; Lomas, T; Poyai, A; Tuantranont, A

    2010-09-01

    In this paper, we present design, fabrication and coupled multifield analysis of hollow out-of-plane silicon microneedles with piezoelectrically actuated microfluidic device for transdermal drug delivery (TDD) system for treatment of cardiovascular or hemodynamic disorders such as hypertension. The mask layout design and fabrication process of silicon microneedles and reservoir involving deep reactive ion etching (DRIE) is first presented. This is followed by actual fabrication of silicon hollow microneedles by a series of combined isotropic and anisotropic etching processes using inductively coupled plasma (ICP) etching technology. Then coupled multifield analysis of a MEMS based piezoelectrically actuated device with integrated silicon microneedles is presented. The coupledfield analysis of hollow silicon microneedle array integrated with piezoelectric micropump has involved structural and fluid field couplings in a sequential structural-fluid analysis on a three-dimensional model of the microfluidic device. The effect of voltage and frequency on silicon membrane deflection and flow rate through the microneedle is investigated in the coupled field analysis using multiple code coupling method. The results of the present study provide valuable benchmark and prediction data to fabricate optimized designs of the silicon hollow microneedle based microfluidic devices for transdermal drug delivery applications.

  20. Delivery of glutamine synthetase gene by baculovirus vectors: a proof of concept for the treatment of acute hyperammonemia.

    PubMed

    Torres-Vega, M A; Vargas-Jerónimo, R Y; Montiel-Martínez, A G; Muñoz-Fuentes, R M; Zamorano-Carrillo, A; Pastor, A R; Palomares, L A

    2015-01-01

    Hyperammonemia, a condition present in patients with urea cycle disorders (UCDs) or liver diseases, can cause neuropsychiatric complications, which in the worst cases result in brain damage, coma or death. Diverse treatments exist for the treatment of hyperammonemia, but they have limited efficacy, adverse effects and elevated cost. Gene therapy is a promising alternative that is explored here. A baculovirus, termed Bac-GS, containing the glutamine synthetase (GS) gene was constructed for the in vitro and in vivo treatment of hyperammonemia. Transduction of MA104 epithelial or L6 myoblast/myotubes cells with Bac-GS resulted in a high expression of the GS gene, an increase in GS concentration, and a reduction of almost half of exogenously added ammonia. When Bac-GS was tested in an acute hyperammonemia rat model by intramuscularly injecting the rear legs, the concentration of ammonia in blood decreased 351 μM, in comparison with controls. A high GS concentration was detected in gastrocnemius muscles from the rats transduced with Bac-GS. These results show that gene delivery for overexpressing GS in muscle tissue is a promising alternative for the treatment of hyperammonemia in patients with acute or chronic liver diseases and hepatic encephalopathy or UCD.

  1. Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study.

    PubMed

    Wei, Kuo-Chen; Chu, Po-Chun; Wang, Hay-Yan Jack; Huang, Chiung-Yin; Chen, Pin-Yuan; Tsai, Hong-Chieh; Lu, Yu-Jen; Lee, Pei-Yun; Tseng, I-Chou; Feng, Li-Ying; Hsu, Peng-Wei; Yen, Tzu-Chen; Liu, Hao-Li

    2013-01-01

    The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.

  2. Fast and accurate Monte Carlo modeling of a kilovoltage X-ray therapy unit using a photon-source approximation for treatment planning in complex media

    PubMed Central

    Zeinali-Rafsanjani, B.; Mosleh-Shirazi, M. A.; Faghihi, R.; Karbasi, S.; Mosalaei, A.

    2015-01-01

    To accurately recompute dose distributions in chest-wall radiotherapy with 120 kVp kilovoltage X-rays, an MCNP4C Monte Carlo model is presented using a fast method that obviates the need to fully model the tube components. To validate the model, half-value layer (HVL), percentage depth doses (PDDs) and beam profiles were measured. Dose measurements were performed for a more complex situation using thermoluminescence dosimeters (TLDs) placed within a Rando phantom. The measured and computed first and second HVLs were 3.8, 10.3 mm Al and 3.8, 10.6 mm Al, respectively. The differences between measured and calculated PDDs and beam profiles in water were within 2 mm/2% for all data points. In the Rando phantom, differences for majority of data points were within 2%. The proposed model offered an approximately 9500-fold reduced run time compared to the conventional full simulation. The acceptable agreement, based on international criteria, between the simulations and the measurements validates the accuracy of the model for its use in treatment planning and radiobiological modeling studies of superficial therapies including chest-wall irradiation using kilovoltage beam. PMID:26170553

  3. Modelling the Protective Efficacy of Alternative Delivery Schedules for Intermittent Preventive Treatment of Malaria in Infants and Children

    PubMed Central

    Cairns, Matthew; Ghani, Azra; Okell, Lucy; Gosling, Roly; Carneiro, Ilona; Anto, Francis; Asoala, Victor; Owusu-Agyei, Seth; Greenwood, Brian; Chandramohan, Daniel; Milligan, Paul

    2011-01-01

    Background Intermittent preventive treatment in infants (IPTi) with sulfadoxine-pyrimethamine (SP) is recommended by WHO where malaria incidence in infancy is high and SP resistance is low. The current delivery strategy is via routine Expanded Program on Immunisation contacts during infancy (EPI-IPTi). However, improvements to this approach may be possible where malaria transmission is seasonal, or where the malaria burden lies mainly outside infancy. Methods and Findings A mathematical model was developed to estimate the protective efficacy (PE) of IPT against clinical malaria in children aged 2-24 months, using entomological and epidemiological data from an EPI-IPTi trial in Navrongo, Ghana to parameterise the model. The protection achieved by seasonally-targeted IPT in infants (sIPTi), seasonal IPT in children (sIPTc), and by case-management with long-acting artemisinin combination therapies (LA-ACTs) was predicted for Navrongo and for sites with different transmission intensity and seasonality. In Navrongo, the predicted PE of sIPTi was 26% by 24 months of age, compared to 16% with EPI-IPTi. sIPTc given to all children under 2 years would provide PE of 52% by 24 months of age. Seasonally-targeted IPT retained its advantages in a range of transmission patterns. Under certain circumstances, LA-ACTs for case-management may provide similar protection to EPI-IPTi. However, EPI-IPTi or sIPT combined with LA-ACTs would be substantially more protective than either strategy used alone. Conclusion Delivery of IPT to infants via the EPI is sub-optimal because individuals are not protected by IPT at the time of highest malaria risk, and because older children are not protected. Alternative delivery strategies to the EPI are needed where transmission varies seasonally or the malaria burden extends beyond infancy. Long-acting ACTs may also make important reductions in malaria incidence. However, delivery systems must be developed to ensure that both forms of chemoprevention

  4. Helical Tomotherapy-Based STAT Stereotactic Body Radiation Therapy: Dosimetric Evaluation for a Real-Time SBRT Treatment Planning and Delivery Program

    SciTech Connect

    Dunlap, Neal; McIntosh, Alyson; Sheng Ke; Yang Wensha; Turner, Benton; Shoushtari, Asal; Sheehan, Jason; Jones, David R.; Lu Weigo; Ruchala, Keneth; Olivera, Gustavo; Parnell, Donald; Larner, James L.; Benedict, Stanley H.; Read, Paul W.

    2010-01-01

    iterations or 135 sec for STAT RT liver and lung SBRT plans and 7 iterations or 315 sec for STAT RT spine SBRT plans. Helical TomoTherapy-based STAT RT treatment planning with the 'full scatter' algorithm provides levels of dosimetric conformality, heterogeneity, and OAR avoidance for SBRT treatments that are clinically equivalent to those generated with the Helical TomoTherapy 'beamlet' algorithm. STAT RT calculation times for simple SBRT treatments are fast enough to warrant further investigation into their potential incorporation into an SBRT program with daily real-time planning. Development of methods for accurate target and OAR determination on megavoltage computed tomography scans incorporating high-resolution diagnostic image co-registration software and CT detector-based exit dose measurement for quality assurance are necessary to build a real-time SBRT planning and delivery program.

  5. Delivery of multiple siRNAs using lipid-coated PLGA nanoparticles for treatment of prostate cancer.

    PubMed

    Hasan, Warefta; Chu, Kevin; Gullapalli, Anuradha; Dunn, Stuart S; Enlow, Elizabeth M; Luft, J Christopher; Tian, Shaomin; Napier, Mary E; Pohlhaus, Patrick D; Rolland, Jason P; DeSimone, Joseph M

    2012-01-11

    Nanotechnology can provide a critical advantage in developing strategies for cancer management and treatment by helping to improve the safety and efficacy of novel therapeutic delivery vehicles. This paper reports the fabrication of poly(lactic acid-co-glycolic acid)/siRNA nanoparticles coated with lipids for use as prostate cancer therapeutics made via a unique soft lithography particle molding process called Particle Replication In Nonwetting Templates (PRINT). The PRINT process enables high encapsulation efficiency of siRNA into neutral and monodisperse PLGA particles (32-46% encapsulation efficiency). Lipid-coated PLGA/siRNA PRINT particles were used to deliver therapeutic siRNA in vitro to knockdown genes relevant to prostate cancer.

  6. Delivery of Multiple siRNAs Using Lipid-coated PLGA Nanoparticles for Treatment of Prostate Cancer

    PubMed Central

    Hasan, Warefta; Chu, Kevin; Gullapalli, Anuradha; Dunn, Stuart S.; Enlow, Elizabeth M.; Luft, J. Christopher; Tian, Shaomin; Napier, Mary E.; Pohlhaus, Patrick D.; Rolland, Jason P.; DeSimone, Joseph M.

    2012-01-01

    Nanotechnology can provide a critical advantage in developing strategies for cancer management and treatment by helping to improve the safety and efficacy of novel therapeutic delivery vehicles. This paper reports the fabrication of poly(lactic acid-co-glycolic acid)/siRNA nanoparticles coated with lipids for use as prostate cancer therapeutics made via a unique soft lithography particle molding process called PRINT (Particle Replication In Nonwetting Templates). The PRINT process enables high encapsulation efficiency of siRNA into neutral and monodisperse PLGA particles (32–46% encapsulation efficiency). Lipid-coated PLGA/siRNA PRINT particles were used to deliver therapeutic siRNA in vitro to knockdown genes relevant to prostate cancer. PMID:22165988

  7. Telemedicine for Improved Delivery of Psychosocial Treatments for Post Traumatic Stress Disorder

    DTIC Science & Technology

    2013-06-01

    therapy (which works by inviting people to revisit their memories of traumatic events and to face objectively safe situations they have avoided). However...revisit their memories of traumatic events and to face objectively safe situations they have avoided). However, individuals with PTSD may not get the...assessment. Learning and memory tests will be given before treatment begins to examine whether cognitive functioning influences treatment outcome, and

  8. A novel and facile synthesis of porous SiO2-coated ultrasmall Se particles as a drug delivery nanoplatform for efficient synergistic treatment of cancer cells

    NASA Astrophysics Data System (ADS)

    Liu, Xijian; Deng, Guoying; Wang, Yeying; Wang, Qian; Gao, Zhifang; Sun, Yangang; Zhang, Wenlong; Lu, Jie; Hu, Junqing

    2016-04-01

    A novel and facile synthetic route has been developed to fabricate porous SiO2-coated ultrasmall Se particles (Se@SiO2 nanospheres) as a drug delivery nanoplatform which combines Se quantum dots and doxorubicin (DOX) for efficient synergistic treatment of cancer cells.A novel and facile synthetic route has been developed to fabricate porous SiO2-coated ultrasmall Se particles (Se@SiO2 nanospheres) as a drug delivery nanoplatform which combines Se quantum dots and doxorubicin (DOX) for efficient synergistic treatment of cancer cells. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr02298g

  9. Dendritic cells serve as a “Trojan horse” for oncolytic adenovirus delivery in the treatment of mouse prostate cancer

    PubMed Central

    Li, Zhao-lun; Liang, Xuan; Li, He-cheng; Wang, Zi-ming; Chong, Tie

    2016-01-01

    Aim: Adenovirus-mediated gene therapy is a novel therapeutic approach for the treatment of cancer, in which replication of the virus itself is the anticancer method. However, the success of this novel therapy is limited due to inefficient delivery of the virus to the target sites. In this study, we used dendritic cells (DCs) as carriers for conditionally replicating adenoviruses (CRAds) in targeting prostate carcinoma (PCa). Methods: Four types of CRAds, including Ad-PC (without PCa-specific promoter and a recombinant human tumor necrosis factor, rmhTNF, sequence), Ad-PC-rmhTNF (without PCa-specific promoter), Ad-PPC-NCS (without an rmhTNF sequence) and Ad-PPC-rmhTNF, were constructed. The androgen-insensitive mouse PCa RM-1 cells were co-cultured with CRAd-loading DCs, and the viability of RM-1 cells was examined using MTT assay. The in vivo effects of CRAd-loading DCs on PCa were evaluated in RM-1 xenograft mouse model. Results: Two PCa-specific CRAds (Ad-PPC-NCS, Ad-PPC-rmhTNF) exhibited more potent suppression on the viability of RM-1 cells in vitro than the PCa-non-specific CRAds (Ad-PC, Ad-PC-rmhTNF). In PCa-bearing mice, intravenous injection of the PCa-specific CRAd-loading DCs significantly inhibited the growth of xenografted tumors, extended the survival time, and induced T-cell activation. Additionally, the rmhTNF-containing CRAds exhibited greater tumor killing ability than CRAds without rmhTNF. Conclusion: DCs may be an effective vector for the delivery of CRAds in the treatment of PCa. PMID:27345628

  10. Buccal mucosal delivery of a potent peptide leads to therapeutically-relevant plasma concentrations for the treatment of autoimmune diseases.

    PubMed

    Jin, Liang; Boyd, Ben J; White, Paul J; Pennington, Michael W; Norton, Raymond S; Nicolazzo, Joseph A

    2015-02-10

    Stichodactyla helianthus neurotoxin (ShK) is an immunomodulatory peptide currently under development for the treatment of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis by parenteral administration. To overcome the low patient compliance of conventional self-injections, we have investigated the potential of the buccal mucosa as an alternative delivery route for ShK both in vitro and in vivo. After application of fluorescent 5-Fam-ShK to untreated porcine buccal mucosa, there was no detectable peptide in the receptor chamber using an in vitro Ussing chamber model. However, the addition of the surfactants sodium taurodeoxycholate hydrate or cetrimide, and formulation of ShK in a chitosan mucoadhesive gel, led to 0.05-0.13% and 1.1% of the applied dose, respectively, appearing in the receptor chamber over 5h. Moreover, confocal microscopic studies demonstrated significantly enhanced buccal mucosal retention of the peptide (measured by mucosal fluorescence associated with 5-Fam-ShK) when enhancement strategies were employed. Administration of 5-Fam-ShK to mice (10mg/kg in a mucoadhesive chitosan-based gel (3%, w/v) with or without cetrimide (5%, w/w)) resulted in average plasma concentrations of 2.6-16.2nM between 2 and 6h, which were substantially higher than the pM concentrations required for therapeutic activity. This study demonstrated that the buccal mucosa is a promising administration route for the systemic delivery of ShK for the treatment of autoimmune diseases.

  11. Macrophage mediated biomimetic delivery system for the treatment of lung metastasis of breast cancer.

    PubMed

    Fu, Jijun; Wang, Dan; Mei, Dong; Zhang, Haoran; Wang, Zhaoyang; He, Bing; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Zhang, Qiang

    2015-04-28

    The biomimetic delivery system (BDS) based on special types of endogenous cells like macrophages and T cells, has been emerging as a novel strategy for cancer therapy, due to its tumor homing property and biocompatibility. However, its development is impeded by complicated construction, low drug loading or negative effect on the cell bioactivity. The present report constructed a BDS by loading doxorubicin (DOX) into a mouse macrophage-like cell line (RAW264.7). It was found that therapeutically meaningful amount of DOX could be loaded into the RAW264.7 cells by simply incubation, without significantly affecting the viability of the cells. Drug could release from the BDS and maintain its activity. RAW264.7 cells exhibited obvious tumor-tropic capacity towards 4T1 mouse breast cancer cells both in vitro and in vivo, and drug loading did not alter this tendency. Importantly, the DOX loaded macrophage system showed promising anti-cancer efficacy in terms of tumor suppression, life span prolongation and metastasis inhibition, with reduced toxicity. In conclusion, it is demonstrated that the BDS developed here seems to overcome some of the main issues related to a BDS. The DOX loaded macrophages might be a potential BDS for targeted cancer therapy.

  12. Establishing a transport protocol for the delivery of melanocytes and keratinocytes for the treatment of vitiligo.

    PubMed

    Eves, Paula C; Baran, Marta; Bullett, Nial A; Way, Louise; Haddow, David; Mac Neil, Sheila

    2011-04-01

    We have previously developed a cell delivery and transfer technology for delivering autologous keratinocytes and melanocytes to patients with vitiligo. However, for this technology to benefit many patients geographically distant from the cell culture facility transportation issues need to be overcome. In this study we begin to investigate this by looking at what role surface chemistry and medium supplements, including fetal calf serum, CO₂ gassing, and temperature, play in influencing cell viability. Cells were maintained on carriers for up to 48 h outside of a CO₂ incubator at 37 °C and their subsequent ability to adhere and become organized into a new epithelium with appropriately located melanocytes was assessed. Consistently good viability and performance on an in vitro wound bed model was achieved by maintaining cells for 48 h adherent to a 20% acrylic acid coated carrier at lower (around 23 °C rather than 37 °C) temperatures in the medium preperfused with CO₂ before transport. Under these circumstances fetal calf serum was not required. In summary, the surface chemistry of the transport substrate and an appropriately CO₂ buffered medium at near room temperature can extend the effective performance life of these cultured cells to at least 48 h from when they leave standard incubator conditions.

  13. Treatment planning and delivery of shell dose distribution for precision irradiation

    NASA Astrophysics Data System (ADS)

    Matinfar, Mohammad; Iyer, Santosh; Ford, Eric; Wong, John; Kazanzides, Peter

    2010-02-01

    The motivation for shell dose irradiation is to deliver a high therapeutic dose to the surrounding supplying blood-vessels of a lesion. Our approach's main utility is in enabling laboratory experiments to test the much disputed hypothesis about tumor vascular damage. That is, at high doses, tumor control is driven by damage to the tumor vascular supply and not the damage to the tumor cells themselves. There is new evidence that bone marrow derived cells can reconstitute tumor blood vessels in mice after irradiation. Shell dosimetry is also of interest to study the effect of radiation on neurogenic stem cells that reside in small niche surface of the mouse ventricles, a generalized form of shell. The type of surface that we are considering as a shell is a sphere which is created by intersection of cylinders. The results are then extended to create the contours of different organ shapes. Specifically, we present a routine to identify the 3-D structure of a mouse brain, project it into 2-D contours and convert the contours into trajectories that can be executed by our platform. We use the Small Animal Radiation Research Platform (SARRP) to demonstrate the dose delivery procedure. The SARRP is a portable system for precision irradiation with beam sizes down to 0.5 mm and optimally planned radiation with on-board cone-beam CT guidance.

  14. Competence in aspects of behavioral treatment and consultation: implications for service delivery and graduate training.

    PubMed Central

    McGimsey, J F; Greene, B F; Lutzker, J R

    1995-01-01

    This study examined the extent to which competence in applying behavioral procedures (time-out from positive reinforcement) was sufficient to establish competence in teaching others to apply the same procedures. During baseline, graduate students attempted to instruct parents with a history of child abuse and neglect in the use of time-out. Students were then instructed in the use of time-out until they achieved proficiency in a role-play context. They then reattempted to instruct the parents. Finally, the students were instructed in certain consultation skills (i.e., teaching others to apply behavioral procedures) and again attempted to instruct parents in the application of time-out. Observations of students' consultation skills, parents' proficiency at administering time-out, and children's compliance to parental instructions revealed that explicit training in behavioral consulting skills was necessary to produce improvements in these behaviors. Students proficiency at administering time-out was insufficient to enable them to instruct others in its application. These results were corroborated by surveys of both students and staff. The implications for graduate training and service delivery are discussed. PMID:7592146

  15. Nanoparticle Based Delivery of Quercetin for the Treatment of Carbon Tetrachloride Mediated Liver Cirrhosis in Rats.

    PubMed

    Verma, Shashi Kant; Rastogil, Shweta; Arora, Indu; Javed, Kalim; Akhtar, Mohd; Samim, Mohd

    2016-02-01

    Liver fibrosis is the common response to chronic liver injury and ultimately leads to cirrhosis. There is a pressing need in the pharmaceutical industry to develop efficient well-targeted drug delivery systems, which are lacking to date. This study was designed to investigate the efficacy of a nanoquercetin NQ; i.e., quercetin encapsulated in PAG (p-aminophenyl-1-thio-β-D-galactopryranoside)-coated NIPAAM (N-isopropyl acrylamide) nanopolymer in liver compared with naked quercetin (Q) using a carbon tetrachloride (CCl₄)-mediated liver cirrhosis model. NQ was more effective at restoring liver membrane integrity as indicated by significantly reduced serum markers, including Alanine Transaminase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH), compared with naked Q. The findings of reduced collagen and histopathology also show that the NQ effects were much better than those of naked Q. Biochemical parameters, including antioxidant defense enzymes, also provide supporting evidence. Furthermore, the decrease in NF-κB and NOS-2 expression in the NQ-treated groups was also much stronger than in the naked Q-treated group. Thus, the data clearly suggest that NQ not only provides significant hepatoprotection compared with naked Q, but it also substantially lowered the required concentration (1,000 to 10,000-fold lower) by increasing the bioavailability.

  16. Ultrasound mediated delivery of oxygen and LLL12 loaded stimuli responsive microdroplets for the treatment of hypoxic cancer cells.

    PubMed

    Xu, Jinshun; Yuan, Shuai; Tian, Jilai; Martin, Kyle A; Song, Jinhua; Li, Chenglong; Wang, Zhigang; Lin, Jiayuh; Si, Ting; Xu, Ronald X

    2017-03-21

    LLL12 exhibits high specificity for inhibiting STAT3 phosphorylation and dimerization, and inducing apoptosis to constitutively activated STAT3 cancer cells without cytotoxicity to normal cells with dormant STAT3. However, clinical deployment of LLL12 in cancer treatment is hindered by its low bioavailability and hypoxia-induced resistance. To overcome these limitations, we encapsulate both oxygen and LLL12 in stimuli responsive microdroplets (SRMs) by a gas-driven coaxial flow focusing (CFF) process for ultrasound mediated treatment of hypoxic cancer cells. Our benchtop experiments demonstrate that the CFF process is able to produce SRMs with uniform size distribution, large oxygen loading capacity, high LLL12 encapsulation efficiency, well protection of bioactivity, and steadily long shelf time. The in vitro therapeutic studies in pancreatic cancer cells (PANC-1 and CAPAN-1) demonstrate the immediate release of oxygen and LLL12 in exposure to therapeutic ultrasound pulses as well as the improved anticancer effects under hypoxic conditions. The findings suggest that the proposed oxygen and LLL12 loaded SRMs provide a promising drug delivery strategy for more effective treatment of hypoxic cancer cells.

  17. Ultrasound mediated delivery of oxygen and LLL12 loaded stimuli responsive microdroplets for the treatment of hypoxic cancer cells

    PubMed Central

    Xu, Jinshun; Yuan, Shuai; Tian, Jilai; Martin, Kyle A.; Song, Jinhua; Li, Chenglong; Wang, Zhigang; Lin, Jiayuh; Si, Ting; Xu, Ronald X.

    2017-01-01

    LLL12 exhibits high specificity for inhibiting STAT3 phosphorylation and dimerization, and inducing apoptosis to constitutively activated STAT3 cancer cells without cytotoxicity to normal cells with dormant STAT3. However, clinical deployment of LLL12 in cancer treatment is hindered by its low bioavailability and hypoxia-induced resistance. To overcome these limitations, we encapsulate both oxygen and LLL12 in stimuli responsive microdroplets (SRMs) by a gas-driven coaxial flow focusing (CFF) process for ultrasound mediated treatment of hypoxic cancer cells. Our benchtop experiments demonstrate that the CFF process is able to produce SRMs with uniform size distribution, large oxygen loading capacity, high LLL12 encapsulation efficiency, well protection of bioactivity, and steadily long shelf time. The in vitro therapeutic studies in pancreatic cancer cells (PANC-1 and CAPAN-1) demonstrate the immediate release of oxygen and LLL12 in exposure to therapeutic ultrasound pulses as well as the improved anticancer effects under hypoxic conditions. The findings suggest that the proposed oxygen and LLL12 loaded SRMs provide a promising drug delivery strategy for more effective treatment of hypoxic cancer cells. PMID:28322306

  18. A preliminary study of painless and effective transdermal botulinum toxin A delivery by jet nebulization for treatment of primary hyperhidrosis

    PubMed Central

    Iannitti, Tommaso; Palmieri, Beniamino; Aspiro, Anna; Di Cerbo, Alessandro

    2014-01-01

    Background Hyperhidrosis is a chronic disease characterized by increased sweat production. Local injections of botulinum toxin A (BTX-A) have been extensively used for treatment of primary hyperhidrosis (idiopathic). The current treatment for this condition involves several intradermal injections, resulting in poor patient compliance due to injection-related pain. Therefore, new protocols, including an improved anesthetic regimen, are required. Aim We designed the present study to determine whether JetPeel™-3, a medical device used for transdermal delivery of drugs by jet nebulization, could be used to deliver lidocaine prior to the standard multiple BTX-A injections or deliver lidocaine together with BTX-A in order to determine the protocol giving better results in terms of procedure-related pain, sweating, and patient satisfaction in subjects affected by primary axillary, palmar or plantar hyperhidrosis. Materials and methods Twenty patients with a visual analog scale (VAS) sweating score ≥ 8 cm were randomized to receive lidocaine 2% (5 mL) delivered by JetPeel™-3 followed by multiple injections of BTX-A (100 units) or lidocaine 2% (5 mL) and BTX-A (50 units) delivered together by JetPeel™-3. Effect of treatment on sweating was measured by VAS (0= minimum sweating; 10= maximum sweating) at 3-month follow-up. Pain induced by the procedure was assessed by VAS (0= minimum pain; 10= maximum pain) immediately after the procedure. Patient satisfaction was assessed at 3-month follow-up using a 5-point scale (1= not at all satisfied; 2= not satisfied; 3= partially satisfied; 4= satisfied; 5= highly satisfied). Results Both treatment modalities reduced sweating at 3-month follow-up, if compared with baseline (all P<0.001). Delivery of lidocaine and BTX-A by JetPeel™-3 resulted in lower procedure-related pain and reduced sweating, if compared with lidocaine delivered by JetPeel™-3 followed by multiple BTX-A injections (all P<0.001). Patient satisfaction with

  19. Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain.

    PubMed

    Manda, Prashanth; Kushwaha, Avadhesh Singh; Kundu, Santanu; Shivakumar, H N; Jo, Seong Bong; Murthy, S Narasimha

    2016-02-28

    The purpose of the current study was to investigate the plausibility of delivery of ziconotide to the cerebrospinal fluid (CSF) via intranasal administration. Ziconotide was administered either in the form of solution or Kolliphor P 407 gels (KP 407) intranasally in Sprague-Dawley rats. The effect of incorporation of chitosan in the formulation was also investigated. Time course of drug in the CSF was investigated by collecting CSF from cisterna magna. Pharmacokinetics of ziconotide in CSF following intrathecal and intravenous (i.v.) administration of ziconotide was investigated. Upon intrathecal administration the elimination rate constant of ziconotide in CSF was found to be 1.01±0.34h(-1). The Cmax and Tmax of ziconotide in CSF following intravenous administration were found to be 37.78±6.8ng/mL and ~2h respectively. The time required to attain maximum concentration (Tmax) in CSF was less upon intranasal administration (15min) compared to i.v. administration (120min). Presence of chitosan enhanced the overall bioavailability of ziconotide from intranasal solution and gel formulations. The elimination rate constant of ziconotide in CSF following intranasal and intravenous administration of ziconotide solution was found to be 0.54±0.08h(-1) and 0.42±0.10h(-1) respectively. Whereas, intranasal administration of ziconotide in the form of in situ forming gel lowered the elimination rate significantly. These results suggest that intranasal administration could be a potential noninvasive and patient compliant method of delivering ziconotide to CSF to treat chronic pain.

  20. Tea nanoparticles for immunostimulation and chemo-drug delivery in cancer treatment.

    PubMed

    Yi, Sijia; Wang, Yongzhong; Huang, Yujian; Xia, Lijin; Sun, Leming; Lenaghan, Scott C; Zhang, Mingjun

    2014-06-01

    Many health benefits have been associated with tea consumption. In an effort to elucidate the source of these health benefits, numerous phytochemicals have been extracted from tea infusions, some of which have demonstrated promise as clinical therapeutics for cancer therapy. Considering the advantageous properties of organic nanoparticles, the purpose of this study is to develop a method for isolating nanoparticles from tea leaves, and explore potential biomedical applications for these nanoparticles. First, an infusion-dialysis procedure for isolating tea nanoparticles (TNPs) from green tea infusions is developed. Second, atomic force microscopy and scanning electron microscopy reveal that the TNPs are spherical with diameters of 100-300 nm. Third, electrophoretic light scattering is used to determine that the TNPs have a zeta potential of -26.52 mV at pH 7.0. Finally, chemical analysis demonstrates that (-) Epigallocatechin gallate, caffeine, and theobromine are not found in the TNPs. Interestingly, the TNPs do enhance the in vitro secretion of cytokines IL-6, TNF-alpha, and G-CSF, as well as the chemokines RANTES, IP-10, MDC from mouse macrophages RAW264.7, indicating an immunostimulatory effect. As a nanocarrier, the TNPs are able to form complexes with doxorubicin (DOX) and have the potential for applications in drug delivery. Further the DOX-loaded TNPs increase the cellular DOX uptake, compared to free DOX, leading to higher cytotoxicity in the A549 human lung cancer and MCF-7 breast cancer cells. More importantly, the DOX-loaded TNPs significantly increase the DOX uptake and cytotoxicity in MCF-7/ADR multidrug resistant breast cancer cells. In this work, an infusion-dialysis procedure is developed for isolation of the TNPs from green tea, and the potential of these nanoparticles as a multifunctional nanocarrier for cancer therapy in vitro is explored.

  1. Dual drug delivery of tamoxifen and quercetin: Regulated metabolism for anticancer treatment with nanosponges.

    PubMed

    Lockhart, Jacob N; Stevens, David M; Beezer, Dain B; Kravitz, Ariel; Harth, Eva

    2015-12-28

    We report the synthesis and encapsulation of polyester nanosponge particles (NPs) co-loaded with tamoxifen (TAM) and quercetin (QT) to investigate the loading, release and in vitro metabolism of a dual drug formulation. The NPs are made in two variations, 4% and 8% crosslinking densities, to evaluate the effects on metabolism and release kinetics. The NP-4% formulation with a particle size of 89.3 ± 14.8 nm was found to have loading percentages of 6.91 ± 0.13% TAM and 7.72 ± 0.15% QT after targeting 10% (w/w) each. The NP-8% formulation with a particle size of 91.5 ± 9.8 nm was found to have loading percentages of 7.26 ± 0.10% TAM and 7.80 ± 0.12% QT. The stability of the formulation was established in simulated gastrointestinal fluids, and the metabolism of TAM was shown to be reduced 2-fold and 3-fold for NP-4%s and NP-8%s, respectively, while QT metabolism was reduced 3 and 4-fold. The implications for improved bioavailability of the NP formulations were supported by cytotoxicity results that showed a similar efficacy to free dual drug formulations and even enhanced anti-cancer effects in the recovery condition. This work demonstrates the suitability of the nanosponges not only as a dual release drug delivery system but also enabling a regulated metabolism through the capacity of a nanonetwork. The variation in crosslinking enables a dual release with tailored release kinetics and suggests improved bioavailability aided by a reduced metabolism.

  2. Long-Term Effects of Methylphenidate Transdermal Delivery System Treatment of ADHD on Growth

    ERIC Educational Resources Information Center

    Faraone, Stephen V.; Giefer, Eldred E.

    2007-01-01

    Objective: To examine the long-term effects of the methylphenidate transdermal system (MTS) on the growth of children being treated for attention-deficit/hyperactivity disorder. Method: Height, weight, and body mass index (BMI) were measured in 127 children ages 6 to 12 at longitudinal assessments for up to 36 months of treatment with MTS. These…

  3. Early Intervention and Treatment Acceptability: Multiple Perspectives for Improving Service Delivery in Home Settings.

    ERIC Educational Resources Information Center

    Paget, Kathleen D.

    1991-01-01

    This article examines issues related to treatment acceptability in early intervention programs, by applying concepts pertaining to collaboration, cultural difference, compliance and freedom of choice, family life cycles, and systems theory. A paradigm for designing home-based intervention plans with families of preschoolers with behavior disorders…

  4. SU-E-P-25: Evaluation of Motion in Pancreas SBRT Treatment Deliveries

    SciTech Connect

    Xiong, L; Halvorsen, P

    2015-06-15

    Purpose: Stereotactic Body Radiation Therapy (SBRT) procedures for pancreatic cancer present a challenge in motion management because the target is directly adjacent to critical structures and the target is subject to significant respiratory motion. Gated treatment is usually planned with a tight (few mm) PTV margin. The positioning and setup relies on on-board-imaging (OBI) of internal fiducials. This study evaluates the corrections for inter- and intra-fractional target motion as evidenced by the OBI. Methods: 20 patients with gated pancreas SBRT treatment were setup with KV imaging guidance before and during each treatment. The couch position was fine-tuned to align with the internal fiducials for each patient. The data for 148 intra- and 111 inter-fractional couch movements were captured and analyzed. Results: The mean ± standard deviation of couch shifts for the initial daily setup is 4.9±4.1 mm for couch vertical, 5.3±4.6 mm for couch longitudinal, and 3.7±4.0 mm for couch lateral. The mean ± standard deviation of intra-treatment adjustments are 1.1±1.6, 2.5±3.8, and 1.1±1.8 mm for couch vertical, longitudinal and lateral. The probability of intra-fractional motion in the three orthogonal directions with magnitude no more than 2 mm, 3 mm and 5 mm is 55%, 68% and 84% respectively. Conclusion: The intra-treatment target motion for pancreas SBRT patients indicates that a PTV margin of 5mm may be necessary.

  5. Nanotechnology-based drug delivery treatments and specific targeting therapy for age-related macular degeneration.

    PubMed

    Lin, Tai-Chi; Hung, Kuo-Hsuan; Peng, Chi-Hsien; Liu, Jorn-Hon; Woung, Lin-Chung; Tsai, Ching-Yao; Chen, Shih-Jen; Chen, Yan-Ting; Hsu, Chih-Chien

    2015-11-01

    Nanoparticles combined with cells, drugs, and specially designed genes provide improved therapeutic efficacy in studies and clinical setting, demonstrating a new era of treatment strategy, especially in retinal diseases. Nanotechnology-based drugs can provide an essential platform for sustaining, releasing and a specific targeting design to treat retinal diseases. Poly-lactic-co-glycolic acid is the most widely used biocompatible and biodegradable polymer approved by the Food and Drug Administration. Many studies have attempted to develop special devices for delivering small-molecule drugs, proteins, and other macromolecules consistently and slowly. In this article, we first review current progress in the treatment of age-related macular degeneration. Then, we discuss the function of vascular endothelial growth factor (VEGF) and the pharmacological effects of anti-VEGF-A antibodies and soluble or modified VEGF receptors. Lastly, we summarize the combination of antiangiogenic therapy and nanomedicines, and review current potential targeting therapy in age-related macular degeneration.

  6. Targeted Delivery of Therapeutic Oligonucleotides for the Treatment of Prostate Cancer

    DTIC Science & Technology

    2004-05-01

    ODN were entrapped in a lipid vector that was 200 stable in human plasma. This involves the formation in 0. Im= and extraction of cationic lipid/ODN...more pro- (8) Cumin , F., Asselbergs, F., Lartigot, M., and Felder, E. (1993) nounced with increasing amounts of ceramide PEG Modulation of human...oligonucleotides, Mol.Pharmacol. 41 (1992) 1023-1033. treatment. A much lower dose of DOX was re- [4] F. Cumin , F. Asselbergs, M. Lartigot, E. Felder

  7. An adaptive drug delivery design using neural networks for effective treatment of infectious diseases: a simulation study.

    PubMed

    Padhi, Radhakant; Bhardhwaj, Jayender R

    2009-06-01

    An adaptive drug delivery design is presented in this paper using neural networks for effective treatment of infectious diseases. The generic mathematical model used describes the coupled evolution of concentration of pathogens, plasma cells, antibodies and a numerical value that indicates the relative characteristic of a damaged organ due to the disease under the influence of external drugs. From a system theoretic point of view, the external drugs can be interpreted as control inputs, which can be designed based on control theoretic concepts. In this study, assuming a set of nominal parameters in the mathematical model, first a nonlinear controller (drug administration) is designed based on the principle of dynamic inversion. This nominal drug administration plan was found to be effective in curing "nominal model patients" (patients whose immunological dynamics conform to the mathematical model used for the control design exactly. However, it was found to be ineffective in curing "realistic model patients" (patients whose immunological dynamics may have off-nominal parameter values and possibly unwanted inputs) in general. Hence, to make the drug delivery dosage design more effective for realistic model patients, a model-following adaptive control design is carried out next by taking the help of neural networks, that are trained online. Simulation studies indicate that the adaptive controller proposed in this paper holds promise in killing the invading pathogens and healing the damaged organ even in the presence of parameter uncertainties and continued pathogen attack. Note that the computational requirements for computing the control are very minimal and all associated computations (including the training of neural networks) can be carried out online. However it assumes that the required diagnosis process can be carried out at a sufficient faster rate so that all the states are available for control computation.

  8. Patient Satisfaction with HIV/AIDS Care and Treatment in the Decentralization of Services Delivery in Vietnam

    PubMed Central

    Tran, Bach Xuan; Nguyen, Nhung Phuong Thi

    2012-01-01

    Objective We evaluated the patient satisfaction with HIV/AIDS care and treatment and its determinants across levels of health service administration in Vietnam. Methods We interviewed 1016 patients at 7 hospitals and health centers in three epicenters, including Hanoi, Hai Phong, and Ho Chi Minh City. The Satisfaction with HIV/AIDS Treatment Interview Scale (SATIS) was developed, and 3 dimensions were constructed using factor analysis, namely “Quality and Convenience”; “Availability and Responsiveness”; and “Competence of health care workers”. Results In a band score of (0; 10), the mean scores of all domains were large; it was the highest in “Competence of health workers” (9.34±0.84), and the lowest in “Quality and Convenience” (9.03±1.04). The percentages of respondents completely satisfied with overall service quality and treatment outcomes were 42.4% and 18.8%, respectively. In multivariate analysis, factors related to higher satisfaction included female sex, older age, and living with spouses or partners. Meanwhile, lower satisfaction was found among patients who were attending provincial and district clinics; in the richest group; had higher CD4 count; and drug users. Conclusion This study highlights the importance of improving the quality of HIV/AIDS services at the provincial and district clinics. Potential strategies include capacity building for health workers, integrative service delivery, engagements of family members in treatment supports, and additional attention and comprehensive care for drug users with HIV/AIDS. PMID:23071611

  9. Evaluation of the biological differences of canine and human factor VIII in gene delivery: implications in human hemophilia treatment

    PubMed Central

    Wang, Qizhao; Dong, Biao; Firrman, Jenni; Wu, Wenman; Roberts, Sean; Moore, Andrea Rossi; Liu, LinShu; Chin, Mario P.S.; Diao, Yong; Kost, Joseph; Xiao, Weidong

    2016-01-01

    The canine is the most important large animal model for testing novel hemophilia A(HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, the different biological properties between cFVIII and human FVIII(hFVIII) indicated that the development of novel HA treatment may require careful characterization of non-human FVIII. To investigate whether the data obtained using cFVIII can translate to HA treatment in human, we analyzed the differential biological properties of canine heavy chain (cHC) and light chain (cLC) by comparing with human HC (hHC) and LC (hLC). The secretion of cHC was 5~30 fold higher than hHC, with or without LCs. cHC+hLC group exhibited ~18-fold increase in coagulation activity compared with hHC+hLC delivery by recombinant adeno-associated viral vectors. Unlike hHC, the secretion of cHC was independent of LCs. cLC improves the specific activity of FVIII by 2~3-fold compared with hLC. Moreover, the cLC but not cHC, contributes the high stability of cFVIII. Our results suggested that the cFVIII expression results in the canine model should be interpreted with caution as the cHC secreted more efficiently than hHC and cLC exhibited a more active and stable phenotype than hLC. PMID:27064790

  10. Evaluation of the biological differences of canine and human factor VIII in gene delivery: implications in human hemophilia treatment.

    PubMed

    Wang, Q; Dong, B; Firrman, J; Wu, W; Roberts, S; Moore, A R; Liu, L S; Chin, M P S; Diao, Y; Kost, J; Xiao, W

    2016-07-01

    The canine is the most important large animal model for testing novel hemophilia A (HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, different biological properties between cFVIII and human FVIII (hFVIII) indicated that the development of novel HA treatment may require careful characterization of non-human FVIII. To investigate whether the data obtained using cFVIII can translate to HA treatment in human, we analyzed the differential biological properties of canine heavy chain (cHC) and light chain (cLC) by comparing with human heavy chain (hHC) and light chain (hLC). The secretion of cHC was 5-30-fold higher than hHC, with or without light chains (LCs). cHC+hLC group exhibited ~18-fold increase in coagulation activity compared with hHC+hLC delivery by recombinant adeno-associated viral vectors. Unlike hHC, the secretion of cHC was independent of LCs. cLC improves the specific activity of FVIII by two- to threefold compared with hLC. Moreover, the cLC, but not cHC, contributes to the higher stability of cFVIII. Our results suggested that the cFVIII expression results in the canine model should be interpreted with caution as the cHC secreted more efficiently than hHC and cLC exhibited a more active and stable phenotype than hLC.

  11. Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model

    PubMed Central

    Ware, Matthew J.; Krzykawska-Serda, Martyna; Chak-Shing Ho, Jason; Newton, Jared; Suki, Sarah; Law, Justin; Nguyen, Lam; Keshishian, Vazrik; Serda, Maciej; Taylor, Kimberly; Curley, Steven A.; Corr, Stuart J.

    2017-01-01

    Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30–40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors. PMID:28287120

  12. Near-infrared light triggered drug delivery system for higher efficacy of combined chemo-photothermal treatment.

    PubMed

    Chen, Yi; Li, Haohuan; Deng, Yueyang; Sun, Haifeng; Ke, Xue; Ci, Tianyuan

    2017-03-15

    The combination of chemotherapy and photothermal therapy is a promising strategy for cancer treatment. In the present study, indocyanine green (ICG), a widely used near-infrared (NIR) dye in photothermal therapy, and chemotherapeutic drug-doxorubicin (DOX) were loaded within the nanoparticles of novel designed arylboronic ester and cholesterol modified hyaluronic acid (PPE-Chol1-HA), denoted as PCH-DI. We take advantage of reactive oxygen species (ROS) production capability of ICG and ROS-sensitivity of arylboronic ester to realize controllable drug release. It was confirmed that PCH-DI exhibited remarkable photothermal effect and light-triggered faster release of DOX with NIR laser irradiation. DOX in PCH-DI/Laser group exhibited the most efficient nucleus binding toward HCT-116 colon cells in vitro. Furthermore, enhanced cytotoxicity and promoted tumor growth suppression effect of PCH-DI on HCT-116 tumor xenograft nude mice and AOM-induced murine orthotopic colorectal cancer model was achieved under NIR laser irradiation. Thus, the co-delivery system based on PCH appears to be a promising platform for the combined chemo-photothermal therapy in tumor treatment.

  13. Dual-functional transdermal drug delivery system with controllable drug loading based on thermosensitive poloxamer hydrogel for atopic dermatitis treatment

    NASA Astrophysics Data System (ADS)

    Wang, Wenyi; Wat, Elaine; Hui, Patrick C. L.; Chan, Ben; Ng, Frency S. F.; Kan, Chi-Wai; Wang, Xiaowen; Hu, Huawen; Wong, Eric C. W.; Lau, Clara B. S.; Leung, Ping-Chung

    2016-04-01

    The treatment of atopic dermatitis (AD) has long been viewed as a problematic issue by the medical profession. Although a wide variety of complementary therapies have been introduced, they fail to combine the skin moisturizing and drug supply for AD patients. This study reports the development of a thermo-sensitive Poloxamer 407/Carboxymethyl cellulose sodium (P407/CMCs) composite hydrogel formulation with twin functions of moisture and drug supply for AD treatment. It was found that the presence of CMCs can appreciably improve the physical properties of P407 hydrogel, which makes it more suitable for tailored drug loading. The fabricated P407/CMCs composite hydrogel was also characterized in terms of surface morphology by field emission scanning electron microscopy (FE-SEM), rheological properties by a rheometer, release profile in vitro by dialysis method and cytotoxicity test. More importantly, the findings from transdermal drug delivery behavior revealed that P407/CMCs showed desirable percutaneous performance. Additionally, analysis of cytotoxicity test suggested that P407/CMCs composite hydrogel is a high-security therapy for clinical trials and thus exhibits a promising way to treat AD with skin moisturizing and medication.

  14. Dual-functional transdermal drug delivery system with controllable drug loading based on thermosensitive poloxamer hydrogel for atopic dermatitis treatment

    PubMed Central

    Wang, Wenyi; Wat, Elaine; Hui, Patrick C. L.; Chan, Ben; Ng, Frency S. F.; Kan, Chi-Wai; Wang, Xiaowen; Hu, Huawen; Wong, Eric C. W.; Lau, Clara B. S.; Leung, Ping-Chung

    2016-01-01

    The treatment of atopic dermatitis (AD) has long been viewed as a problematic issue by the medical profession. Although a wide variety of complementary therapies have been introduced, they fail to combine the skin moisturizing and drug supply for AD patients. This study reports the development of a thermo-sensitive Poloxamer 407/Carboxymethyl cellulose sodium (P407/CMCs) composite hydrogel formulation with twin functions of moisture and drug supply for AD treatment. It was found that the presence of CMCs can appreciably improve the physical properties of P407 hydrogel, which makes it more suitable for tailored drug loading. The fabricated P407/CMCs composite hydrogel was also characterized in terms of surface morphology by field emission scanning electron microscopy (FE-SEM), rheological properties by a rheometer, release profile in vitro by dialysis method and cytotoxicity test. More importantly, the findings from transdermal drug delivery behavior revealed that P407/CMCs showed desirable percutaneous performance. Additionally, analysis of cytotoxicity test suggested that P407/CMCs composite hydrogel is a high-security therapy for clinical trials and thus exhibits a promising way to treat AD with skin moisturizing and medication. PMID:27090158

  15. Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model

    NASA Astrophysics Data System (ADS)

    Ware, Matthew J.; Krzykawska-Serda, Martyna; Chak-Shing Ho, Jason; Newton, Jared; Suki, Sarah; Law, Justin; Nguyen, Lam; Keshishian, Vazrik; Serda, Maciej; Taylor, Kimberly; Curley, Steven A.; Corr, Stuart J.

    2017-03-01

    Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30–40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors.

  16. Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model.

    PubMed

    Ware, Matthew J; Krzykawska-Serda, Martyna; Chak-Shing Ho, Jason; Newton, Jared; Suki, Sarah; Law, Justin; Nguyen, Lam; Keshishian, Vazrik; Serda, Maciej; Taylor, Kimberly; Curley, Steven A; Corr, Stuart J

    2017-03-13

    Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30-40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors.

  17. Polymers in the Co-delivery of siRNA and Anticancer Drugs for the Treatment of Drug-resistant Cancers.

    PubMed

    Sun, Haotian; Yarovoy, Iven; Capeling, Meghan; Cheng, Chong

    2017-04-01

    Recently, co-delivery of siRNA and anticancer drugs has drawn much attention in the treatment of drug-resistant cancers. Drug resistance is exhibited by cancer cells, which limits the efficacy of chemotherapy. When siRNA and anticancer drugs are delivered into cancer cells simultaneously, the siRNA is expected to silence the genes related to drug resistance, decreasing the drug efflux pumps and activating the cell's apoptosis pathways. In a timeframe following the release of siRNA, the accumulation of the co-delivered anti-cancer drug inside of the cancer cells will increase, resulting in promoted chemotherapeutic effects. Several classes of nanocarriers have been designed based on polymers for co-delivery, including surface-modified polymer nanoparticles (NPs), polymer micelles, dendrimers, polymer nanocapsules, polymer-modified liposomes, and polymer-modified silica and gold NPs. Compared with separate delivery, co-delivery showed significant advantages in the treatment of drug-resistant cancers. This review focuses on polymers in the co-delivery of siRNA and anticancer drugs, and summarizes key advances in the recent several years.

  18. Intrafraction tumor motion management techniques in imaging, treatment planning, and IMRT delivery

    NASA Astrophysics Data System (ADS)

    Ehler, Eric Drew

    Anatomic motion can affect the radiation treatment of disease sites in the thorax and abdomen. With four dimensional (4D) imaging modalities, respiratory motion can be defined on a patient specific basis. From 4D data sets, radiotherapy techniques can be devised to account for tissue motion. Systematic and random uncertainties must be characterized for each 4D imaging modality utilized. Some modalities, such as 4D-CT, require multiple motion trajectories in order to fully define the uncertainties associated with the imaging system. This is investigated in this work for a clinical 4D-CT scanning protocol and the methods used can be applied to any 4D imaging modality. Once all of the relevant tissues and their associated motion have been defined, with corrections to account for any associated uncertainties in the 4D data sets, treatment plans can be generated. For lung cancer, unique challenges arise when inverse planning is used, typically in the case of IMRT, because density differences between lung tissue and other tissues can result in quite different dose distributions. Because inverse planning is an optimization algorithm, the degree of optimization is dependent on the input parameters. One important input factor is the image set that is used for the dose calculation. For three image sets supplied to a commercial inverse planning algorithm (Average Image and an exhale phase image with motion envelope defined from a maximum intensity projection image, both with and without a density override to the motion envelope), dose calculated on the Average Image was found to be in best agreement with the dose calculated on the 4D-CT. Finally, when IMRT is delivered to mobile tumors, it is possible for the dose to the tumor to vary from treatment to treatment. Therefore, numerous methods have been investigated in order to reduce this variation. A computer simulation algorithm has been developed to predict the variation on a two spatial dimension plane and comparisons are

  19. New scanner fiber optic delivery system for laser phototherapy in the treatment of neonatal jaundice

    NASA Astrophysics Data System (ADS)

    Hamza, Mostafa; Hamza, Mohammad S. E.

    1995-05-01

    The authors have introduced laser phototherapy for the treatment of neonatal jaundice. Clinical trials have demonstrated its high efficacy compared to the conventionally used fluorescent phototherapy. In this paper a new modification to laser irradiation in phototherapy can be achieved by scanning the laser output beam in the selected wavelength of irradiation (488 nm) through a fiberoptic bundle which irradiate the skin of the baby. Scanning of the laser beam provides intermittent irradiation at high frequency, which can provide the same therapeutic efficacy with almost half the power of laser irradiation.

  20. Delivery of LLKKK18 loaded into self-assembling hyaluronic acid nanogel for tuberculosis treatment.

    PubMed

    Silva, João P; Gonçalves, Carine; Costa, César; Sousa, Jeremy; Silva-Gomes, Rita; Castro, António G; Pedrosa, Jorge; Appelberg, Rui; Gama, F Miguel

    2016-08-10

    Tuberculosis (TB), a disease caused by the human pathogen Mycobacterium tuberculosis, recently joined HIV/AIDS on the top rank of deadliest infectious diseases. Low patient compliance due to the expensive, long-lasting and multi-drug standard therapies often results in treatment failure and emergence of multi-drug resistant strains. In this scope, antimicrobial peptides (AMPs) arise as promising candidates for TB treatment. Here we describe the ability of the exogenous AMP LLKKK18 to efficiently kill mycobacteria. The peptide's potential was boosted by loading into self-assembling Hyaluronic Acid (HA) nanogels. These provide increased stability, reduced cytotoxicity and degradability, while potentiating peptide targeting to main sites of infection. The nanogels were effectively internalized by macrophages and the peptide presence and co-localization with mycobacteria within host cells was confirmed. This resulted in a significant reduction of the mycobacterial load in macrophages infected in vitro with the opportunistic M. avium or the pathogenic M. tuberculosis, an effect accompanied by lowered pro-inflammatory cytokine levels (IL-6 and TNF-α). Remarkably, intra-tracheal administration of peptide-loaded nanogels significantly reduced infection levels in mice infected with M. avium or M. tuberculosis, after just 5 or 10 every other day administrations. Considering the reported low probability of resistance acquisition, these findings suggest a great potential of LLKKK18-loaded nanogels for TB therapeutics.

  1. Double layer adhesive silicone dressing as a potential dermal drug delivery film in scar treatment.

    PubMed

    Mojsiewicz-Pieńkowska, Krystyna; Jamrógiewicz, Marzena; Żebrowska, Maria; Mikolaszek, Barbara; Sznitowska, Małgorzata

    2015-03-15

    The present studies focused on the evaluation of design of an adhesive silicone film intended for scar treatment. Developed silicone double layer film was examined in terms of its future relevance to therapy and applicability on the human skin considering properties which included in vitro permeability of water vapor and oxygen. In order to adapt the patches for medical use in the future there were tested such properties as in vitro adhesion and occlusion related to in vivo hydration. From the silicone rubbers double layer silicone film was prepared: a non-adhesive elastomer as a drug carrier (the matrix for active substances - enoxaparin sodium - low molecular weight heparin) and an adhesive elastomer, applied on the surface of the matrix. The novel adhesive silicone film was found to possess optimal properties in comparison to commercially available silicone dressing: adhesion in vivo, adhesion in vitro - 11.79N, occlusion F=85% and water vapor permeability in vitro - WVP=105g/m(2)/24h, hydration of stratum corneum in vivoH=61-89 (RSD=1.6-0.9%), oxygen permeation in vitro - 119-391 cm(3)/m(2)/24 (RSD=0.17%). In vitro release studies indicated sufficient LMWH release rate from silicone matrix. Developed novel adhesive silicone films were considered an effective treatment of scars and keloids and a potential drug carrier able to improve the effectiveness of therapy.

  2. A Highly Accurate Technique for the Treatment of Flow Equations at the Polar Axis in Cylindrical Coordinates using Series Expansions. Appendix A

    NASA Technical Reports Server (NTRS)

    Constantinescu, George S.; Lele, S. K.

    2001-01-01

    Numerical methods for solving the flow equations in cylindrical or spherical coordinates should be able to capture the behavior of the exact solution near the regions where the particular form of the governing equations is singular. In this work we focus on the treatment of these numerical singularities for finite-differences methods by reinterpreting the regularity conditions developed in the context of pseudo-spectral methods. A generally applicable numerical method for treating the singularities present at the polar axis, when nonaxisymmetric flows are solved in cylindrical, coordinates using highly accurate finite differences schemes (e.g., Pade schemes) on non-staggered grids, is presented. Governing equations for the flow at the polar axis are derived using series expansions near r=0. The only information needed to calculate the coefficients in these equations are the values of the flow variables and their radial derivatives at the previous iteration (or time) level. These derivatives, which are multi-valued at the polar axis, are calculated without dropping the accuracy of the numerical method using a mapping of the flow domain from (0,R)*(0,2pi) to (-R,R)*(0,pi), where R is the radius of the computational domain. This allows the radial derivatives to be evaluated using high-order differencing schemes (e.g., compact schemes) at points located on the polar axis. The proposed technique is illustrated by results from simulations of laminar-forced jets and turbulent compressible jets using large eddy simulation (LES) methods. In term of the general robustness of the numerical method and smoothness of the solution close to the polar axis, the present results compare very favorably to similar calculations in which the equations are solved in Cartesian coordinates at the polar axis, or in which the singularity is removed by employing a staggered mesh in the radial direction without a mesh point at r=0, following the method proposed recently by Mohseni and Colonius

  3. Intravenous route of cell delivery for treatment of neurological disorders: a meta-analysis of preclinical results.

    PubMed

    Janowski, Miroslaw; Walczak, Piotr; Date, Isao

    2010-01-01

    The last decade has been marked by a growing interest in an employment of intravenous cell delivery for treatment of neurological disorders. Numerous preclinical experimental studies have reported functional benefits, and have recently been followed by clinical trials. Some early clinical studies have indicated only modest positive effects, suggesting that the optimal conditions have not been defined yet. Thus, the evaluation of factors that influence outcomes, on the level of the whole population of preclinical studies by advanced statistical analysis, is warranted. PubMed search was conducted from the inception through 2006, and 60 preclinical studies were found and subjected to analysis. Categorical and continuous independent variables (IVs) were extracted. Three distinct outcomes of interest were selected as dependent variables (DVs) and named treatment effects: morphological, behavioral, and molecular, respectively. Mean outcomes, standard deviations (SDs), and animal numbers were retrieved and calculated by individual comparisons of experimental and control groups, based on the Hedges g formula, and were expressed as effect sizes (ESs) and variances. Publication bias and homogeneity were evaluated. The mainspring analyses were performed under a random effect model using Proc Mixed (SAS, version 9.2). A significant heterogeneity and publication bias were found. The ES pooling revealed large treatment effects. Univariate and multivariate meta-regression revealed that cell-related variables explained most of the heterogeneity. Cells retrieved from established lines and genetic modification of cells warrants the highest efficiency, in a dose-dependent manner. The stratified analysis of molecular effect measures revealed that apoptosis inhibition is the strongest brain tissue-positive change induced by cell therapy.

  4. Combined sonodynamic and antimetabolite therapy for the improved treatment of pancreatic cancer using oxygen loaded microbubbles as a delivery vehicle.

    PubMed

    McEwan, Conor; Kamila, Sukanta; Owen, Joshua; Nesbitt, Heather; Callan, Bridgeen; Borden, Mark; Nomikou, Nikolitsa; Hamoudi, Rifat A; Taylor, Mark A; Stride, Eleanor; McHale, Anthony P; Callan, John F

    2016-02-01

    In this manuscript we describe the preparation of an oxygen-loaded microbubble (O2MB) platform for the targeted treatment of pancreatic cancer using both sonodynamic therapy (SDT) and antimetabolite therapy. O2MB were prepared with either the sensitiser Rose Bengal (O2MB-RB) or the antimetabolite 5-fluorouracil (O2MB-5FU) attached to the microbubble (MB) surface. The MB were characterised with respect to size, physical stability and oxygen retention. A statistically significant reduction in cell viability was observed when three different pancreatic cancer cell lines (BxPc-3, MIA PaCa-2 and PANC-1), cultured in an anaerobic cabinet, were treated with both SDT and antimetabolite therapy compared to either therapy alone. In addition, a statistically significant reduction in tumour growth was also observed when ectopic human xenograft BxPC-3 tumours in SCID mice were treated with the combined therapy compared to treatment with either therapy alone. These results illustrate not only the potential of combined SDT/antimetabolite therapy as a stand alone treatment option in pancreatic cancer, but also the capability of O2-loaded MBs to deliver O2 to the tumour microenvironment in order to enhance the efficacy of therapies that depend on O2 to mediate their therapeutic effect. Furthermore, the use of MBs to facilitate delivery of O2 as well as the sensitiser/antimetabolite, combined with the possibility to activate the sensitiser using externally applied ultrasound, provides a more targeted approach with improved efficacy and reduced side effects when compared with conventional systemic administration of antimetabolite drugs alone.

  5. N-succinyl chitosan as buccal penetration enhancer for delivery of herbal agents in treatment of oral mucositis.

    PubMed

    Dhawan, Neha; Kumar, Krishan; Kalia, A N; Arora, Saahil

    2014-01-01

    Oral mucositis is one of the major side effects of cancer chemotherapy (30-76%) and radiotherapy (over 50%). Current palliative treatments of oral mucositis include specialized agents like pelifermin, platelet derived factors etc. or oral hygienic agents which suffered from various drawbacks like systemic side effect, least effect owing to fast wash out of buccal mucosa, patient unfriendly delivery systems, and mere symptomatic relief. In this research work, N-succinyl chitosan gel delivery system of microemulsified eugenol, honey and sodium hyaluronate was prepared to explore their multiple and synergistic effects on various pathological factors of oral mucositis. N-succinyl chitosan was synthesized in our laboratory and loaded with microemulsified eugenol (10% v/v), honey (10% v/v) and sodium hyaluronate (0.2% w/v) to prepare orogel with optimum pH, spreadability, mucoadhesion strength, and viscosity. In vitro eugenol release from N-succinyl chitosan gel after 8 hours in PBS (pH-6.4) was found to be 87.45±0.14%, which was better in comparison to that released from chitosan gel. Ex vivo penetration studies using rat buccal mucosal tissue also suggested better J-efflux of eugenol through N-succinyl chitosan in comparison to chitosan gel with enhancement ratio (ER) of 1.71. The antimicrobial effect of N-succinyl chitosan based orogel against S. aureus and C. albicans efficacy was found to be statistically high in comparison to chitosan based orogel as well as marketed formulation of chlorhexidine (p<0.05). The N-succinyl chitosan orogel in 5-fluoro uracil induced oral mucositis animal (Wistar rats) model showed enhanced survival ratio, weight gain and high tissue regeneration activity than chitosan gel formulation within 15 days. The formulation was successful in elevating the survival and reducing the inflammation in the oral mucosa of animals compared to disease control (p<0.05) and hence suggesting the potential of N-succinyl chitosan orogel in the treatment of

  6. Polarity-sensitive nanocarrier for oral delivery of Sb(V) and treatment of cutaneous leishmaniasis.

    PubMed

    Lanza, Juliane S; Fernandes, Flaviana R; Corrêa-Júnior, José D; Vilela, José Mc; Magalhães-Paniago, Rogério; Ferreira, Lucas Am; Andrade, Margareth S; Demicheli, Cynthia; Melo, Maria N; Frézard, Frédéric

    2016-01-01

    There is a great need for orally active drugs for the treatment of the neglected tropical disease leishmaniasis. Amphiphilic Sb(V) complexes, such as 1:3 Sb-N-octanoyl-N-methylglucamide complex (SbL8), are promising drug candidates. It has been previously reported that SbL8 forms kinetically stabilized nanoassemblies in water and that this simple dispersion exhibits antileishmanial activity when given by oral route to a murine model of visceral leishmaniasis. The main objective of the present work was to interfere in the structural organization of these nanoassemblies so as to investigate their influence on the oral bioavailability of Sb, and ultimately, optimize an oral formulation of SbL8 for the treatment of cutaneous leishmaniasis. The structural organization of SbL8 nanoassemblies was manipulated through addition of propylene glycol (PG) to the aqueous dispersion of SbL8. The presence of 50% (v/v) PG resulted in the loss of hydrophobic microenvironment, as evidenced by fluorescence probing. However, nanostructures were still present, as demonstrated by dynamic light scattering, small-angle X-ray scattering, and atomic force microscopy (AFM). A remarkable property of these nanoassemblies, as revealed by AFM analysis, is the flexibility of their supramolecular organization, which showed changes as a function of the solvent and substrate polarities. The formulation of SbL8 in 1:1 water:PG given orally to mice promoted significantly higher and more sustained serum levels of Sb, when compared to SbL8 in water. The new formulation, when given as repeated doses (200 mg Sb/kg/day) to BALB/c mice infected with Leishmania amazonensis, was significantly more effective in reducing the lesion parasite burden, compared to SbL8 in water, and even, the conventional drug Glucantime(®) given intraperitoneally at the same dose. In conclusion, this work introduces a new concept of polarity-sensitive nanocarrier that was successfully applied to optimize an oral formulation of Sb

  7. Polarity-sensitive nanocarrier for oral delivery of Sb(V) and treatment of cutaneous leishmaniasis

    PubMed Central

    Lanza, Juliane S; Fernandes, Flaviana R; Corrêa-Júnior, José D; Vilela, José MC; Magalhães-Paniago, Rogério; Ferreira, Lucas AM; Andrade, Margareth S; Demicheli, Cynthia; Melo, Maria N; Frézard, Frédéric

    2016-01-01

    There is a great need for orally active drugs for the treatment of the neglected tropical disease leishmaniasis. Amphiphilic Sb(V) complexes, such as 1:3 Sb–N-octanoyl-N-methylglucamide complex (SbL8), are promising drug candidates. It has been previously reported that SbL8 forms kinetically stabilized nanoassemblies in water and that this simple dispersion exhibits antileishmanial activity when given by oral route to a murine model of visceral leishmaniasis. The main objective of the present work was to interfere in the structural organization of these nanoassemblies so as to investigate their influence on the oral bioavailability of Sb, and ultimately, optimize an oral formulation of SbL8 for the treatment of cutaneous leishmaniasis. The structural organization of SbL8 nanoassemblies was manipulated through addition of propylene glycol (PG) to the aqueous dispersion of SbL8. The presence of 50% (v/v) PG resulted in the loss of hydrophobic microenvironment, as evidenced by fluorescence probing. However, nanostructures were still present, as demonstrated by dynamic light scattering, small-angle X-ray scattering, and atomic force microscopy (AFM). A remarkable property of these nanoassemblies, as revealed by AFM analysis, is the flexibility of their supramolecular organization, which showed changes as a function of the solvent and substrate polarities. The formulation of SbL8 in 1:1 water:PG given orally to mice promoted significantly higher and more sustained serum levels of Sb, when compared to SbL8 in water. The new formulation, when given as repeated doses (200 mg Sb/kg/day) to BALB/c mice infected with Leishmania amazonensis, was significantly more effective in reducing the lesion parasite burden, compared to SbL8 in water, and even, the conventional drug Glucantime® given intraperitoneally at the same dose. In conclusion, this work introduces a new concept of polarity-sensitive nanocarrier that was successfully applied to optimize an oral formulation of Sb

  8. One System Integrated Project Team: Retrieval and Delivery of Hanford Tank Wastes for Vitrification in the Waste Treatment Plant - 13234

    SciTech Connect

    Harp, Benton J.; Kacich, Richard M.; Skwarek, Raymond J.

    2013-07-01

    The One System Integrated Project Team (IPT) was formed in late 2011 as a way for improving the efficiency of delivery and treatment of highly radioactive waste stored in underground tanks at the U.S. Department of Energy's (DOE's) 586-square-mile Hanford Site in southeastern Washington State. The purpose of the One System IPT is to improve coordination and integration between the Hanford's Waste Treatment Plant (WTP) contractor and the Tank Operations Contractor (TOC). The vision statement is: One System is a WTP and TOC safety-conscious team that, through integrated management and implementation of risk-informed decision and mission-based solutions, will enable the earliest start of safe and efficient treatment of Hanford's tank waste, to protect the Columbia River, environment and public. The IPT is a formal collaboration between Bechtel National, Inc. (BNI), which manages design and construction of the WTP for the U.S. Department of Energy's Office of River Protection (DOEORP), and Washington River Protection Solutions (WRPS), which manages the TOC for ORP. More than fifty-six (56) million gallons of highly radioactive liquid waste are stored in one hundred seventy-seven (177) aging, underground tanks. Most of Hanford's waste tanks - one hundred forty-nine (149) of them - are of an old single-shell tank (SST) design built between 1944 and 1964. More than sixty (60) of these tanks have leaked in the past, releasing an estimated one million gallons of waste into the soil and threatening the nearby Columbia River. There are another twenty-eight (28) new double-shelled tanks (DSTs), built from 1968 to 1986, that provide greater protection to the environment. In 1989, DOE, the U.S. Environmental Protection Agency (EPA), and the Washington State Department of Ecology (Ecology) signed a landmark agreement that required Hanford to comply with federal and state environmental standards. It also paved the way for agreements that set deadlines for retrieving the tank

  9. One System Integrated Project Team: Retrieval And Delivery Of The Hanford Tank Wastes For Vitrification In The Waste Treatment Plant

    SciTech Connect

    Harp, Benton J.; Kacich, Richard M.; Skwarek, Raymond J.

    2012-12-20

    The One System Integrated Project Team (IPT) was formed in late 2011 as a way for improving the efficiency of delivery and treatment of highly radioactive waste stored in underground tanks at the U.S. Department of Energy's (DOE's) 586-square-mile Hanford Site in southeastern Washington State. The purpose of the One System IPT is to improve coordination and integration between the Hanford's Waste Treatment Plant (WTP) contractor and the Tank Operations Contractor (TOC). The vision statement is: One System is a WTP and TOC safety conscious team that, through integrated management and implementation of risk-informed decision and mission-based solutions, will enable the earliest start of safe and efficient treatment of Hanford's tank waste, to protect the Columbia River, environment and public. The IPT is a formal collaboration between Bechtel National, Inc. (BNI), which manages design and construction of the WTP for the U.S. Department of Energy's Office of River Protection (DOEORP), and Washington River Protection Solutions (WRPS), which manages the TOC for ORP. More than fifty-six (56) million gallons of highly radioactive liquid waste are stored in one hundred seventy-seven (177) aging, underground tanks. Most of Hanford's waste tanks - one hundred forty-nine (149) of them - are of an old single-shell tank (SST) design built between 1944 and 1964. More than sixty (60) of these tanks have leaked in the past, releasing an estimated one million gallons of waste into the soil and threatening the nearby Columbia River. There are another twenty-eight (28) new double-shelled tanks (DSTs), built from 1968 to 1986, that provide greater protection to the environment. In 1989, DOE, the U.S. Environmental Protection Agency (EPA), and the Washington State Department of Ecology (Ecology) signed a landmark agreement that required Hanford to comply with federal and state environmental standards. It also paved the way for agreements that set deadlines for retrieving the tank

  10. The impacts of dental filling materials on RapidArc treatment planning and dose delivery: Challenges and solution

    SciTech Connect

    Mail, Noor; Al-Ghamdi, S.; Saoudi, A.; Albarakati, Y.; Ahmad Khan, M.; Saeedi, F.; Safadi, N.

    2013-08-15

    Purpose: The presence of high-density material in the oral cavity creates dose perturbation in both downstream and upstream directions at the surfaces of dental filling materials (DFM). In this study, the authors have investigated the effect of DFM on head and neck RapidArc treatment plans and delivery. Solutions are proposed to address (1) the issue of downstream dose perturbation, which might cause target under dosage, and (2) to reduce the upstream dose from DFM which may be the primary source of mucositis. In addition, an investigation of the clinical role of a custom-made plastic dental mold/gutter (PDM) in sparing the oral mucosa and tongue reaction is outlined.Methods: The influence of the dental filling artifacts on dose distribution was investigated using a geometrically well-defined head and neck intensity modulated radiation therapy (IMRT) verification phantom (PTW, Freiberg, Germany) with DFM inserts called amalgam, which contained 50% mercury, 25% silver, 14% tin, 8% copper, and 3% other trace metals. Three RapidArc plans were generated in the Varian Eclipse System to treat the oral cavity using the same computer tomography (CT) dataset, including (1) a raw CT image, (2) a streaking artifacts region, which was replaced with a mask of 10 HU, and (3) a 2 cm-thick 6000 HU virtual filter [a volume created in treatment planning system to compensate for beam attenuation, where the thickness of this virtual filter is based on the measured percent depth dose (PDD) data and Eclipse calculation]. The dose delivery for the three plans was verified using Gafchromic-EBT2 film measurements. The custom-made PDM technique to reduce backscatter dose was clinically tested on four head and neck cancer patients (T3, N1, M0) with DFM, two patients with PDM and the other two patients without PDM. The thickness calculation of the PDM toward the mucosa and tongue was purely based on the measured upstream dose. Patients’ with oral mucosal reaction was clinically examined

  11. Antibiotic treatment at delivery shapes the initial oral microbiome in neonates

    PubMed Central

    Gomez-Arango, Luisa F.; Barrett, Helen L.; McIntyre, H. David.; Callaway, Leonie K.; Morrison, Mark; Dekker Nitert, Marloes

    2017-01-01

    Oral microorganisms are important determinants of health and disease. The source of the initial neonatal microbiome and the factors dictating initial human oral microbiota development are unknown. This study aimed to investigate this in placental, oral and gut microbiome profiles from 36 overweight or obese mother-baby dyads as determined by 16S rRNA sequencing. Expression of five antibiotic resistance genes of the β-lactamase class was analysed in the infant oral microbiota samples by QPCR. The neonatal oral microbiota was 65.35% of maternal oral, 3.09% of placental, 31.56% of unknown and 0% of maternal gut origin. Two distinct neonatal oral microbiota profiles were observed: one strongly resembling the maternal oral microbiota and one with less similarity. Maternal exposure to intrapartum antibiotics explained the segregation of the profiles. Families belonging to Proteobacteria were abundant after antibiotics exposure while the families Streptococcaceae, Gemellaceae and Lactobacillales dominated in unexposed neonates. 26% of exposed neonates expressed the Vim-1 antibiotic resistance gene. These findings indicate that maternal intrapartum antibiotic treatment is a key regulator of the initial neonatal oral microbiome. PMID:28240736

  12. Brain-Delivery of Zinc-Ions as Potential Treatment for Neurological Diseases: Mini Review

    PubMed Central

    Grabrucker, Andreas M.; Rowan, Magali; Garner, Craig C.

    2011-01-01

    Homeostasis of metal ions such as Zn2+ is essential for proper brain function. Moreover, the list of psychiatric and neurodegenerative disorders involving a dysregulation of brain Zn2+-levels is long and steadily growing, including Parkinson’s and Alzheimer’s disease as well as schizophrenia, attention deficit and hyperactivity disorder, depression, amyotrophic lateral sclerosis, Down's syndrome, multiple sclerosis, Wilson’s disease and Pick’s disease. Furthermore, alterations in Zn2+-levels are seen in transient forebrain ischemia, seizures, traumatic brain injury and alcoholism. Thus, the possibility of altering Zn2+-levels within the brain is emerging as a new target for the prevention and treatment of psychiatric and neurological diseases. Although the role of Zn2+ in the brain has been extensively studied over the past decades, methods for controlled regulation and manipulation of Zn2+ concentrations within the brain are still in their infancy. Since the use of dietary Zn2+ supplementation and restriction has major limitations, new methods and alternative approaches are currently under investigation, such as the use of intracranial infusion of Zn2+ chelators or nanoparticle technologies to elevate or decrease intracellular Zn2+ levels. Therefore, this review briefly summarizes the role of Zn2+ in psychiatric and neurodegenerative diseases and highlights key findings and impediments of brain Zn2+-level manipulation. Furthermore, some methods and compounds, such as metal ion chelation, redistribution and supplementation that are used to control brain Zn2+-levels in order to treat brain disorders are evaluated. PMID:22102982

  13. Skeletal Muscle in Motor Neuron Diseases: Therapeutic Target and Delivery Route for Potential Treatments

    PubMed Central

    Dupuis, Luc; Echaniz-Laguna, Andoni

    2010-01-01

    Lower motor neuron (LMN) degeneration occurs in several diseases that affect patients from neonates to elderly and can either be genetically transmitted or occur sporadically. Among diseases involving LMN degeneration, spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (Kennedy’s disease, SBMA) are pure genetic diseases linked to loss of the SMN gene (SMA) or expansion of a polyglutamine tract in the androgen receptor gene (SBMA) while amyotrophic lateral sclerosis (ALS) can either be of genetic origin or occur sporadically. In this review, our aim is to put forward the hypothesis that muscle fiber atrophy and weakness might not be a simple collateral damage of LMN degeneration, but instead that muscle fibers may be the site of crucial pathogenic events in these diseases. In SMA, the SMN gene was shown to be required for muscle structure and strength as well as for neuromuscular junction formation, and a subset of SMA patients develop myopathic pathology. In SBMA, the occurence of myopathic histopathology in patients and animal models, along with neuromuscular phenotype of animal models expressing the androgen receptor in muscle only has lead to the proposal that SBMA may indeed be a muscle disease. Lastly, in ALS, at least part of the phenotype might be explained by pathogenic events occuring in skeletal muscle. Apart from its potential pathogenic role, skeletal muscle pathophysiological events might be a target for treatments and/or be a preferential route for targeting motor neurons. PMID:20840067

  14. Reactor beam calculations to determine optimum delivery of epithermal neutrons for treatment of brain tumors

    SciTech Connect

    Wheeler, F.J.; Nigg, D.W.; Capala, J.

    1997-10-01

    Studies were performed to assess theoretical tumor control probability (TCP) for brain-tumor treatment with boron neutron capture therapy (BNCT) using epithermal neutron sources from reactors. The existing epithermal-neutron beams at the Brookhaven Medical Research Reactor Facility (BMRR), the Petten High Flux Reactor Facility (HWR) and the Finnish Research Reactor 1 (FIR1) have been analyzed and characterized using common analytical and measurement methods allowing for this inter-comparison. Each of these three facilities is unique and each offers an advantage in some aspect of BNCT, but none of these existing facilities excel in all neutron-beam attributes as related to BNCT. A comparison is therefore also shown for a near-optimum reactor beam which does not currently exist but which would be feasible with existing technology. This hypothetical beam is designated BNCT-1 and has a spectrum similar to the FIR-1, the mono-directionality of the HFR and the intensity of the BMRR. A beam very similar to the BNCT-1 could perhaps be achieved with modification of the BMRR, HFR, or FIR, and could certainly be realized in a new facility with today`s technology.

  15. Targeted delivery of albumin bound paclitaxel in the treatment of advanced breast cancer.

    PubMed

    Di Costanzo, Francesco; Gasperoni, Silvia; Rotella, Virginia; Di Costanzo, Federica

    2009-02-18

    Taxanes are chemotherapeutic agents with a large spectrum of antitumor activity when used as monotherapy or in combination regimens. Paclitaxel and docetaxel have poor solubility and require a complex solvent system for their commercial formulation, Cremophor EL(R) (CrEL) and Tween 80(R) respectively. Both these biological surfactants have recently been implicated as contributing not only to the hypersensitivity reactions, but also to the degree of peripheral neurotoxicity and myelosuppression, and may antagonize the cytotoxicity. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel (ABI-007; Abraxane(R)), is a novel formulation of paclitaxel that does not employ the CrEL solvent system. Nab-paclitaxel demonstrates greater efficacy and a favorable safety profile compared with standard paclitaxel in patients with advanced disease (breast cancer, non-small cell lung cancer, melanoma, ovarian cancer). Clinical studies in breast cancer have shown that nab-paclitaxel is significantly more effective than standard paclitaxel in terms of overall objective response rate (ORR) and time to progression. Nab-paclitaxel in combination with gemcitabine, capecitabine or bevacizumab has been shown to be very active in patients with advanced breast cancer. An economic analysis showed that nab-paclitaxel would be an economically reasonable alternative to docetaxel or standard paclitaxel in metastatic breast cancer. Favorable tumor ORR and manageable toxicities have been reported for nab-paclitaxel as monotherapy or in combination treatment in advanced breast cancer.

  16. Local Delivery of a Synthetic Endostatin Fragment for the Treatment of Experimental Gliomas

    PubMed Central

    Pradilla, Gustavo; Legnani, Federico G.; Petrangolini, Giovanna; Francescato, Pierangelo; Chillemi, Francesco; Tyler, Betty M.; Gaini, Sergio M.; Brem, Henry; Olivi, Alessandro; DiMeco, Francesco

    2006-01-01

    OBJECTIVE: Endostatin is an anti-angiogenic agent that blocks matrix-metalloproteinase-2 and inhibits endothelial cell proliferation. Currently, endostatin is available through recombinant technology, which limits its broader use. In this study, a synthetic endostatin fragment (EF) was analyzed to determine its anti-angiogenic properties when locally delivered by controlled-release polymers and to establish its effect as a treatment for experimental gliomas. METHODS: Cytotoxicity of EF against 9L gliosarcoma and F98 glioma was determined in vitro. EF was loaded into polyanhydride-poly-(bis-[carboxyphenoxy-propane]-sebacic-acid) (pCPP:SA) polymers at increasing concentrations. Pharmacokinetics of the EF/polymer formulations were defined in vitro. Anti-angiogenic properties of the EF/polymer formulations were evaluated in the rat-cornea micropocket assay. Toxicity and efficacy of locally delivered EF polymers either alone or combined with systemic bischloroethylnitrosourea (carmustine) were determined in rats intracranially challenged with 9L gliosarcoma. RESULTS: EF showed scarce cytotoxicity against 9L and F98 in vitro. EF/pCPP:SA formulations showed sustained release by day 19. Mean corneal angiogenesis index 20 days after tumor implantation was 4.5 ± 0.7 for corneas implanted with 40% EF/pCPP:SA compared with controls (8.5 ± 1.3, P = 0.02). Intracranial efficacy studies showed that EF polymers alone did not prolong animal survival. Combination of 40% EF/pCPP:SA polymers with systemic bischloroethylnitrosourea (carmustine) prolonged survival (median survival of 44 d, P = 0.001) and generated 33% long-term survivors. CONCLUSION: Controlled-release polymers can effectively deliver a biologically active EF in a sustained fashion. EF inhibits angiogenesis in vitro and in vivo, and even though EF does not prolong survival as a single agent, it exhibits a synergistic effect when combined with systemic bischloroethylnitrosourea (carmustine) in the intracranial 9L

  17. Cardiac-targeted delivery of regulatory RNA molecules and genes for the treatment of heart failure

    PubMed Central

    Poller, Wolfgang; Hajjar, Roger; Schultheiss, Heinz-Peter; Fechner, Henry

    2010-01-01

    Ribonucleic acid (RNA) in its many facets of structure and function is becoming more fully understood, and, therefore, it is possible to design and use RNAs as valuable tools in molecular biology and medicine. Understanding of the role of RNAs within the cell has changed dramatically during the past few years. Therapeutic strategies based on non-coding regulatory RNAs include RNA interference (RNAi) for the silencing of specific genes, and microRNA (miRNA) modulations to alter complex gene expression patterns. Recent progress has allowed the targeting of therapeutic RNAi to the heart for the treatment of heart failure, and we discuss current strategies in this field. Owing to the peculiar biochemical properties of small RNA molecules, the actual therapeutic translation of findings in vitro or in cell cultures is more demanding than with small molecule drugs or proteins. The critical requirement for animal studies after pre-testing of RNAi tools in vitro likewise applies for miRNA modulations, which also have complex consequences for the recipient that are dependent on stability and distribution of the RNA tools. Problems in the field that are not yet fully solved are the prediction of targets and specificity of the RNA tools as well as their tissue-specific and regulatable expression. We discuss analogies and differences between regulatory RNA therapy and classical gene therapy, since recent breakthroughs in vector technology are of importance for both. Recent years have witnessed parallel progress in the fields of gene-based and regulatory RNA-based therapies that are likely to significantly expand the cardiovascular therapeutic repertoire within the next decade. PMID:20176815

  18. SU-D-16A-04: Accuracy of Treatment Plan TCP and NTCP Values as Determined Via Treatment Course Delivery Simulations

    SciTech Connect

    Siebers, J; Xu, H; Gordon, J

    2014-06-01

    Purpose: To to determine if tumor control probability (TCP) and normal tissue control probability (NTCP) values computed on the treatment planning image are representative of TCP/NTCP distributions resulting from probable positioning variations encountered during external-beam radiotherapy. Methods: We compare TCP/NTCP as typically computed on the planning PTV/OARs with distributions of those parameters computed for CTV/OARs via treatment delivery simulations which include the effect of patient organ deformations for a group of 19 prostate IMRT pseudocases. Planning objectives specified 78 Gy to PTV1=prostate CTV+5 mm margin, 66 Gy to PTV2=seminal vesicles+8 mm margin, and multiple bladder/rectum OAR objectives to achieve typical clinical OAR sparing. TCP were computed using the Poisson Model while NTCPs used the Lyman-Kutcher-Bruman model. For each patient, 1000 30-fraction virtual treatment courses were simulated with each fractional pseudo- time-oftreatment anatomy sampled from a principle component analysis patient deformation model. Dose for each virtual treatment-course was determined via deformable summation of dose from the individual fractions. CTVTCP/ OAR-NTCP values were computed for each treatment course, statistically analyzed, and compared with the planning PTV-TCP/OARNTCP values. Results: Mean TCP from the simulations differed by <1% from planned TCP for 18/19 patients; 1/19 differed by 1.7%. Mean bladder NTCP differed from the planned NTCP by >5% for 12/19 patients and >10% for 4/19 patients. Similarly, mean rectum NTCP differed by >5% for 12/19 patients, >10% for 4/19 patients. Both mean bladder and mean rectum NTCP differed by >5% for 10/19 patients and by >10% for 2/19 patients. For several patients, planned NTCP was less than the minimum or more than the maximum from the treatment course simulations. Conclusion: Treatment course simulations yield TCP values that are similar to planned values, while OAR NTCPs differ significantly, indicating the

  19. Novel borate glass/chitosan composite as a delivery vehicle for teicoplanin in the treatment of chronic osteomyelitis.

    PubMed

    Jia, Wei-Tao; Zhang, Xin; Luo, Shi-Hua; Liu, Xin; Huang, Wen-Hai; Rahaman, Mohamed N; Day, Delbert E; Zhang, Chang-Qing; Xie, Zong-Ping; Wang, Jian-Qiang

    2010-03-01

    Composite materials composed of borate bioactive glass and chitosan (designated BGC) were investigated in vitro and in vivo as a new delivery system for teicoplanin in the treatment of chronic osteomyelitis induced by methicillin-resistant Staphylococcus aureus (MRSA). In vitro, the release of teicoplanin from BGC pellets into phosphate-buffered saline (PBS), as well as its antibacterial activity, were determined. The compressive strength of the pellets was measured after specific immersion times, and the structure of the pellets was characterized using scanning electron microscopy and X-ray diffraction. In vivo, the tibial cavity of New Zealand White rabbits was injected with MRSA strain to induce chronic osteomyelitis, treated by debridement after 4weeks, implanted with teicoplanin-loaded BGC pellets (designated TBGC) or BGC pellets, or injected intravenously with teicoplanin. After 12weeks' implantation, the efficacy of the TBGC pellets for treating osteomyelitis was evaluated using hematological, radiological, microbiological and histological techniques. When immersed in PBS, the TBGC pellets provided a sustained release of teicoplanin, while the surface of the pellets was converted to hydroxyapatite (HA). In vivo, the best therapeutic effect was observed in animals implanted with TBGC pellets, resulting in significantly lower radiological and histological scores, a lower positive rate of MRSA culture, and an excellent bone defect repair, without local or systemic side effects. The results indicate that TBGC pellets are effective in treating chronic osteomyelitis by providing a sustained release of teicoplanin, in addition to participating in bone regeneration.

  20. The effectiveness of a magnetic nanoparticle-based delivery system for BCNU in the treatment of gliomas.

    PubMed

    Hua, Mu-Yi; Liu, Hao-Li; Yang, Hung-Wei; Chen, Pin-Yuan; Tsai, Rung-Ywan; Huang, Chiung-Yin; Tseng, I-Chou; Lyu, Lee-Ang; Ma, Chih-Chun; Tang, Hsiang-Jun; Yen, Tzu-Chen; Wei, Kuo-Chen

    2011-01-01

    This study describes the creation and characterization of drug carriers prepared using the polymer poly[aniline-co-N-(1-one-butyric acid) aniline] (SPAnH) coated on Fe(3)O(4) cores to form three types of magnetic nanoparticles (MNPs); these particles were used to enhance the therapeutic capacity and improve the thermal stability of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a compound used to treat brain tumors. The average hydrodynamic diameter of the MNPs was 89.2 ± 8.5 nm and all the MNPs displayed superparamagnetic properties. A maximum effective dose of 379.34 μg BCNU could be immobilized on 1 mg of MNP-3 (bound-BCNU-3). Bound-BCNU-3 was more stable than free-BCNU when stored at 4 °C, 25 °C or 37 °C. Bound-BCNU-3 could be concentrated at targeted sites in vitro and in vivo using an externally applied magnet. When applied to brain tumors, magnetic targeting increased the concentration and retention of bound-BCNU-3. This drug delivery system promises to provide more effective tumor treatment using lower therapeutic doses and potentially reducing the side effects of chemotherapy.

  1. Oral 5-fluorouracil colon-specific delivery through in vivo pellet coating for colon cancer and aberrant crypt foci treatment.

    PubMed

    Bose, A; Elyagoby, A; Wong, T W

    2014-07-01

    In situ coating of 5-fluorouracil pellets by ethylcellulose and pectin powder mixture (8:3 weight ratio) in capsule at simulated gastrointestinal media provides colon-specific drug release in vitro. This study probes into pharmacodynamic and pharmacokinetic profiles of intra-capsular pellets coated in vivo in rats with reference to their site-specific drug release outcomes. The pellets were prepared by extrusion-spheronization technique. In vitro drug content, drug release, in vivo pharmacokinetics, local colonic drug content, tumor, aberrant crypt foci, systemic hematology and clinical chemistry profiles of coated and uncoated pellets were examined against unprocessed drug. In vivo pellet coating led to reduced drug bioavailability and enhanced drug accumulation at colon (179.13 μg 5-FU/g rat colon content vs 4.66 μg/g of conventional in vitro film-coated pellets at 15 mg/kg dose). The in vivo coated pellets reduced tumor number and size, through reforming tubular epithelium with basement membrane and restricting expression of cancer from adenoma to adenocarcinoma. Unlike uncoated pellets and unprocessed drug, the coated pellets eliminated aberrant crypt foci which represented a putative preneoplastic lesion in colon cancer. They did not inflict additional systemic toxicity. In vivo pellet coating to orally target 5-fluorouracil delivery at cancerous colon is a feasible therapeutic treatment approach.

  2. CD9 monoclonal antibody-conjugated PEGylated liposomes for targeted delivery of rapamycin in the treatment of cellular senescence.

    PubMed

    Nguyen, Hanh Thuy; Thapa, Raj Kumar; Shin, Beom Soo; Jeong, Jee-Heon; Kim, Jae-Ryong; Yong, Chul Soon; Kim, Jong Oh

    2017-03-03

    Premature cellular senescence refers to the state of irreversible cell cycle arrest due to DNA damage or other stresses. In this study, CD9 monoclonal antibody (CD9mAb) was successfully conjugated to the surface of PEGylated liposomes for targeted delivery of rapamycin (LR-CD9mAb) to overcome senescence of CD9 receptor-overexpressing cells. LR-CD9mAb has a small particle size (143.3 ± 2.4 nm), narrow size distribution (polydispersity index: 0.220 ± 0.036), and negative zeta potential (-14.6 ± 1.2 mV). The uptake of CD9-targeted liposomes by premature senescent human dermal fibroblasts (HDFs) was higher than that by young HDFs, as displayed by confocal microscopic images. The senescence might not be reversed by treatment with rapamycin; however, the drug promoted cell proliferation and reduced the number of cells that expressed the senescence-associated-β-galactosidase (SA-β-gal). These effects were further confirmed by cell viability, cell cycle, and Western blotting analyses. Moreover, CD9-targeted liposomes showed better anti-senescence activity, in comparison with free rapamycin or the conventional liposomal formulation, suggesting the potential application of this system in further in vivo studies.

  3. Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse

    PubMed Central

    Liu, Yuchen; Li, Dameng; Liu, Zhengya; Zhou, Yu; Chu, Danping; Li, Xihan; Jiang, Xiaohong; Hou, Dongxia; Chen, Xi; Chen, Yuda; Yang, Zhanzhao; Jin, Ling; Jiang, Waner; Tian, Chenfei; Zhou, Geyu; Zen, Ke; Zhang, Junfeng; Zhang, Yujing; Li, Jing; Zhang, Chen-Yu

    2015-01-01

    Cell-derived exosomes have been demonstrated to be efficient carriers of small RNAs to neighbouring or distant cells, highlighting the preponderance of exosomes as carriers for gene therapy over other artificial delivery tools. In the present study, we employed modified exosomes expressing the neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver opioid receptor mu (MOR) siRNA into the brain to treat morphine addiction. We found that MOR siRNA could be efficiently packaged into RVG exosomes and was associated with argonaute 2 (AGO2) in exosomes. These exosomes efficiently and specifically delivered MOR siRNA into Neuro2A cells and the mouse brain. Functionally, siRNA-loaded RVG exosomes significantly reduced MOR mRNA and protein levels. Surprisingly, MOR siRNA delivered by the RVG exosomes strongly inhibited morphine relapse via the down-regulation of MOR expression levels. In conclusion, our results demonstrate that targeted RVG exosomes can efficiently transfer siRNA to the central nervous system and mediate the treatment of morphine relapse by down-regulating MOR expression levels. Our study provides a brand new strategy to treat drug relapse and diseases of the central nervous system. PMID:26633001

  4. New silica nanostructure for the improved delivery of topical antibiotics used in the treatment of staphylococcal cutaneous infections.

    PubMed

    Grumezescu, Alexandru Mihai; Ghitulica, Cristina Daniela; Voicu, Georgeta; Huang, Keng-Shiang; Yang, Chih-Hui; Ficai, Anton; Vasile, Bogdan Stefan; Grumezescu, Valentina; Bleotu, Coralia; Chifiriuc, Mariana Carmen

    2014-03-25

    In this paper, we report the synthesis, characterization (FT-IR, XRD, BET, HR-TEM) and bioevaluation of a novel γ-aminobutiric acid/silica (noted GABA-SiO₂ or γ-SiO₂) hybrid nanostructure, for the improved release of topical antibiotics, used in the treatment of Staphylococcus aureus infections. GABA-SiO₂ showed IR bands which were assigned to Si-O-Si (stretch mode). The XRD pattern showed a broad peak in the range of 18-30° (2θ), indicating an amorphous structure. Based on the BET analysis, estimations about surface area (438.14 m²/g) and pore diameters (4.76 nm) were done. TEM observation reveals that the prepared structure presented homogeneity and an average size of particles not exceeding 10nm. The prepared nanostructure has significantly improved the anti-staphylococcal activity of bacitracin and kanamycin sulfate, as demonstrated by the drastic decrease of the minimal inhibitory concentration of the respective antibiotics loaded in the GABA-SiO₂ nanostructure. These results, correlated with the high biocompatibility of this porous structure, are highlighting the possibility of using this carrier for the local delivery of the antimicrobial substances in lower active doses, thus reducing their cytotoxicity and side-effects.

  5. A New Form of Intraoral Delivery of Antifungal Drugs for the Treatment of Denture-Induced Oral Candidosis

    PubMed Central

    Amin, Wala M.; Al-Ali, Muna H.; Salim, Nesreen A.; Al-Tarawneh, Sandra K.

    2009-01-01

    Objectives To monitor the release of the antifungal drugs Fluconazole, Chlorhexidine and a combination of the two from an auto-polymerized poly (methyl methacrylate) (PMMA) denture base resin; and to investigate the effect of the released drugs upon the growth of Candida albicans. Methods A high performance liquid chromatography-Ultra violet (HPLC-UV) method was used in the analysis of the released drugs into distilled water from PMMA discs doped with the antifungal drugs Fluconazole (10%), Chlorhexidine (10%) and a combination of the two drugs (5% each). The antifungal efficacy of the released drugs was monitored, microbiologically, employing “well” technique on a Saborauds culture medium inoculated with a resistant strain of Candida albicans. Results It was shown that Fluconazole, Chlorhexidine and the combination of the two drugs can be successfully incorporated with PMMA. It was found that the drugs leach steadily out of the PMMA resin into distilled water at mouth temperature and that sustained drug release continued throughout the 28 days test period. It was also shown that the released drugs demonstrated an antifungal activity against the resistant Candida albicans and this was most remarkable in the combined drugs samples. Conclusions The findings of this investigation have a clinical value in terms of their significant contribution to the treatment of fungal infections of the oral cavity. The sustained release of anti-fungal drugs from the PMMA resin clearly constitutes a new dosage form of these drugs via the poly (methyl methacrylate) delivery system. PMID:19826596

  6. Co-delivery of antiviral and antifungal therapeutics for the treatment of sexually transmitted infections using a moldable, supramolecular hydrogel.

    PubMed

    Lee, Ashlynn L Z; Ng, Victor W L; Poon, Ghim Lee; Ke, Xiyu; Hedrick, James L; Yang, Yi Yan

    2015-02-18

    In this investigation, a therapeutic co-delivery hydrogel system is developed to provide effective HIV prophylaxis, alongside the prevention and/or treatment of candidiasis. Two components-a HIV reverse transcriptase inhibitor, tenofovir, and a cationic macromolecular antifungal agent derived from a vitamin D-functionalized polycarbonate (VD/BnCl (1:30))-are formulated into biodegradable vitamin D-functionalized polycarbonate/PEG-based supramolecular hydrogels. The hydrogels exhibit thixotropic properties and can be easily spread across surfaces for efficient drug absorption. Sustained release of tenofovir from the hydrogel is observed, where approximately 85% tenofovir is released within 3 h. VD/BnCl (1:30) does not impede drug diffusion from the hydrogel as the drug release profiles are similar with and without the polycation. Antimicrobial efficacy studies indicate that the hydrogels kill C. albicans efficiently with a minimum bactericidal concentration (MBC) of 0.25-0.5 g L(-1) . These hydrogels also eradicate C. albicans biofilm effectively at 4× MBC. When human dermal fibroblasts (as model mammalian cells) are treated with these hydrogels, cell viability remains high at above 80%, demonstrating excellent biocompatibility. When applied topically, this dual-functional hydrogel can potentially prevent HIV transmission and eliminate microbes that cause infections in the vulvovagina region.

  7. CD9 monoclonal antibody-conjugated PEGylated liposomes for targeted delivery of rapamycin in the treatment of cellular senescence

    NASA Astrophysics Data System (ADS)

    Thuy Nguyen, Hanh; Thapa, Raj Kumar; Shin, Beom Soo; Jeong, Jee-Heon; Kim, Jae-Ryong; Yong, Chul Soon; Kim, Jong Oh

    2017-03-01

    Premature cellular senescence refers to the state of irreversible cell cycle arrest due to DNA damage or other stresses. In this study, CD9 monoclonal antibody (CD9mAb) was successfully conjugated to the surface of PEGylated liposomes for targeted delivery of rapamycin (LR-CD9mAb) to overcome senescence of CD9 receptor-overexpressing cells. LR-CD9mAb has a small particle size (143.3 ± 2.4 nm), narrow size distribution (polydispersity index: 0.220 ± 0.036), and negative zeta potential (‑14.6 ± 1.2 mV). The uptake of CD9-targeted liposomes by premature senescent human dermal fibroblasts (HDFs) was higher than that by young HDFs, as displayed by confocal microscopic images. The senescence might not be reversed by treatment with rapamycin; however, the drug promoted cell proliferation and reduced the number of cells that expressed the senescence-associated-β-galactosidase (SA-β-gal). These effects were further confirmed by cell viability, cell cycle, and Western blotting analyses. Moreover, CD9-targeted liposomes showed better anti-senescence activity, in comparison with free rapamycin or the conventional liposomal formulation, suggesting the potential application of this system in further in vivo studies.

  8. Monochorionic twin delivery after conservative surgical treatment of a patient with severe diffuse uterine adenomyosis without uterine rupture

    PubMed Central

    Kwack, Jae Young; Jeon, Su-Bun; Kim, Keuna; Lee, Soo-Jeong

    2016-01-01

    A 31-year-old nulliparous woman with severe diffuse uterine adenomyosis, which replaced nearly the whole uterine myometrium, visited our hospital due to severe dysmenorrhea, menorrhagia, and a desire to have a baby. The patient had a history of two spontaneous abortions. Laparotomic adenomyomectomy with transient occlusion of uterine arteries (TOUA) was performed safely and the patient tried in vitro fertilization and achieved a intrauterine twin pregnancy after recovery time of the operation. At 31+6 weeks of gestation, a male neonate baby weighing 1,620 g and a male neonate baby weighing 1,480 g were born by transverse lower segment cesarean delivery. There was no complication after the operation. The babies were discharged after receiving routine neonatal intensive care for neonatal respiratory distress syndrome. Adenomyomectomy with TOUA technique would be an option for conservative surgical treatment in patients with severe diffuse whole uterine adenomyosis. This is the first report of twin pregnancy after diffuse whole uterine adenomyomectomy with TOUA. PMID:27462599

  9. Formulation, characterization and evaluation of cyclodextrin-complexed bendamustine-encapsulated PLGA nanospheres for sustained delivery in cancer treatment.

    PubMed

    Gidwani, Bina; Vyas, Amber

    2016-03-01

    PLGA nanospheres are considered to be promising drug carrier in the treatment of cancer. Inclusion complex of bendamustine (BM) with epichlorohydrin beta cyclodextrin polymer was prepared by freeze-drying method. Phase solubility study revealed formation of AL type complex with stability constant (Ks = 645 M(-1)). This inclusion complex was encapsulated into PLGA nanospheres using solid-in-oil-in-water (S/O/W) technique. The particle size and zeta potential of PLGA nanospheres loaded with cyclodextrin-complexed BM were about 151.4 ± 2.53 nm and - 31.9 ± (-3.08) mV. In-vitro release study represented biphasic release pattern with 20% burst effect and sustained slow release. DSC studies indicated that inclusion complex incorporated in PLGA nanospheres was not in a crystalline state but existed in an amorphous or molecular state. The cytotoxicity experiment was studied in Z-138 cells and IC50 value was found to be 4.3 ± 0.11 µM. Cell viability studies revealed that the PLGA nanospheres loaded with complex exerts a more pronounced effect on the cancer cells as compared to the free drug. In conclusion, PLGA nanospheres loaded with inclusion complex of BM led to sustained drug delivery. The nanospheres were stable after 3 months of storage conditions with slight change in their particle size, zeta potential and entrapment efficiency.

  10. Are mobile phones and handheld computers being used to enhance delivery of psychiatric treatment? A systematic review.

    PubMed

    Ehrenreich, Benjamin; Righter, Bryan; Rocke, Di Andra; Dixon, Lisa; Himelhoch, Seth

    2011-11-01

    The rapid diffusion of communication technology has provided opportunities to enhance the delivery of mental health care. We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to conduct a qualitative review of randomized controlled trials that reported on the efficacy of mobile phones or handheld computers used to enhance the treatment of psychiatric disorders. We identified eight randomized controlled trials. Five studies used mobile phones to target smoking cessation. Those receiving the smoking cessation intervention were significantly more likely to achieve abstinence compared with those under the control condition. Three studies used non-personal digital assistant (PDA) handheld computers targeting anxiety. Compared with those in the control condition, those who received the non-PDA handheld computer intervention had significant improvement in anxiety outcomes in only one of the three studies. The limited number of rigorous evaluations of mobile phone, PDA, or smartphone interventions for mental health problems underscores the opportunities to enhance our interventions using the available tools of contemporary technology.

  11. Deconvolution of insulin secretion, insulin hepatic extraction post-hepatic delivery rates and sensitivity during 24-hour standardized meals: time course of glucose homeostasis in leptin replacement treatment.

    PubMed

    Andreev, V P; Paz-Filho, G; Wong, M-L; Licinio, J

    2009-02-01

    Minimally invasive methodology, mathematical model, and software for analysis of glucose homeostasis by deconvolution of insulin secretion, hepatic extraction, post-hepatic delivery, and sensitivity from 24-hour standardized meals test have been developed and illustrated by the study of glucose homeostasis of a genetically based leptin-deficient patient before and after leptin replacement treatment. The only genetically leptin-deficient adult man identified in the world was treated for 24 months with recombinant methionyl human leptin. Blood was collected every 7 minutes for 24 hours, with standardized meals consumed during the 4 visits: at baseline, one-week, 18-months, and 24-months after initiation of the treatment. Concentrations of insulin, C-peptide, and plasma glucose were measured. Insulin secretion was obtained by deconvolution of C-peptide data. Hepatic insulin extraction was determined based on our modifications of the insulin kinetics model . Insulin sensitivity for each of the four meals was calculated by using the minimal glucose model approach. Hepatic extraction of insulin was the first element of glucose homeostasis to respond to leptin replacement treatment and increased 2-fold after one week of treatment. Insulin secretion and delivery rates decreased more than 2-fold and insulin sensitivity increased 10-fold after 24 months of treatment. Computer programs for analysis of 24-hour insulin secretion, extraction, delivery, and action are available upon request.

  12. BIOACCESSIBILITY TESTS ACCURATELY ESTIMATE ...

    EPA Pesticide Factsheets

    Hazards of soil-borne Pb to wild birds may be more accurately quantified if the bioavailability of that Pb is known. To better understand the bioavailability of Pb to birds, we measured blood Pb concentrations in Japanese quail (Coturnix japonica) fed diets containing Pb-contaminated soils. Relative bioavailabilities were expressed by comparison with blood Pb concentrations in quail fed a Pb acetate reference diet. Diets containing soil from five Pb-contaminated Superfund sites had relative bioavailabilities from 33%-63%, with a mean of about 50%. Treatment of two of the soils with P significantly reduced the bioavailability of Pb. The bioaccessibility of the Pb in the test soils was then measured in six in vitro tests and regressed on bioavailability. They were: the “Relative Bioavailability Leaching Procedure” (RBALP) at pH 1.5, the same test conducted at pH 2.5, the “Ohio State University In vitro Gastrointestinal” method (OSU IVG), the “Urban Soil Bioaccessible Lead Test”, the modified “Physiologically Based Extraction Test” and the “Waterfowl Physiologically Based Extraction Test.” All regressions had positive slopes. Based on criteria of slope and coefficient of determination, the RBALP pH 2.5 and OSU IVG tests performed very well. Speciation by X-ray absorption spectroscopy demonstrated that, on average, most of the Pb in the sampled soils was sorbed to minerals (30%), bound to organic matter 24%, or present as Pb sulfate 18%. Ad

  13. Minocycline Ointment as a Local Drug Delivery in the Treatment of Generalized Chronic Periodontitis - A Clinical Study

    PubMed Central

    Abbas, Sara; Ari, Geetha

    2016-01-01

    Introduction The primary goal in periodontal therapy includes removal of the etiological factors by mechanical periodontal treatment, which sometimes fail to eliminate the anaerobic infection at the base of the pocket and requires adjuvant chemical therapy. Aim The aim of the study was to evaluate the effectiveness of 2% minocycline ointment when used as an adjunct to periodontal flap surgery and post-operative maintenance period for the treatment of generalized chronic periodontitis. Materials and Methods The study included 30 subjects comprising of 60 posterior sextants in a split mouth design in which 30 sextants were treated as experimental and 30 sextants as control with a probing pocket depth≥6mm. In Group A (experimental group) 30 sextants were treated with open flap debridement followed by the application of minocycline ointment as a local drug delivery. In Group B (control group) 30 sextants were treated with open flap debridement alone. Minocycline hydrochloride ointment was applied on the 0 day and 3rd month. The clinical parameters such as plaque index, probing pocket depth, clinical attachment level and gingival bleeding index were recorded at 0 day, 3rd month and 6th month in both the groups. Paired and unpaired t-test were used to compare the means of the two groups. Results When Group A and Group B were compared, Group A showed significantly greater reduction in gingival bleeding index, probing pocket depth and gain in clinical attachment level than Group B, from 0 day to 3 months and from 0 day to 6 months. Group A showed significant reduction in plaque index than Group B when they were compared at 6 months. Conclusion The results demonstrate that there was significant reduction in the clinical parameters with improvement in the periodontal status on application of minocycline ointment as an adjunct to periodontal flap surgery in generalized chronic periodontitis. PMID:27504402

  14. Bimatoprost-Loaded Ocular Inserts as Sustained Release Drug Delivery Systems for Glaucoma Treatment: In Vitro and In Vivo Evaluation

    PubMed Central

    Franca, Juçara Ribeiro; Foureaux, Giselle; Fuscaldi, Leonardo Lima; Ribeiro, Tatiana Gomes; Rodrigues, Lívia Bomfim; Bravo, Renata; Castilho, Rachel Oliveira; Yoshida, Maria Irene; Cardoso, Valbert Nascimento; Fernandes, Simone Odília; Cronemberger, Sebastião; Ferreira, Anderson José; Faraco, André Augusto Gomes

    2014-01-01

    The purpose of the present study was to develop and assess a novel sustained-release drug delivery system of Bimatoprost (BIM). Chitosan polymeric inserts were prepared using the solvent casting method and characterized by swelling studies, infrared spectroscopy, differential scanning calorimetry, drug content, scanning electron microscopy and in vitro drug release. Biodistribution of 99mTc-BIM eye drops and 99mTc-BIM-loaded inserts, after ocular administration in Wistar rats, was accessed by ex vivo radiation counting. The inserts were evaluated for their therapeutic efficacy in glaucomatous Wistar rats. Glaucoma was induced by weekly intracameral injection of hyaluronic acid. BIM-loaded inserts (equivalent to 9.0 µg BIM) were administered once into conjunctival sac, after ocular hypertension confirmation. BIM eye drop was topically instilled in a second group of glaucomatous rats for 15 days days, while placebo inserts were administered once in a third group. An untreated glaucomatous group was used as control. Intraocular pressure (IOP) was monitored for four consecutive weeks after treatment began. At the end of the experiment, retinal ganglion cells and optic nerve head cupping were evaluated in the histological eye sections. Characterization results revealed that the drug physically interacted, but did not chemically react with the polymeric matrix. Inserts sustainedly released BIM in vitro during 8 hours. Biodistribution studies showed that the amount of 99mTc-BIM that remained in the eye was significantly lower after eye drop instillation than after chitosan insert implantation. BIM-loaded inserts lowered IOP for 4 weeks, after one application, while IOP values remained significantly high for the placebo and untreated groups. Eye drops were only effective during the daily treatment period. IOP results were reflected in RGC counting and optic nerve head cupping damage. BIM-loaded inserts provided sustained release of BIM and seem to be a promising system

  15. Bimatoprost-loaded ocular inserts as sustained release drug delivery systems for glaucoma treatment: in vitro and in vivo evaluation.

    PubMed

    Franca, Juçara Ribeiro; Foureaux, Giselle; Fuscaldi, Leonardo Lima; Ribeiro, Tatiana Gomes; Rodrigues, Lívia Bomfim; Bravo, Renata; Castilho, Rachel Oliveira; Yoshida, Maria Irene; Cardoso, Valbert Nascimento; Fernandes, Simone Odília; Cronemberger, Sebastião; Ferreira, Anderson José; Faraco, André Augusto Gomes

    2014-01-01

    The purpose of the present study was to develop and assess a novel sustained-release drug delivery system of Bimatoprost (BIM). Chitosan polymeric inserts were prepared using the solvent casting method and characterized by swelling studies, infrared spectroscopy, differential scanning calorimetry, drug content, scanning electron microscopy and in vitro drug release. Biodistribution of 99mTc-BIM eye drops and 99mTc-BIM-loaded inserts, after ocular administration in Wistar rats, was accessed by ex vivo radiation counting. The inserts were evaluated for their therapeutic efficacy in glaucomatous Wistar rats. Glaucoma was induced by weekly intracameral injection of hyaluronic acid. BIM-loaded inserts (equivalent to 9.0 µg BIM) were administered once into conjunctival sac, after ocular hypertension confirmation. BIM eye drop was topically instilled in a second group of glaucomatous rats for 15 days days, while placebo inserts were administered once in a third group. An untreated glaucomatous group was used as control. Intraocular pressure (IOP) was monitored for four consecutive weeks after treatment began. At the end of the experiment, retinal ganglion cells and optic nerve head cupping were evaluated in the histological eye sections. Characterization results revealed that the drug physically interacted, but did not chemically react with the polymeric matrix. Inserts sustainedly released BIM in vitro during 8 hours. Biodistribution studies showed that the amount of 99mTc-BIM that remained in the eye was significantly lower after eye drop instillation than after chitosan insert implantation. BIM-loaded inserts lowered IOP for 4 weeks, after one application, while IOP values remained significantly high for the placebo and untreated groups. Eye drops were only effective during the daily treatment period. IOP results were reflected in RGC counting and optic nerve head cupping damage. BIM-loaded inserts provided sustained release of BIM and seem to be a promising system

  16. Co-delivery of docetaxel and endostatin by a biodegradable nanoparticle for the synergistic treatment of cervical cancer

    NASA Astrophysics Data System (ADS)

    Qiu, Bo; Ji, Minghui; Song, Xiaosong; Zhu, Yongqiang; Wang, Zhongyuan; Zhang, Xudong; Wu, Shu; Chen, Hongbo; Mei, Lin; Zheng, Yi

    2012-12-01

    Cervical cancer remains a major problem in women's health worldwide. In this research, a novel biodegradable d-α-tocopheryl polyethylene glycol 1000 succinate- b-poly(ɛ-caprolactone- ran-glycolide) (TPGS- b-(PCL- ran-PGA)) nanoparticle (NP) was developed as a co-delivery system of docetaxel and endostatin for the synergistic treatment of cervical cancer. Docetaxel-loaded TPGS- b-(PCL- ran-PGA) NPs were prepared and further modified by polyethyleneimine for coating plasmid pShuttle2-endostatin. All NPs were characterized in size, surface charge, morphology, and in vitro release of docetaxel and pDNA. The uptake of coumarin 6-loaded TPGS- b-(PCL- ran-PGA)/PEI-pDsRED by HeLa cells was observed via fluorescent microscopy and confocal laser scanning microscopy. Endostatin expression in HeLa cells transfected by TPGS- b-(PCL- ran-PGA)/PEI-pShuttle2-endostatin NPs was detected using Western blot analysis, and the cell viability of different NP-treated HeLa cells was determined by MTT assay. The HeLa cells from the tumor model, nude mice, were treated with various NPs including docetaxel-loaded-TPGS- b-(PCL- ran-PGA)/PEI-endostatin NPs, and their survival time, tumor volume and body weight were monitored during regimen process. The tumor tissue histopathology was analyzed using hematoxylin and eosin staining, and microvessel density in tumor tissue was evaluated immunohistochemically. The results showed that the TPGS- b-(PCL- ran-PGA)/PEI NPs can efficiently and simultaneously deliver both coumarin-6 and plasmids into HeLa cells, and the expression of endostatin was verified via Western blot analysis. Compared with control groups, the TPGS- b-(PCL- ran-PGA)/PEI-pShuttle2-endostatin NPs significantly decreased the cell viability of HeLa cells ( p < 0.01), inhibited the growth of tumors, and even eradicated the tumors. The underlying mechanism is attributed to synergistic anti-tumor effects by the combined use of docetaxel, endostatin, and TPGS released from NPs. The TPGS

  17. Control Point Analysis comparison for 3 different treatment planning and delivery complexity levels using a commercial 3-dimensional diode array

    SciTech Connect

    Abdellatif, Ady; Gaede, Stewart

    2014-07-01

    To investigate the use of “Control Point Analysis” (Sun Nuclear Corporation, Melbourne, FL) to analyze and compare delivered volumetric-modulated arc therapy (VMAT) plans for 3 different treatment planning complexity levels. A total of 30 patients were chosen and fully anonymized for the purpose of this study. Overall, 10 lung stereotactic body radiotherapy (SBRT), 10 head-and-neck (H and N), and 10 prostate VMAT plans were generated on Pinnacle{sup 3} and delivered on a Varian linear accelerator (LINAC). The delivered dose was measured using ArcCHECK (Sun Nuclear Corporation, Melbourne, FL). Each plan was analyzed using “Sun Nuclear Corporation (SNC) Patient 6” and “Control Point Analysis.” Gamma passing percentage was used to assess the differences between the measured and planned dose distributions and to assess the role of various control point binning combinations. Of the different sites considered, the prostate cases reported the highest gamma passing percentages calculated with “SNC Patient 6” (97.5% to 99.2% for the 3%, 3 mm) and “Control Point Analysis” (95.4% to 98.3% for the 3%, 3 mm). The mean percentage of passing control point sectors for the prostate cases increased from 51.8 ± 7.8% for individual control points to 70.6 ± 10.5% for 5 control points binned together to 87.8 ± 11.0% for 10 control points binned together (2%, 2-mm passing criteria). Overall, there was an increasing trend in the percentage of sectors passing gamma analysis with an increase in the number of control points binned together in a sector for both the gamma passing criteria (2%, 2 mm and 3%, 3 mm). Although many plans passed the clinical quality assurance criteria, plans involving the delivery of high Monitor Unit (MU)/control point (SBRT) and plans involving high degree of modulation (H and N) showed less delivery accuracy per control point compared with plans with low MU/control point and low degree of modulation (prostate)

  18. Feasibility of a remote, automated daily delivery verification of volumetric-modulated arc therapy treatments using a commercial record and verify system.

    PubMed

    Fontenot, Jonas D

    2012-03-08

    Volumetric-modulated arc therapy (VMAT) is an effective but complex technique for delivering radiation therapy. VMAT relies on precise combinations of dose rate, gantry speed, and multileaf collimator (MLC) shapes to deliver intensity-modulated patterns. Such complexity warrants the development of correspondingly robust performance verification systems. In this work, we report on a remote, automated software system for daily delivery verification of VMAT treatments. The performance verification software system consists of three main components: (1) a query module for retrieving daily MLC, gantry, and jaw positions reported by the linear accelerator control system to the record and verify system; (2) an analysis module which reads the daily delivery report generated from the database query module, compares the reported treatment positions against the planned positions, and compiles delivery position error reports; and (3) a graphical reporting module which displays reports initiated by a user anywhere within the institutional network or which can be configured to alert authorized users when predefined tolerance values are exceeded. The utility of the system was investigated through analysis of patient data collected at our clinic. Nearly 2500 VMAT fractions have been analyzed with the delivery verification system at our institution. The average percentage of reported MLC leaf positions within 3 mm, gantry positions within 2°, and jaw positions within 3 mm of their planned positions was 92.9% ± 5.5%, 95.9%± 2.9%, and 99.7% ± 0.6%, respectively. The level of agreement between planned and reported MLC positions decreased for treatment plans requiring larger MLC leaf movements between control points. Differences in the reported MLC position error between the delivery verification system and data extracted manually from the control system were noted; however, the differences are likely systematic and, therefore, may be characterized if appropriately accounted for

  19. Intranasal delivery of rotigotine to the brain with lactoferrin-modified PEG-PLGA nanoparticles for Parkinson’s disease treatment

    PubMed Central

    Bi, Chenchen; Wang, Aiping; Chu, Yongchao; Liu, Sha; Mu, Hongjie; Liu, Wanhui; Wu, Zimei; Sun, Kaoxiang; Li, Youxin

    2016-01-01

    Sustainable and safe delivery of brain-targeted drugs is highly important for successful therapy in Parkinson’s disease (PD). This study was designed to formulate biodegradable poly(ethylene glycol)–poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NPs), which were surface-modified with lactoferrin (Lf), for efficient intranasal delivery of rotigotine to the brain for the treatment of PD. Rotigotine NPs were prepared by nanoprecipitation, and the effect of various independent process variables on the resulting properties of NPs was investigated by a Box–Behnken experimental design. The physicochemical and pharmaceutical properties of the NPs and Lf-NPs were characterized, and the release kinetics suggested that both NPs and Lf-NPs provided continuous, slow release of rotigotine for 48 h. Neither rotigotine NPs nor Lf-NPs reduced the viability of 16HBE and SH-SY5Y cells; in contrast, free rotigotine was cytotoxic. Qualitative and quantitative cellular uptake studies demonstrated that accumulation of Lf-NPs was greater than that of NPs in 16HBE and SH-SY5Y cells. Following intranasal administration, brain delivery of rotigotine was much more effective with Lf-NPs than with NPs. The brain distribution of rotigotine was heterogeneous, with a higher concentration in the striatum, the primary region affected in PD. This strongly suggested that Lf-NPs enable the targeted delivery of rotigotine for the treatment of PD. Taken together, these results demonstrated that Lf-NPs have potential as a carrier for nose-to-brain delivery of rotigotine for the treatment of PD. PMID:27994458

  20. Oral delivery of Acid Alpha Glucosidase epitopes expressed in plant chloroplasts suppresses antibody formation in treatment of Pompe mice

    PubMed Central

    Su, Jin; Sherman, Alexandra; Doerfler, Phillip A.; Byrne, Barry J.; Herzog, Roland W.; Daniell, Henry

    2015-01-01

    Summary Deficiency of acid alpha glucosidase (GAA) causes Pompe disease in which the patients systemically accumulate lysosomal glycogen in muscles and nervous systems, often resulting in infant mortality. Although enzyme replacement therapy (ERT) is effective in treating patients with Pompe disease, formation of antibodies against rhGAA complicates treatment. In this report, we investigated induction of tolerance by oral administration of GAA expressed in chloroplasts. Because full-length GAA could not be expressed, N-terminal 410-amino acids of GAA (as determined by T-cell epitope mapping) were fused with the transmucosal carrier CTB. Tobacco transplastomic lines expressing CTB-GAA were generated through site-specific integration of transgenes into the chloroplast genome. Homoplasmic lines were confirmed by Southern blot analysis. Despite low-level expression of CTB-GAA in chloroplasts, yellow or albino phenotype of transplastomic lines was observed due to binding of GAA to a chloroplast protein that has homology to mannose-6 phosphate receptor. Oral administration of the plant-made CTB-GAA fusion protein even at 330-fold lower dose (1.5 μg) significantly suppressed immunoglobulin formation against GAA in Pompe mice injected with 500 μg rhGAA per dose, with several-fold lower titre of GAA-specific IgG1 and IgG2a. Lyophilization increased CTB-GAA concentration by 30-fold (up to 190 μg per g of freeze-dried leaf material), facilitating long-term storage at room temperature and higher dosage in future investigations. This study provides the first evidence that oral delivery of plant cells is effective in reducing antibody responses in ERT for lysosomal storage disorders facilitating further advances in clinical investigations using plant cell culture system or in vitro propagation. PMID:26053072

  1. SU-E-T-62: A Preliminary Experience of Using EPID Transit Dosimetry for Monitoring Daily Dose Variations in Radiation Treatment Delivery

    SciTech Connect

    Yao, R; Chisela, W

    2015-06-15

    Purpose: To investigate the use of EPID transit dosimetry for monitoring daily dose variations in radiation treatment delivery. Methods: A patient with head and neck cancer treated using nine field IMRT beams was used in this study. The prescription was 45 Gy in 25 fractions. A KV CBCT was acquired before each treatment on a Varian NTX linear accelerator. Integrated images using MV EPID were acquired for each treatment beam. Planning CT images, treatment plan, and daily integrated images were imported into a commercial QA software Dosimetry Check (v4r4 Math Resolutions, LLC, Columbia, MD) to calculate 3D dose of the day assuming 25 fractions treatment. Planning CT images were deformed and registered to each daily CBCT using Varian SmartAdapt (v11.MR2). ROIs were then propagated from planning CT to daily CBCT. The correlation between maximum, average dose of ROIs and ROI volume, center of mass shift, Dice Similarity Coefficient (DSC) were investigated. Results: Not all parameters investigated showed strong correlations. For PTV and CTV, the average dose has inverse correlation with their volume change (correlation coefficient −0.52, −0.50, respectively) and DSC (−0.59, −0.59, respectively). The average dose of right parotid has correlation with its volume change (0.56). The maximum dose of spinal cord has correlation with the center of mass superior-inferior shift (0.52) and inverse correlation with the center of mass anterior-posterior shift (−0.73). Conclusion: Transit dosimetry using EPID images collected during treatment delivery offers great potential to monitor daily dose variations due to patient anatomy change, motion, and setup errors in radiation treatment delivery. It can provide a patient-specific QA tool valuable for adaptive radiation therapy. Further work is needed to validate the technique.

  2. Copper sulfide nanoparticle-based localized drug delivery system as an effective cancer synergistic treatment and theranostic platform.

    PubMed

    Hou, Lin; Shan, Xiaoning; Hao, Lisha; Feng, Qianhua; Zhang, Zhenzhong

    2017-03-06

    Localized cancer treatment with combination therapy has attracted increasing attention for effective inhibition of tumor growth. In this work, we introduced diffusion molecular retention (DMR) tumor targeting effect, a new strategy that employed transferrin (Tf) modified hollow mesoporous CuS nanoparticles (HMCuS NPs) to undergo extensive diffuse through the interstitium and tumor retention after a peritumoral (PT) injection. Herein, HMCuS NPs with strong near-infrared (NIR) absorption and photothermal conversion efficiency could serve as not only a drug carrier but also a powerful contrast agent for photoacoustic imaging to guide chemo-phototherapy. The iron-dependent artesunate (AS), which possessed profound cytotoxicity against tumor cell, was used as model drug. As a result, this AS loaded Tf-HMCuS NPs (AS/Tf-HMCuS NPs) system could specially target to tumor cells and synchronously deliver AS as well as irons into tumor to achieve enhanced antitumor activity. It was found that AS/Tf-HMCuS NPs was taken up by MCF-7 cells via Tf-mediated endocytosis, and could effectively convert NIR light into heat for photothermal therapy as well as generated high levels of reactive oxygen species (ROS) for photodynamic therapy. In addition, in vivo antitumor efficacy studies showed that tumor-bearing mice treated with AS/Tf-HMCuS NPs through peritumoral (PT) injection under NIR laser irradiation displayed the strongest inhibition rate of about 74.8%, even with the reduced frequency of administration. Furthermore, to demonstrate DMR, the optical imaging, photoacoustic tomography and immunofluorescence after PT injection were adopted to track the behavior of AS/Tf-HMCuS NPs in vivo. The results exhibited that Tf-HMCuS NPs prolonged the local accumulation and retention together with slow vascular uptake and extensive interstitial diffusion, which was consistent with the biodistribution studies of AS/Tf-HMCuS NPs. Therefore, the approach of localized delivery through DMR combined

  3. Service delivery and pharmacotherapy for alcohol use disorder in the era of health reform: Data from a national sample of treatment organizations

    PubMed Central

    Knudsen, Hannah K.; Roman, Paul M.

    2015-01-01

    Background Although there is a growing literature examining organizational characteristics and medication adoption, little is known about service delivery differences between specialty treatment organizations that have and have not adopted pharmacotherapy for alcohol use disorder (AUD). This study compares adopters and non-adopters across a range of treatment services, including levels of care, availability of tailored services for specific populations, treatment philosophy and counseling orientations, and adoption of comprehensive wraparound services. Methods In-person interviews were conducted with program leaders from a national sample of 372 organizations that deliver AUD treatment services in the US. Results About 23.6% of organizations had adopted at least one AUD medication. Organizations offering pharmacotherapy were similar to non-adopters across many measures of levels of care, tailored services, treatment philosophy, and social services. The primary area of difference between the two groups was for services related to health problems other than AUD. Pharmacotherapy adopters were more likely to offer primary medical care, medications for smoking cessation, and services to address co-occurring psychiatric conditions. Conclusions Service delivery differences were modest between adopters and non-adopters of AUD pharmacotherapy, with the exception of health-related services. However, the greater adoption of health-related services by organizations offering AUD pharmacotherapy represents greater medicalization of treatment, which may mean these programs are more strongly positioned to respond to opportunities for integration under health reform. PMID:25893539

  4. Delivery validation of an automated modulated electron radiotherapy plan

    SciTech Connect

    Connell, T. Papaconstadopoulos, P.; Alexander, A.; Serban, M.; Devic, S.; Seuntjens, J.

    2014-06-15

    Purpose: Modulated electron radiation therapy (MERT) represents an active area of interest that offers the potential to improve healthy tissue sparing in treatment of certain cancer cases. Challenges remain however in accurate beamlet dose calculation, plan optimization, collimation method, and delivery accuracy. In this work, the authors investigate the accuracy and efficiency of an end-to-end MERT plan and automated delivery method. Methods: Treatment planning was initiated on a previously treated whole breast irradiation case including an electron boost. All dose calculations were performed using Monte Carlo methods and beam weights were determined using a research-based treatment planning system capable of inverse optimization. The plan was delivered to radiochromic film placed in a water equivalent phantom for verification, using an automated motorized tertiary collimator. Results: The automated delivery, which covered four electron energies, 196 subfields, and 6183 total MU was completed in 25.8 min, including 6.2 min of beam-on time. The remainder of the delivery time was spent on collimator leaf motion and the automated interfacing with the accelerator in service mode. Comparison of the planned and delivered film dose gave 3%/3mm gamma pass rates of 62.1%, 99.8%, 97.8%, 98.3%, and 98.7% for the 9, 12, 16, and 20 MeV, and combined energy deliveries, respectively. Delivery was also performed with a MapCHECK device and resulted in 3%/3  mm gamma pass rates of 88.8%, 86.1%, 89.4%, and 94.8% for the 9, 12, 16, and 20 MeV energies, respectively. Conclusions: Results of the authors’ study showed that an accurate delivery utilizing an add-on tertiary electron collimator is possible using Monte Carlo calculated plans and inverse optimization, which brings MERT closer to becoming a viable option for physicians in treating superficial malignancies.

  5. Nanocarriers for treatment of ocular neovascularization in the back of the eye: new vehicles for ophthalmic drug delivery.

    PubMed

    Shen, Hsin-Hui; Chan, Elsa C; Lee, Jia Hui; Bee, Youn-Shen; Lin, Tsung-Wu; Dusting, Gregory J; Liu, Guei-Sheung

    2015-01-01

    Pathologic neovascularization of the retina is a major cause of substantial and irreversible loss of vision. Drugs are difficult to deliver to the lesions in the back of the eye and this is a major obstacle for the therapeutics. Current pharmacological approach involves an intravitreal injection of anti-VEGF agents to prevent aberrant growth of blood vessels, but it has limitations including therapeutic efficacy and side-effects associated with systemic exposure and invasive surgery. Nanotechnology provides novel opportunities to overcome the limitations of conventional delivery system to reach the back of the eye through fabrication of nanostructures capable of encapsulating and delivering small molecules. This review article introduces various forms of nanocarrier that can be adopted by ocular drug delivery systems to improve current therapy. The application of nanotechnology in medicine brings new hope for ocular drug delivery in the back of the eye to manage the major causes of blindness associated with ocular neovascularization.

  6. EGFR/EGFRvIII-targeted immunotoxin therapy for the treatment of glioblastomas via convection-enhanced delivery

    PubMed Central

    Bao, Xuhui; Pastan, Ira; Bigner, Darell D.; Chandramohan, Vidyalakshmi

    2016-01-01

    Glioblastoma is the most aggressive malignant brain tumor among all primary brain and central nervous system tumors. The median survival time for glioblastoma patients given the current standard of care treatment (surgery, radiation, and chemotherapy) is less than 15 months. Thus, there is an urgent need to develop more efficient therapeutics to improve the poor survival rates of patients with glioblastoma. To address this need, we have developed a novel tumor-targeted immunotoxin (IT), D2C7-(scdsFv)-PE38KDEL (D2C7-IT), by fusing the single chain variable fragment (scFv) from the D2C7 monoclonal antibody (mAb) with the Pseudomonas Exotoxin (PE38KDEL). D2C7-IT reacts with both the wild-type epidermal growth factor receptor (EGFRwt) and EGFR variant III (EGFRvIII), two onco-proteins frequently amplified or overexpressed in glioblastomas. Surface plasmon resonance and flow cytometry analyses demonstrated a significant binding capacity of D2C7-IT to both EGFRwt and EGFRvIII proteins. In vitro cytotoxicity data showed that D2C7-IT can effectively inhibit protein synthesis and kill a variety of EGFRwt-, EGFRvIII-, and both EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells and human tumor cell lines. Furthermore, D2C7-IT exhibited a robust anti-tumor efficacy in orthotopic mouse glioma models when administered via intracerebral convection-enhanced delivery (CED). A preclinical toxicity study was therefore conducted to determine the maximum tolerated dose (MTD) and no-observed-adverse-effect-level (NOAEL) of D2C7-IT via intracerebral CED for 72 hours in rats. Based on this successful rat toxicity study, an Investigational New Drug (IND) application (#116855) was approved by the Food and Drug Administration (FDA), and is now in effect for a Phase I/II D2C7-IT clinical trial (D2C7 for Adult Patients with Recurrent Malignant Glioma, https://clinicaltrials.gov/ct2/show/NCT02303678). While it is still too early to draw conclusions from the trial, results thus far are

  7. 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

  8. A magnetic mesoporous silica nanoparticle-based drug delivery system for photosensitive cooperative treatment of cancer with a mesopore-capping agent and mesopore-loaded drug

    NASA Astrophysics Data System (ADS)

    Knežević, Nikola Ž.; Lin, Victor S.-Y.

    2013-01-01

    Lately, there has been a growing interest in anticancer therapy with a combination of different drugs that work by different mechanisms of action, which decreases the possibility that resistant cancer cells will develop. Herein we report on the development of a drug delivery system for photosensitive delivery of a known anticancer drug camptothecin along with cytotoxic cadmium sulfide nanoparticles from a magnetic drug nanocarrier. Core-shell nanoparticles consisting of magnetic iron-oxide-cores and mesoporous silica shells are synthesized with a high surface area (859 m2 g-1) and hexagonal packing of mesopores, which are 2.6 nm in diameter. The mesopores are loaded with anticancer drug camptothecin while entrances of the mesopores are blocked with 2-nitro-5-mercaptobenzyl alcohol functionalized CdS nanoparticles through a photocleavable carbamate linkage. Camptothecin release from this magnetic drug delivery system is successfully triggered upon irradiation with UV light, as measured by fluorescence spectroscopy. Photosensitive anticancer activity of the drug delivery system is monitored by viability studies on Chinese hamster ovarian cells. The treatment of cancer cells with drug loaded magnetic material leads to a decrease in viability of the cells due to the activity of capping CdS nanoparticles. Upon exposure to low power UV light (365 nm) the loaded camptothecin is released which induces additional decrease in viability of CHO cells. Hence, the capping CdS nanoparticles and loaded camptothecin exert a cooperative anticancer activity. Responsiveness to light irradiation and magnetic activity of the nanocarrier enable its potential application for selective targeted treatment of cancer.

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

    PubMed

    Long, Ling; Cai, Xiaodong; Guo, Ruomi; Wang, Ping; Wu, Lili; Yin, Tinghui; Liao, Siyuan; Lu, Zhengqi

    2017-01-01

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

  10. Comparing Different Short-Term Service Delivery Methods of Visual-Motor Treatment for First Grade Students in Mainstream Schools

    ERIC Educational Resources Information Center

    Ratzon, Navah Z.; Lahav, Orit; Cohen-Hamsi, Shifra; Metzger, Yehiela; Efraim, Daniela; Bart, Orit

    2009-01-01

    To compare the efficacy of three different short-term service delivery methods on first grade children with soft neurological signs who suffer from visual-motor difficulties. One hundred and forty seven first grade students who scored below the 21st percentile on the Visual-Motor Integration Test (VMI) were recruited from schools and randomly…

  11. Treatment approach, delivery, and follow-up evaluation for cardiac rhythm disease management patients receiving radiation therapy: Retrospective physician surveys including chart reviews at numerous centers

    SciTech Connect

    Gossman, Michael S.; Wilkinson, Jeffrey D.; Mallick, Avishek

    2014-01-01

    In a 2-part study, we first examined the results of 71 surveyed physicians who provided responses on how they address the management of patients who maintained either a pacemaker or a defibrillator during radiation treatment. Second, a case review study is presented involving 112 medical records reviewed at 18 institutions to determine whether there was a change in the radiation prescription for the treatment of the target cancer, the method of radiation delivery, or the method of radiation image acquisition. Statistics are provided to illustrate the level of administrative policy; the level of communication between radiation oncologists and heart specialists; American Joint Committee on Cancer (AJCC) staging and classification; National Comprehensive Cancer Network (NCCN) guidelines; tumor site; patient's sex; patient's age; device type; manufacturer; live monitoring; and the reported decisions for planning, delivery, and imaging. This survey revealed that 37% of patient treatments were considered for some sort of change in this regard, whereas 59% of patients were treated without regard to these alternatives when available. Only 3% of all patients were identified with an observable change in the functionality of the device or patient status in comparison with 96% of patients with normal behavior and operating devices. Documented changes in the patient's medical record included 1 device exhibiting failure at 0.3-Gy dose, 1 device exhibiting increased sensor rate during dose delivery, 1 patient having an irregular heartbeat leading to device reprogramming, and 1 patient complained of twinging in the chest wall that resulted in a respiratory arrest. Although policies and procedures should directly involve the qualified medical physicist for technical supervision, their sufficient involvement was typically not requested by most respondents. No treatment options were denied to any patient based on AJCC staging, classification, or NCCN practice standards.

  12. Treatment approach, delivery, and follow-up evaluation for cardiac rhythm disease management patients receiving radiation therapy: retrospective physician surveys including chart reviews at numerous centers.

    PubMed

    Gossman, Michael S; Wilkinson, Jeffrey D; Mallick, Avishek

    2014-01-01

    In a 2-part study, we first examined the results of 71 surveyed physicians who provided responses on how they address the management of patients who maintained either a pacemaker or a defibrillator during radiation treatment. Second, a case review study is presented involving 112 medical records reviewed at 18 institutions to determine whether there was a change in the radiation prescription for the treatment of the target cancer, the method of radiation delivery, or the method of radiation image acquisition. Statistics are provided to illustrate the level of administrative policy; the level of communication between radiation oncologists and heart specialists; American Joint Committee on Cancer (AJCC) staging and classification; National Comprehensive Cancer Network (NCCN) guidelines; tumor site; patient׳s sex; patient׳s age; device type; manufacturer; live monitoring; and the reported decisions for planning, delivery, and imaging. This survey revealed that 37% of patient treatments were considered for some sort of change in this regard, whereas 59% of patients were treated without regard to these alternatives when available. Only 3% of all patients were identified with an observable change in the functionality of the device or patient status in comparison with 96% of patients with normal behavior and operating devices. Documented changes in the patient׳s medical record included 1 device exhibiting failure at 0.3-Gy dose, 1 device exhibiting increased sensor rate during dose delivery, 1 patient having an irregular heartbeat leading to device reprogramming, and 1 patient complained of twinging in the chest wall that resulted in a respiratory arrest. Although policies and procedures should directly involve the qualified medical physicist for technical supervision, their sufficient involvement was typically not requested by most respondents. No treatment options were denied to any patient based on AJCC staging, classification, or NCCN practice standards.

  13. MO-A-BRD-10: A Fast and Accurate GPU-Based Proton Transport Monte Carlo Simulation for Validating Proton Therapy Treatment Plans

    SciTech Connect

    Wan Chan Tseung, H; Ma, J; Beltran, C

    2014-06-15

    Purpose: To build a GPU-based Monte Carlo (MC) simulation of proton transport with detailed modeling of elastic and non-elastic (NE) protonnucleus interactions, for use in a very fast and cost-effective proton therapy treatment plan verification system. Methods: Using the CUDA framework, we implemented kernels for the following tasks: (1) Simulation of beam spots from our possible scanning nozzle configurations, (2) Proton propagation through CT geometry, taking into account nuclear elastic and multiple scattering, as well as energy straggling, (3) Bertini-style modeling of the intranuclear cascade stage of NE interactions, and (4) Simulation of nuclear evaporation. To validate our MC, we performed: (1) Secondary particle yield calculations in NE collisions with therapeutically-relevant nuclei, (2) Pencil-beam dose calculations in homogeneous phantoms, (3) A large number of treatment plan dose recalculations, and compared with Geant4.9.6p2/TOPAS. A workflow was devised for calculating plans from a commercially available treatment planning system, with scripts for reading DICOM files and generating inputs for our MC. Results: Yields, energy and angular distributions of secondaries from NE collisions on various nuclei are in good agreement with the Geant4.9.6p2 Bertini and Binary cascade models. The 3D-gamma pass rate at 2%–2mm for 70–230 MeV pencil-beam dose distributions in water, soft tissue, bone and Ti phantoms is 100%. The pass rate at 2%–2mm for treatment plan calculations is typically above 98%. The net computational time on a NVIDIA GTX680 card, including all CPU-GPU data transfers, is around 20s for 1×10{sup 7} proton histories. Conclusion: Our GPU-based proton transport MC is the first of its kind to include a detailed nuclear model to handle NE interactions on any nucleus. Dosimetric calculations demonstrate very good agreement with Geant4.9.6p2/TOPAS. Our MC is being integrated into a framework to perform fast routine clinical QA of pencil

  14. Absolute Measurements of Macrophage Migration Inhibitory Factor and Interleukin-1-β mRNA Levels Accurately Predict Treatment Response in Depressed Patients

    PubMed Central

    Ferrari, Clarissa; Uher, Rudolf; Bocchio-Chiavetto, Luisella; Riva, Marco Andrea; Pariante, Carmine M.

    2016-01-01

    Background: Increased levels of inflammation have been associated with a poorer response to antidepressants in several clinical samples, but these findings have had been limited by low reproducibility of biomarker assays across laboratories, difficulty in predicting response probability on an individual basis, and unclear molecular mechanisms. Methods: Here we measured absolute mRNA values (a reliable quantitation of number of molecules) of Macrophage Migration Inhibitory Factor and interleukin-1β in a previously published sample from a randomized controlled trial comparing escitalopram vs nortriptyline (GENDEP) as well as in an independent, naturalistic replication sample. We then used linear discriminant analysis to calculate mRNA values cutoffs that best discriminated between responders and nonresponders after 12 weeks of antidepressants. As Macrophage Migration Inhibitory Factor and interleukin-1β might be involved in different pathways, we constructed a protein-protein interaction network by the Search Tool for the Retrieval of Interacting Genes/Proteins. Results: We identified cutoff values for the absolute mRNA measures that accurately predicted response probability on an individual basis, with positive predictive values and specificity for nonresponders of 100% in both samples (negative predictive value=82% to 85%, sensitivity=52% to 61%). Using network analysis, we identified different clusters of targets for these 2 cytokines, with Macrophage Migration Inhibitory Factor interacting predominantly with pathways involved in neurogenesis, neuroplasticity, and cell proliferation, and interleukin-1β interacting predominantly with pathways involved in the inflammasome complex, oxidative stress, and neurodegeneration. Conclusion: We believe that these data provide a clinically suitable approach to the personalization of antidepressant therapy: patients who have absolute mRNA values above the suggested cutoffs could be directed toward earlier access to more

  15. SU-E-T-375: Evaluation of a MapCHECK2(tm) Planar 2-D Diode Array for High-Dose-Rate Brachytherapy Treatment Delivery Verifications

    SciTech Connect

    Macey, N; Siebert, M; Shvydka, D; Parsai, E

    2015-06-15

    Purpose: Despite improvements of HDR brachytherapy delivery systems, verification of source position is still typically based on the length of the wire reeled out relative to the parked position. Yet, the majority of errors leading to medical events in HDR treatments continue to be classified as missed targets or wrong treatment sites. We investigate the feasibility of using dose maps acquired with a two-dimensional diode array to independently verify the source locations, dwell times, and dose during an HDR treatment. Methods: Custom correction factors were integrated into frame-by-frame raw counts recorded for a Varian VariSource™ HDR afterloader Ir-192 source located at various distances in air and in solid water from a MapCHECK2™ diode array. The resultant corrected counts were analyzed to determine the dwell position locations and doses delivered. The local maxima of polynomial equations fitted to the extracted dwell dose profiles provided the X and Y coordinates while the distance to the source was determined from evaluation of the full width at half maximum (FWHM). To verify the approach, the experiment was repeated as the source was moved through dwell positions at various distances along an inclined plane, mimicking a vaginal cylinder treatment. Results: Dose map analysis was utilized to provide the coordinates of the source and dose delivered over each dwell position. The accuracy in determining source dwell positions was found to be +/−1.0 mm of the preset values, and doses within +/−3% of those calculated by the BrachyVision™ treatment planning system for all measured distances. Conclusion: Frame-by-frame data furnished by a 2 -D diode array can be used to verify the dwell positions and doses delivered by the HDR source over the course of treatment. Our studies have verified that measurements provided by the MapCHECK2™ can be used as a routine QA tool for HDR treatment delivery verification.

  16. Development and testing of gold nanoparticles for drug delivery and treatment of heart failure: a theranostic potential for PPP cardiology

    PubMed Central

    2013-01-01

    Introduction Nanoscale gold particles (AuNPs) have wide perspectives for biomedical applications because of their unique biological properties, as antioxidative activity and potentials for drug delivery. Aims and objectives The aim was to test effects of AuNPs using suggested heart failure rat model to compare with proved medication Simdax, to test gold nanoparticle for drug delivery, and to test sonoporation effect to increase nanoparticles delivery into myocardial cells. Material and methods We performed biosafety and biocompatibility tests for AuNPs and conjugate with Simdax. For in vivo tests, we included Wistar rats weighing 180–200 g (n = 54), received doxorubicin in cumulative dose of 12.0 mg/kg to model advance heart failure, registered by ultrasonography. We formed six groups: the first three groups of animals received, respectively, 0.06 ml Simdax, AuNPs, and conjugate (AuNPs-Simdax), intrapleurally, and the second three received them intravenously. The seventh group was control (saline). We performed dynamic assessment of heart failure regression in vivo measuring hydrothorax. Sonoporation of gold nanoparticles to cardiomyocytes was tested. Results We designed and constructed colloidal, spherical gold nanoparticles, AuNPs-Simdax conjugate, both founded biosafety (in cytotoxicity, genotoxicity, and immunoreactivity). In all animals of the six groups after the third day post-medication injection, no ascites and liver enlargement were registered (P < 0.001 vs controls). Conjugate injection showed significantly higher hydrothorax reduction than Simdax injection only (P < 0.01); gold nanoparticle injection showed significantly higher results than Simdax injection (P < 0.05). AuNPs and conjugate showed no significant difference for rat recovery. Difference in rat life continuity was significant between Simdax vs AuNPs (P < 0.05) and Simdax vs conjugate (P < 0.05). Sonoporation enhances AuNP transfer into the cell and mitochondria that were highly localized

  17. Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

    PubMed Central

    Salegio, E. Aguilar; Kells, A.P.; Richardson, R.M.; Hadaczek, P.; Forsayeth, J.; Bringas, J.; Sardi, S.P.; Passini, M.A.; Shihabuddin, L.S.; Cheng, S.H.; Fiandaca, M.S.

    2010-01-01

    Abstract Gene replacement therapy for the neurological deficits caused by lysosomal storage disorders, such as in Niemann-Pick disease type A, will require widespread expression of efficacious levels of acid sphingomyelinase (ASM) in the infant human brain. At present there is no treatment available for this devastating pediatric condition. This is partly because of inherent constraints associated with the efficient delivery of therapeutic agents into the CNS of higher order models. In this study we used an adeno-associated virus type 2 (AAV2) vector encoding human acid sphingomyelinase tagged with a viral hemagglutinin epitope (AAV2-hASM-HA) to transduce highly interconnected CNS regions such as the brainstem and thalamus. On the basis of our data showing global cortical expression of a secreted reporter after thalamic delivery in nonhuman primates (NHPs), we set out to investigate whether such widespread expression could be enhanced after brainstem infusion. To maximize delivery of the therapeutic transgene throughout the CNS, we combined a single brainstem infusion with bilateral thalamic infusions in naive NHPs. We found that enzymatic augmentation in brainstem, thalamic, cortical, as well subcortical areas provided convincing evidence that much of the large NHP brain can be transduced with as few as three injection sites. PMID:20408734

  18. Exploring the potential of gastro retentive dosage form in delivery of ellagic acid and aloe vera gel powder for treatment of gastric ulcers.

    PubMed

    Ranade, Arati N; Ranpise, Nisharani S; Ramesh, C

    2014-01-01

    Approach of novel drug delivery system (NDDS) overcomes the limitations of conventional dosage forms. However, this concept is still not practiced to a large extent in delivery of herbal drugs in Ayurveda. Thus, the potential of herbal drugs has not been explored to its fullest. Hence, there is a growing need to amalgamate the concept of NDDS in delivery of herbal constituents. The present investigation is designed to deliver and retain two herbal constituents in stomach for better action against Helicobacter pylori induced gastric ulcers. The objective was to develop a bilayer floating tablet of ellagic acid and Aloe vera gel powder through rational combination of excipients to give the lowest possible lag time with maximum drug release in the period of 4 h. Formulation F9 containing 100 mg of HPMC K15M, 27 mg of crospovidone, 80 mg of mannitol and effervescent agents in the ratio 1:2 gave 92% drug release and desired floating properties. In vivo studies showed that combination of ellagic acid and Aloe vera gave 75 % ulcer inhibition in comparison to 57% ulcer inhibition in the group which was administered with ellagic acid alone. This suggests the use of bilayer floating tablet in gastric ulcer treatment.

  19. Women and Heart Disease - Physiologic Regulation of Gene Delivery and Expression: Bioreducible Polymers and Ischemia-Inducible Gene Therapies for the Treatment of Ischemic Heart Disease

    PubMed Central

    Yockman, James W.; Bull, David A.

    2009-01-01

    Ischemic heart disease (IHD) is the leading cause of death in the United States today. This year over 750,000 women will have a new or recurrent myocardial infarction. Currently, the mainstay of therapy for IHD is revascularization. Increasing evidence, however, suggests that revascularization alone is insufficient for the longer-term management of many patients with IHD. To address these issues, innovative therapies that extend beyond revascularization to protection of the myocyte and preservation of ventricular function are required. The emergence of gene therapy and proteomics offers the potential for innovative prophylactic and treatment strategies for IHD. The goal of our research is to develop therapeutic gene constructs for the treatment of myocardial ischemia that are clinically safe and effective. Toward this end, we describe the development of physiologic regulation of gene delivery and expression using bioreducible polymers and ischemia-inducible gene therapies for the potential treatment of ischemic heart disease in women. PMID:19422868

  20. Commissioning of an Integrated Platform for Time-Resolved Treatment Delivery in Scanned Ion Beam Therapy by Means of Optical Motion Monitoring

    PubMed Central

    Fattori, G.; Saito, N.; Seregni, M.; Kaderka, R.; Pella, A.; Constantinescu, A.; Riboldi, M.; Steidl, P.; Cerveri, P.; Bert, C.; Durante, M.; Baroni, G.

    2014-01-01

    The integrated use of optical technologies for patient monitoring is addressed in the framework of time-resolved treatment delivery for scanned ion beam therapy. A software application has been designed to provide the therapy control system (TCS) with a continuous geometrical feedback by processing the external surrogates tridimensional data, detected in real-time via optical tracking. Conventional procedures for phase-based respiratory phase detection were implemented, as well as the interface to patient specific correlation models, in order to estimate internal tumor motion from surface markers. In this paper, particular attention is dedicated to the quantification of time delays resulting from system integration and its compensation by means of polynomial interpolation in the time domain. Dedicated tests to assess the separate delay contributions due to optical signal processing, digital data transfer to the TCS and passive beam energy modulation actuation have been performed. We report the system technological commissioning activities reporting dose distribution errors in a phantom study, where the treatment of a lung lesion was simulated, with both lateral and range beam position compensation. The zero-delay systems integration with a specific active scanning delivery machine was achieved by tuning the amount of time prediction applied to lateral (14.61 ± 0.98 ms) and depth (34.1 ± 6.29 ms) beam position correction signals, featuring sub-millimeter accuracy in forward estimation. Direct optical target observation and motion phase (MPh) based tumor motion discretization strategies were tested, resulting in −0.3(2.3)% and −1.2(9.3)% median (IQR) percentual relative dose difference with respect to static irradiation, respectively. Results confirm the technical feasibility of the implemented strategy towards 4D treatment delivery, with negligible percentual dose deviations with respect to static irradiation. PMID:24354750

  1. Is scoring system of computed tomography based metric parameters can accurately predicts shock wave lithotripsy stone-free rates and aid in the development of treatment strategies?

    PubMed Central

    Badran, Yasser Ali; Abdelaziz, Alsayed Saad; Shehab, Mohamed Ahmed; Mohamed, Hazem Abdelsabour Dief; Emara, Absel-Aziz Ali; Elnabtity, Ali Mohamed Ali; Ghanem, Maged Mohammed; ELHelaly, Hesham Abdel Azim

    2016-01-01

    Objective: The objective was to determine the predicting success of shock wave lithotripsy (SWL) using a combination of computed tomography based metric parameters to improve the treatment plan. Patients and Methods: Consecutive 180 patients with symptomatic upper urinary tract calculi 20 mm or less were enrolled in our study underwent extracorporeal SWL were divided into two main groups, according to the stone size, Group A (92 patients with stone ≤10 mm) and Group B (88 patients with stone >10 mm). Both groups were evaluated, according to the skin to stone distance (SSD) and Hounsfield units (≤500, 500–1000 and >1000 HU). Results: Both groups were comparable in baseline data and stone characteristics. About 92.3% of Group A rendered stone-free, whereas 77.2% were stone-free in Group B (P = 0.001). Furthermore, in both group SWL success rates was a significantly higher for stones with lower attenuation <830 HU than with stones >830 HU (P < 0.034). SSD were statistically differences in SWL outcome (P < 0.02). Simultaneous consideration of three parameters stone size, stone attenuation value, and SSD; we found that stone-free rate (SFR) was 100% for stone attenuation value <830 HU for stone <10 mm or >10 mm but total number SWL sessions and shock waves required for the larger stone group were higher than in the smaller group (P < 0.01). Furthermore, SFR was 83.3% and 37.5% for stone <10 mm, mean HU >830, SSD 90 mm and SSD >120 mm, respectively. On the other hand, SFR was 52.6% and 28.57% for stone >10 mm, mean HU >830, SSD <90 mm and SSD >120 mm, respectively. Conclusion: Stone size, stone density (HU), and SSD is simple to calculate and can be reported by radiologists to applying combined score help to augment predictive power of SWL, reduce cost, and improving of treatment strategies. PMID:27141192

  2. A bioabsorbable delivery system for antibiotic treatment of osteomyelitis. The use of lactic acid oligomer as a carrier.

    PubMed

    Wei, G; Kotoura, Y; Oka, M; Yamamuro, T; Wada, R; Hyon, S H; Ikada, Y

    1991-03-01

    We prepared a composite of D,L-lactic acid oligomer and dideoxykanamycin B for use as a biodegradable antibiotic delivery system with sustained effect. The composite was implanted in the distal portion of the rabbit femur, and the effective concentration of the antibiotic was measured in the cortex, the cancellous bone, and the bone marrow. In all bone tissues around the implant, the concentration of antibiotic exceeded the minimum inhibitory concentration for the common causative organisms of osteomyelitis for six weeks. Most of the implant material had been absorbed and the bone marrow had been repaired to a nearly normal state within nine weeks of implantation. The implant caused no systemic side effects, and it is likely to prove clinically useful as a drug delivery system for treating chronic osteomyelitis.

  3. Stomach specific polymeric low density microballoons as a vector for extended delivery of rabeprazole and amoxicillin for treatment of peptic ulcer.

    PubMed

    Choudhary, Sandeep; Jain, Ashay; Amin, Mohd Cairul Iqbal Mohd; Mishra, Vijay; Agrawal, Govind P; Kesharwani, Prashant

    2016-05-01

    The study was intended to develop a new intra-gastric floating in situ microballoons system for controlled delivery of rabeprazole sodium and amoxicillin trihydrate for the treatment of peptic ulcer disease. Eudragit S-100 and hydroxypropyl methyl cellulose based low density microballoons systems were fabricated by employing varying concentrations of Eudragit S-100 and hydroxypropyl methyl cellulose, to which varying concentrations of drug was added, and formulated by stirring at various speed and time to optimize the process and formulation variable. The formulation variables like concentration and ratio of polymers significantly affected the in vitro drug release from the prepared floating device. The validation of the gastro-retentive potential of the prepared microballoons was carried out in rabbits by orally administration of microballoons formulation containing radio opaque material. The developed formulations showed improved buoyancy and lower ulcer index as compared to that seen with plain drugs. Ulcer protective efficacies were confirmed in ulcer-bearing mouse model. In conclusion, greater compatibility, higher gastro-retention and higher anti-ulcer activity of the presently fabricated formulations to improve potential of formulation for redefining ulcer treatment are presented here. These learning exposed a targeted and sustained drug delivery potential of prepared microballoons in gastric region for ulcer therapeutic intervention as corroborated by in vitro and in vivo findings and, thus, deserves further attention for improved ulcer treatment.

  4. CERE-110, an adeno-associated virus-based gene delivery vector expressing human nerve growth factor for the treatment of Alzheimer's disease.

    PubMed

    Mandel, Ronald J

    2010-04-01

    To date, only five drugs have been approved for the treatment of Alzheimer's disease (AD); however, these agents impact the symptoms rather than the progression of the disease. It is well established that nerve growth factor (NGF) enhances the function and survival of basal forebrain cholinergic neurons that are vulnerable in AD. However, NGF does not cross the blood-brain barrier, and intraventricular NGF injections in animals and humans were associated with significant side effects. Adeno-associated virus (AAV)-based gene delivery is a novel technology being developed for administration of NGF to the brain to treat AD symptoms and progression. Indeed, the efficacy of ex vivo gene delivery was demonstrated in patients with AD who experienced improvements in cerebral metabolism and cognition compared with pre-operative function without adverse events. CERE-110 (AAV2-NGF), under development by Ceregene Inc, is an AAV serotype 2-based vector expressing human NGF delivered to the nucleus basalis of Meynert by stereotactic injection for the treatment of AD. Animal studies have established the preclinical efficacy of CERE-110, revealing an excellent safety profile. CERE-110 has passed phase I clinical testing and a multicenter phase II clinical trial has commenced. CERE-110 is a promising candidate for the treatment of AD.

  5. Accurate Finite Difference Algorithms

    NASA Technical Reports Server (NTRS)

    Goodrich, John W.

    1996-01-01

    Two families of finite difference algorithms for computational aeroacoustics are presented and compared. All of the algorithms are single step explicit methods, they have the same order of accuracy in both space and time, with examples up to eleventh order, and they have multidimensional extensions. One of the algorithm families has spectral like high resolution. Propagation with high order and high resolution algorithms can produce accurate results after O(10(exp 6)) periods of propagation with eight grid points per wavelength.

  6. Accurate monotone cubic interpolation

    NASA Technical Reports Server (NTRS)

    Huynh, Hung T.

    1991-01-01

    Monotone piecewise cubic interpolants are simple and effective. They are generally third-order accurate, except near strict local extrema where accuracy degenerates to second-order due to the monotonicity constraint. Algorithms for piecewise cubic interpolants, which preserve monotonicity as well as uniform third and fourth-order accuracy are presented. The gain of accuracy is obtained by relaxing the monotonicity constraint in a geometric framework in which the median function plays a crucial role.

  7. Early Stage Treatment of Compartment Syndrome Using Polymer Sol-Gel Composite Growth Factor Delivery Wound Dressings

    DTIC Science & Technology

    2008-12-01

    selected as molecular analogs dextran molecules. Thus, we report on the controlled release of dextran of the same molecular size as pro-angiogenic...Sol-gel formulations for the controlled delivery of growth factor analog Dextran -Texas Red conjugated molecules, with molecular weight (MW) of...keeping in mind the sensitivity of dextran to pH: both acid catalyzed and acid - base catalyzed sols were maintained at a pH equal to or above 3 prior to

  8. 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

  9. Clinical and histological results in the treatment of atrophic and hypertrophic scars using a combined method of radiofrequency, ultrasound, and transepidermal drug delivery.

    PubMed

    Trelles, Mario A; Martínez-Carpio, Pedro A

    2016-08-01

    Scars are problematic for thousands of patients. Scarring is a natural part of the healing process after an injury. However, the appearance of a scar and its treatment depend on multiple factors and on the experience of the therapist and the options available. Despite a plethora of rapidly evolving treatment options and technical advances, the management of atrophic and hypertrophic scars remains difficult. Innovative technologies provide an attractive alternative to conventional methods in the treatment of scars. The purpose of this trial was to determine the clinical and histological results of a method of treatment that combines radiofrequency, ultrasound, and transepidermal drug delivery. This was a prospective study conducted on 14 patients with scars of different sizes, types, and characteristics. All patients underwent six treatment sessions with the Legato device. Atrophic scars were treated with retinoic acid and hypertrophic scars with triamcinolone. Photographs and biopsies were taken before treatment and at 6 months after the last treatment session. The scars improved significantly (P < 0.0001). The mean attenuation in the severity of scars was 67% (range: 50-75%), where 100% indicates complete disappearance of the scar. Clinical and histological images of scar tissue in six patients in whom attenuation in the range of 55-75% was achieved are shown. Biopsies show regenerative changes in the scar tissue, in both the epidermis and dermis. The method makes it possible to treat extensive, heterogeneous scars on different sites with good results that are similar and predictable.

  10. SU-E-J-81: Interplay Effect in Non-Gated Dynamic Treatment Delivery of a Lung Phantom with Simulated Respiratory Motion

    SciTech Connect

    Desai, V; Fagerstrom, J; Bayliss, A; Kissick, M

    2014-06-01

    Purpose: To quantify the interplay effect in non-gated VMAT external beam delivery using realistic, clinically relevant 3D motion in an anthropomorphic lung phantom, and to determine if adding margins is sufficient to account for motion or if gating is required in all cases. Methods: A 4D motion stage was used to move a Virtual Water (VW) lung target containing a piece of radiochromic EBT3 film in an anthropomorphic chest phantom. A five-arc stereotactic body radiation therapy (SBRT) treatment was planned using a CT scan of the phantom in its stationary position, using planning parameters chosen to push the optimizer to achieve a highly-modulated plan. Two scenarios were delivered using a Varian TrueBeam: the first was delivered with the phantom and target both stationary and the second was delivered with the phantom stationary but the target moving in a realistic, irregular 3D elliptical pattern. A single piece of 4×4 cm{sup 2} film was used per fraction, located in the central coronal plane of the target. Film was calibrated on a 6 MV beam with dose values from 0.20 to 20 Gy. Results: Preliminary test films were analyzed in ImageJ and MatLab software. Dose maps were calculated on a central region of interest (ROI) delineated on both the motion-induced and stationary films. Both static and dynamic film dose maps agreed with planning values within acceptable uncertainty. Conclusion: Including a large number of arcs in a clinically realistic SBRT treatment could reduce the effect of motion interplay due to averaging. Because all clinics do not employ multiple arcs for SBRT lung treatments, it is still important to consider the effects of motion on treatment delivery. Further analysis on the treatment films, as well as a broader investigation other planning parameters, will be conducted.

  11. Antibiotic-loaded plaster of Paris implants coated with poly lactide-co-glycolide as a controlled release delivery system for the treatment of bone infections.

    PubMed

    Benoit, M A; Mousset, B; Delloye, C; Bouillet, R; Gillard, J

    1997-01-01

    Plaster of Paris implants containing vancomycin (60 mg/g of carrier) were prepared in order to be used as local delivery system for the treatment of bone infections. The regulation of the release rate was performed by coating the carrier with a polylactide-co-glycolide polymer composed by 10% (w/w) polyglycolic acid and 90% (w/w) racemic poly (D,L-lactic acid). The release of the antibiotic from the biodegradable matrix was evaluated in vitro. From this investigation, it is clear that the drug elution depends on the coating depth. After a burst effect occurring on the first day of the experiment, therapeutic concentrations were measured during one week when uncoated implants were used. The coating allowed decrease of the burst effect and extended efficient release to more than five weeks when the implants were embedded with six layers (162 microns) of PLA45GA10. This delivery system was implanted into the femoral condyle of rabbits. It was shown that the in vivo release was also closely regulated by the coating depth. In all bone tissues (bone marrow and cortical bone) surrounding the pellets, the drug concentration exceeded the Minimum Inhibitory Concentration for the common causative organisms of bone infections (Staphylococcus aureus) for at least four weeks without inducing serum toxic levels. Due to its cheapness, facility of use and sterilization, biocompatibility and biodegradability, plaster of Paris coated with PLA45GA10 polymer giving a controlled release of vancomycin appears to be a promising sustained release delivery system of antibiotics for the treatment of bone and joint infections.

  12. A GLP-Compliant Toxicology and Biodistribution Study: Systemic Delivery of an rAAV9 Vector for the Treatment of Mucopolysaccharidosis IIIB

    PubMed Central

    Meadows, Aaron S.; Duncan, F. Jason; Camboni, Marybeth; Waligura, Kathryn; Montgomery, Chrystal; Zaraspe, Kimberly; Naughton, Bartholomew J.; Bremer, William G.; Shilling, Christopher; Walker, Christopher M.; Bolon, Brad; Flanigan, Kevin M.; McBride, Kim L.; McCarty, Douglas M.; Fu, Haiyan

    2015-01-01

    No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease due to defect in α-N-acetylglucosaminidase (NAGLU). In preparation for a clinical trial, we performed an IND-enabling GLP-toxicology study to assess systemic rAAV9-CMV-hNAGLU gene delivery in WT C57BL/6 mice at 1 × 1014 vg/kg and 2 × 1014 vg/kg (n = 30/group, M:F = 1:1), and non-GLP testing in MPS IIIB mice at 2 × 1014 vg/kg. Importantly, no adverse clinical signs or chronic toxicity were observed through the 6 month study duration. The rAAV9-mediated rNAGLU expression was rapid and persistent in virtually all tested CNS and somatic tissues. However, acute liver toxicity occurred in 33% (5/15) WT males in the 2 × 1014 vg/kg cohort, which was dose-dependent, sex-associated, and genotype-specific, likely due to hepatic rNAGLU overexpression. Interestingly, a significant dose response was observed only in the brain and spinal cord, whereas in the liver at 24 weeks postinfection (pi), NAGLU activity was reduced to endogenous levels in the high dose cohort but remained at supranormal levels in the low dose group. The possibility of rAAV9 germline transmission appears to be minimal. The vector delivery resulted in transient T-cell responses and characteristic acute antibody responses to both AAV9 and rNAGLU in all rAAV9-treated animals, with no detectable impacts on tissue transgene expression. This study demonstrates a generally safe and effective profile, and may have identified the upper dosing limit of rAAV9-CMV-hNAGLU via systemic delivery for the treatment of MPS IIIB. PMID:26684447

  13. An acetylated polysaccharide-PTFE membrane-covered stent for the delivery of gemcitabine for treatment of gastrointestinal cancer and related stenosis.

    PubMed

    Moon, Sumi; Yang, Su-Geun; Na, Kun

    2011-05-01

    Gemcitabine (Gem) eluting metal stents were prepared for potential application as drug delivery systems for localized treatment of malignant tumors. Pullulan, a natural polysaccharide, was chemically acetylated (pullulan acetate; PA) by different degrees (1.18, 1.71, and 2.10 acetyl groups per glucose unit of pullulan), layered on polytetrafluoroethylene (PTFE), and applied as part of a Gem-loaded controlled-release membrane for drug-eluting non-vascular stents. PA with a higher degree of acetylation had greater drug-loading capacity with more extended release of Gem over 30 days. The released Gem accumulated in CT-26 colon cancer without systemic exposure inducing total regression of tumors. The long-term biological activity of the released Gem and apoptosis of tumor tissues following localized delivery were confirmed by annexin V binding assays and histology. The controlled release of Gem from PA-PTFE covered drug-eluting stents (DES) may increase the patency of these stents for the treatment of malignant gastrointestinal cancer as well as cancer-related stenosis.

  14. Novel treatment of coronary artery fistulae concealing severe coronary artery lesion: using thrombus aspiration catheter as a delivery guide

    PubMed Central

    Korkmaz, Levent; Acar, Zeydin; Dursun, İhsan; Akyüz, Ali Rıza; Korkmaz, Ayca Ata

    2014-01-01

    In this case report, we present the occlusion of multiple coronary artery fistulae originating from proximal left anterior descending (LAD) and right sinus valsavla and empting to the pulmonary artery at the same place. We occluded LAD fistulae by using thrombus aspiration catheter as a delivery guide. To the best of our knowlege, this is the first case of occlusion of coronary fistulae with the help of thrombus aspiration catheter. Our experience may suggest that thrombus aspiration catheters can be used in treating coronary artery fistulae with difficult anotomy. PMID:24748888

  15. The spacer arm length in cell-penetrating peptides influences chitosan/siRNA nanoparticle delivery for pulmonary inflammation treatment

    NASA Astrophysics Data System (ADS)

    Jeong, Eun Ju; Choi, Moonhwan; Lee, Jangwook; Rhim, Taiyoun; Lee, Kuen Yong

    2015-11-01

    Although chitosan and its derivatives have been frequently utilized as delivery vehicles for small interfering RNA (siRNA), it is challenging to improve the gene silencing efficiency of chitosan-based nanoparticles. In this study, we hypothesized that controlling the spacer arm length between a cell-penetrating peptide (CPP) and a nanoparticle could be critical to enhancing the cellular uptake as well as the gene silencing efficiency of conventional chitosan/siRNA nanoparticles. A peptide consisting of nine arginine units (R9) was used as a CPP, and the spacer arm length was controlled by varying the number of glycine units between the peptide (R9Gn) and the nanoparticle (n = 0, 4, and 10). Various physicochemical characteristics of R9Gn-chitosan/siRNA nanoparticles were investigated in vitro. Increasing the spacing arm length did not significantly affect the complex formation between R9Gn-chitosan and siRNA. However, R9G10-chitosan was much more effective in delivering genes both in vitro and in vivo compared with non-modified chitosan (without the peptide) and R9-chitosan (without the spacer arm). Chitosan derivatives modified with oligoarginine containing a spacer arm can be considered as potential delivery vehicles for various genes.Although chitosan and its derivatives have been frequently utilized as delivery vehicles for small interfering RNA (siRNA), it is challenging to improve the gene silencing efficiency of chitosan-based nanoparticles. In this study, we hypothesized that controlling the spacer arm length between a cell-penetrating peptide (CPP) and a nanoparticle could be critical to enhancing the cellular uptake as well as the gene silencing efficiency of conventional chitosan/siRNA nanoparticles. A peptide consisting of nine arginine units (R9) was used as a CPP, and the spacer arm length was controlled by varying the number of glycine units between the peptide (R9Gn) and the nanoparticle (n = 0, 4, and 10). Various physicochemical characteristics of

  16. SU-E-T-789: Validation of 3DVH Accuracy On Quantifying Delivery Errors Based On Clinical Relevant DVH Metrics

    SciTech Connect

    Ma, T; Kumaraswamy, L

    2015-06-15

    Purpose: Detection of treatment delivery errors is important in radiation therapy. However, accurate quantification of delivery errors is also of great importance. This study aims to evaluate the 3DVH software’s ability to accurately quantify delivery errors. Methods: Three VMAT plans (prostate, H&N and brain) were randomly chosen for this study. First, we evaluated whether delivery errors could be detected by gamma evaluation. Conventional per-beam IMRT QA was performed with the ArcCHECK diode detector for the original plans and for the following modified plans: (1) induced dose difference error up to ±4.0% and (2) control point (CP) deletion (3 to 10 CPs were deleted) (3) gantry angle shift error (3 degree uniformly shift). 2D and 3D gamma evaluation were performed for all plans through SNC Patient and 3DVH, respectively. Subsequently, we investigated the accuracy of 3DVH analysis for all cases. This part evaluated, using the Eclipse TPS plans as standard, whether 3DVH accurately can model the changes in clinically relevant metrics caused by the delivery errors. Results: 2D evaluation seemed to be more sensitive to delivery errors. The average differences between ECLIPSE predicted and 3DVH results for each pair of specific DVH constraints were within 2% for all three types of error-induced treatment plans, illustrating the fact that 3DVH is fairly accurate in quantifying the delivery errors. Another interesting observation was that even though the gamma pass rates for the error plans are high, the DVHs showed significant differences between original plan and error-induced plans in both Eclipse and 3DVH analysis. Conclusion: The 3DVH software is shown to accurately quantify the error in delivered dose based on clinically relevant DVH metrics, where a conventional gamma based pre-treatment QA might not necessarily detect.

  17. Nanoscale Drug Delivery and Hyperthermia: The Materials Design and Preclinical and Clinical Testing of Low Temperature-Sensitive Liposomes Used in Combination with Mild Hyperthermia in the Treatment of Local Cancer

    PubMed Central

    Landon, Chelsea D.; Park, Ji-Young; Needham, David; Dewhirst, Mark W.

    2012-01-01

    The overall objective of liposomal drug delivery is to selectively target drug delivery to diseased tissue, while minimizing drug delivery to critical normal tissues. The purpose of this review is to provide an overview of temperature-sensitive liposomes in general and the Low Temperature-Sensitive Liposome (LTSL) in particular. We give a brief description of the material design of LTSL and highlight the likely mechanism behind temperature-triggered drug release. A complete review of the progress and results of the latest preclinical and clinical studies that demonstrate enhanced drug delivery with the combined treatment of hyperthermia and liposomes is provided as well as a clinical perspective on cancers that would benefit from hyperthermia as an adjuvant treatment for temperature-triggered chemotherapeutics. This review discusses the ideas, goals, and processes behind temperature-sensitive liposome development in the laboratory to the current use in preclinical and clinical settings. PMID:23807899

  18. Optimization of novel pentablock copolymer based composite formulation for sustained delivery of peptide/protein in the treatment of ocular diseases

    PubMed Central

    Patel, Sulabh P.; Vaishya, Ravi; Patel, Ashaben; Agrahari, Vibhuti; Pal, Dhananjay; Mitra, Ashim K.

    2016-01-01

    This manuscript is focused on the development of pentablock (PB) copolymer based sustained release formulation for the treatment of posterior segment ocular diseases. We have successfully synthesized biodegradable and biocompatible PB copolymers for the preparation of nanoparticles (NPs) and thermosensitive gel. Achieving high drug loading with hydrophilic biotherapeutics (peptides /proteins) is a challenging task. Moreover, small intravitreal injection volume (≤100 μL) requires high loading to develop a long term (6 months) sustained release formulation. We have successfully investigated various formulation parameters to achieve maximum peptide/protein (octreotide, insulin, lysozyme, IgG-Fab, IgG, and catalase) loading in PB NPs. Improvement in drug loading can facilitate delivery of larger doses of therapeutic proteins via limited injection volume. A composite formulation comprised of NPs in gel system exhibited sustained release (without burst effect) of peptides and proteins, may serve as a platform technology for the treatment of posterior segment ocular diseases. PMID:26964498

  19. Three-dimensional aligned nanofibers-hydrogel scaffold for controlled non-viral drug/gene delivery to direct axon regeneration in spinal cord injury treatment

    PubMed Central

    Nguyen, Lan Huong; Gao, Mingyong; Lin, Junquan; Wu, Wutian; Wang, Jun; Chew, Sing Yian

    2017-01-01

    Spinal cord injuries (SCI) often lead to persistent neurological dysfunction due to failure in axon regeneration. Unfortunately, currently established treatments, such as direct drug administration, do not effectively treat SCI due to rapid drug clearance from our bodies. Here, we introduce a three-dimensional aligned nanofibers-hydrogel scaffold as a bio-functionalized platform to provide sustained non-viral delivery of proteins and nucleic acid therapeutics (small non-coding RNAs), along with synergistic contact guidance for nerve injury treatment. A hemi-incision model at cervical level 5 in the rat spinal cord was chosen to evaluate the efficacy of this scaffold design. Specifically, aligned axon regeneration was observed as early as one week post-injury. In addition, no excessive inflammatory response and scar tissue formation was triggered. Taken together, our results demonstrate the potential of our scaffold for neural tissue engineering applications. PMID:28169354

  20. Three-dimensional aligned nanofibers-hydrogel scaffold for controlled non-viral drug/gene delivery to direct axon regeneration in spinal cord injury treatment.

    PubMed

    Nguyen, Lan Huong; Gao, Mingyong; Lin, Junquan; Wu, Wutian; Wang, Jun; Chew, Sing Yian

    2017-02-07

    Spinal cord injuries (SCI) often lead to persistent neurological dysfunction due to failure in axon regeneration. Unfortunately, currently established treatments, such as direct drug administration, do not effectively treat SCI due to rapid drug clearance from our bodies. Here, we introduce a three-dimensional aligned nanofibers-hydrogel scaffold as a bio-functionalized platform to provide sustained non-viral delivery of proteins and nucleic acid therapeutics (small non-coding RNAs), along with synergistic contact guidance for nerve injury treatment. A hemi-incision model at cervical level 5 in the rat spinal cord was chosen to evaluate the efficacy of this scaffold design. Specifically, aligned axon regeneration was observed as early as one week post-injury. In addition, no excessive inflammatory response and scar tissue formation was triggered. Taken together, our results demonstrate the potential of our scaffold for neural tissue engineering applications.

  1. SU-C-17A-07: The Development of An MR Accelerator-Enabled Planning-To-Delivery Technique for Stereotactic Palliative Radiotherapy Treatment of Spinal Metastases

    SciTech Connect

    Hoogcarspel, S J; Kontaxis, C; Velden, J M van der; Bol, G H; Vulpen, M van; Lagendijk, J J W; Raaymakers, B W

    2014-06-01

    Purpose: To develop an MR accelerator-enabled online planning-todelivery technique for stereotactic palliative radiotherapy treatment of spinal metastases. The technical challenges include; automated stereotactic treatment planning, online MR-based dose calculation and MR guidance during treatment. Methods: Using the CT data of 20 patients previously treated at our institution, a class solution for automated treatment planning for spinal bone metastases was created. For accurate dose simulation right before treatment, we fused geometrically correct online MR data with pretreatment CT data of the target volume (TV). For target tracking during treatment, a dynamic T2-weighted TSE MR sequence was developed. An in house developed GPU based IMRT optimization and dose calculation algorithm was used for fast treatment planning and simulation. An automatically generated treatment plan developed with this treatment planning system was irradiated on a clinical 6 MV linear accelerator and evaluated using a Delta4 dosimeter. Results: The automated treatment planning method yielded clinically viable plans for all patients. The MR-CT fusion based dose calculation accuracy was within 2% as compared to calculations performed with original CT data. The dynamic T2-weighted TSE MR Sequence was able to provide an update of the anatomical location of the TV every 10 seconds. Dose calculation and optimization of the automatically generated treatment plans using only one GPU took on average 8 minutes. The Delta4 measurement of the irradiated plan agreed with the dose calculation with a 3%/3mm gamma pass rate of 86.4%. Conclusions: The development of an MR accelerator-enabled planning-todelivery technique for stereotactic palliative radiotherapy treatment of spinal metastases was presented. Future work will involve developing an intrafraction motion adaptation strategy, MR-only dose calculation, radiotherapy quality-assurance in a magnetic field, and streamlining the entire treatment

  2. Interrupting transmission of soil-transmitted helminths: a study protocol for cluster randomised trials evaluating alternative treatment strategies and delivery systems in Kenya

    PubMed Central

    Brooker, Simon J; Mwandawiro, Charles S; Halliday, Katherine E; Njenga, Sammy M; Mcharo, Carlos; Gichuki, Paul M; Wasunna, Beatrice; Kihara, Jimmy H; Njomo, Doris; Alusala, Dorcas; Chiguzo, Athuman; Turner, Hugo C; Teti, Caroline; Gwayi-Chore, Claire; Nikolay, Birgit; Truscott, James E; Hollingsworth, T Déirdre; Balabanova, Dina; Griffiths, Ulla K; Freeman, Matthew C; Allen, Elizabeth; Pullan, Rachel L; Anderson, Roy M

    2015-01-01

    Introduction In recent years, an unprecedented emphasis has been given to the control of neglected tropical diseases, including soil-transmitted helminths (STHs). The mainstay of STH control is school-based deworming (SBD), but mathematical modelling has shown that in all but very low transmission settings, SBD is unlikely to interrupt transmission, and that new treatment strategies are required. This study seeks to answer the question: is it possible to interrupt the transmission of STH, and, if so, what is the most cost-effective treatment strategy and delivery system to achieve this goal? Methods and analysis Two cluster randomised trials are being implemented in contrasting settings in Kenya. The interventions are annual mass anthelmintic treatment delivered to preschool- and school-aged children, as part of a national SBD programme, or to entire communities, delivered by community health workers. Allocation to study group is by cluster, using predefined units used in public health provision—termed community units (CUs). CUs are randomised to one of three groups: receiving either (1) annual SBD; (2) annual community-based deworming (CBD); or (3) biannual CBD. The primary outcome measure is the prevalence of hookworm infection, assessed by four cross-sectional surveys. Secondary outcomes are prevalence of Ascaris lumbricoides and Trichuris trichiura, intensity of species infections and treatment coverage. Costs and cost-effectiveness will be evaluated. Among a random subsample of participants, worm burden and proportion of unfertilised eggs will be assessed longitudinally. A nested process evaluation, using semistructured interviews, focus group discussions and a stakeholder analysis, will investigate the community acceptability, feasibility and scale-up of each delivery system. Ethics and dissemination Study protocols have been reviewed and approved by the ethics committees of the Kenya Medical Research Institute and National Ethics Review Committee, and

  3. Development and evaluation of aerosol delivery of antivirals for the treatment of equine virus induced respiratory infections

    SciTech Connect

    Martens, J.G.

    1985-01-01

    An aerosol delivery system incorporating the DeVilbiss ultrasonic nebulizer was developed for antiviral chemotherapy of equine viral respiratory infections. The system's delivery capabilities were proven effective by two modes of analysis: (a) a non-destructive, non-invasive radioactive tracer method utilizing a saline solution of DTPA labelled 99mTc and, (b) an invasive-terminal study using fluorescent polystyrene monodispersed latex particles. Particles were efficiently distributed throughout the lung parenchyma with deposition more heavily concentrated in the tracheobronchial region. Amantadine HCl was administered to the lungs of a yearling horse and three yearling Shetland ponies over a single 15-30 minute period with no untoward side effects. Likewise, ribavirin was aerosolized into the respiratory trace of an adult pony and a yearling horse for 15-30 minutes twice a day for three and seven days respectively. Neither the horse nor pony demonstrated signs of clinical illness or other signs of ribavirin toxicity. Attempts to produce a reproducible equine influenza disease model were made. During these studies, the authors were unsuccessful in developing a consistent respiratory disease model. Without this model the efficacy of antiviral compounds cannot be assessed. From the data generated in these studies, the implication of equine influenza viruses as the major single etiological agents responsible for equine respiratory disease is brought into question. Further, the author proposed that equine respiratory disease is a multiple agent-induced disease, which needs extensive investigation.

  4. Delivery of Berberine Using Chitosan/Fucoidan-Taurine Conjugate Nanoparticles for Treatment of Defective Intestinal Epithelial Tight Junction Barrier

    PubMed Central

    Wu, Shao-Jung; Don, Trong-Ming; Lin, Cheng-Wei; Mi, Fwu-Long

    2014-01-01

    Bacterial-derived lipopolysaccharides (LPS) can cause defective intestinal barrier function and play an important role in the development of inflammatory bowel disease. In this study, a nanocarrier based on chitosan and fucoidan was developed for oral delivery of berberine (Ber). A sulfonated fucoidan, fucoidan-taurine (FD-Tau) conjugate, was synthesized and characterized by Fourier transform infrared (FTIR) spectroscopy. The FD-Tau conjugate was self-assembled with berberine and chitosan (CS) to form Ber-loaded CS/FD-Tau complex nanoparticles with high drug loading efficiency. Berberine release from the nanoparticles had fast release in simulated intestinal fluid (SIF, pH 7.4), while the release was slow in simulated gastric fluid (SGF, pH 2.0). The effect of the berberine-loaded nanoparticles in protecting intestinal tight-junction barrier function against nitric oxide and inflammatory cytokines released from LPS-stimulated macrophage was evaluated by determining the transepithelial electrical resistance (TEER) and paracellular permeability of a model macromolecule fluorescein isothiocyanate-dextran (FITC-dextran) in a Caco-2 cells/RAW264.7 cells co-culture system. Inhibition of redistribution of tight junction ZO-1 protein by the nanoparticles was visualized using confocal laser scanning microscopy (CLSM). The results suggest that the nanoparticles may be useful for local delivery of berberine to ameliorate LPS-induced intestinal epithelia tight junction disruption, and that the released berberine can restore barrier function in inflammatory and injured intestinal epithelial. PMID:25421323

  5. Well-defined, size-tunable, multi-functional micelles for efficient paclitaxel delivery for cancer treatment

    PubMed Central

    Luo, Juntao; Xiao, Kai; Li, Yuanpei; Lee, Joyce S.; Shi, Lifang; Tan, Yih-Horng; Xing, Li; Cheng, R. Holland; Liu, Gang-Yu; Lam, Kit S.

    2010-01-01

    We have developed a well-defined and biocompatible amphiphilic telodendrimer system (PEG-b-dendritic oligo-cholic acid) which can self-assemble into multifunctional micelles in aqueous solution for efficient delivery of hydrophobic drugs such as paclitaxel. In this telodendrimer system, cholic acid is essential for the formation of stable micelles with high drug loading capacity, owing to its facial amphiphilicity. A series of telodendrimers with variable length of PEG chain and number of cholic acid in the dendritic blocks were synthesized. The structure and molecular weight of each of these telodendrimers were characterized, and their critical micellization concentration (CMC), drug-loading properties, particle sizes and cytotoxicity were examined and evaluated for further optimization for anticancer drug delivery. The sizes of the micelles, with and without paclitaxel loading, could be tuned from 11.5 to 21 nm and from 15 to 141 nm, respectively. Optical imaging studies in xenograft models demonstrated preferential uptakes of the smaller paclitaxel-loaded micelles (17–60 nm) by the tumor, and the larger micelles (150 nm) by the liver and lung. The toxicity and anti-tumor efficacy profiles of these paclitaxel-loaded micelles in xenograft models were found to be superior to those of Taxol® and Abraxane®. PMID:20536174

  6. Novel polyacrylate-based cationic nanoparticles for survivin siRNA delivery combined with mitoxantrone for treatment of breast cancer.

    PubMed

    Arami, Sanam; Mahdavi, Majid; Rashidi, Mohammad Reza; Fathi, Marziyeh; Hejazi, Mohammad-Saeid; Samadi, Nasser

    2016-11-01

    As a gene delivery method in breast cancer therapy, knocking down the undesired genes in the cancerous cells would be promising. Inhibitors of Apoptosis Protein (IAP) family genes are some of the genes whose responsibility is inhibition of apoptosis in cells. Silencing these genes seems to be helpful directing the tumor cells to death. siRNA sequence designed against survivin anti-apoptotic gene can play this role if carried to the cytoplasm. Here we prepared a positive charged biocompatible nano-sized particle made up of a Fe3O4 core covered respectively by polyacrylate (PA) and polyethyleneimine (PEI) layer, which could successfully deliver the siRNA into the MCF-7 cells. The particle structure was checked and having less than 50 nm diameter in size, positive charge and, safety towards MCF-7 cells besides being able to form nanoplexes with the siRNA strand helps it entering into the biologic assays part. The siRNA delivery evaluated via flowcytometry. Apoptosis induction was determined by DAPI staining. The efficiency of survivin gene knockdown was evaluated in mRNA and protein levels using Real time PCR and western blotting methods. Overall, the Fe3O4-PA-PEI nanoparticles can deliver siRNA effectively into the cytoplasm of the MCF-7 breast cancer cells and induce apoptosis.

  7. Tumor-targeted Chlorotoxin-coupled Nanoparticles for Nucleic Acid Delivery to Glioblastoma Cells: A Promising System for Glioblastoma Treatment

    PubMed Central

    Costa, Pedro M; Cardoso, Ana L; Mendonça, Liliana S; Serani, Angelo; Custódia, Carlos; Conceição, Mariana; Simões, Sérgio; Moreira, João N; Pereira de Almeida, Luís; Pedroso de Lima, Maria C

    2013-01-01

    The present work aimed at the development and application of a lipid-based nanocarrier for targeted delivery of nucleic acids to glioblastoma (GBM). For this purpose, chlorotoxin (CTX), a peptide reported to bind selectively to glioma cells while showing no affinity for non-neoplastic cells, was covalently coupled to liposomes encapsulating antisense oligonucleotides (asOs) or small interfering RNAs (siRNAs). The resulting targeted nanoparticles, designated CTX-coupled stable nucleic acid lipid particles (SNALPs), exhibited excellent features for in vivo application, namely small size (<180 nm) and neutral surface charge. Cellular association and internalization studies revealed that attachment of CTX onto the liposomal surface enhanced particle internalization into glioma cells, whereas no significant internalization was observed in noncancer cells. Moreover, nanoparticle-mediated miR-21 silencing in U87 human GBM and GL261 mouse glioma cells resulted in increased levels of the tumor suppressors PTEN and PDCD4, caspase 3/7 activation and decreased tumor cell proliferation. Preliminary in vivo studies revealed that CTX enhances particle internalization into established intracranial tumors. Overall, our results indicate that the developed targeted nanoparticles represent a valuable tool for targeted nucleic acid delivery to cancer cells. Combined with a drug-based therapy, nanoparticle-mediated miR-21 silencing constitutes a promising multimodal therapeutic approach towards GBM. PMID:23778499

  8. The spacer arm length in cell-penetrating peptides influences chitosan/siRNA nanoparticle delivery for pulmonary inflammation treatment.

    PubMed

    Jeong, Eun Ju; Choi, Moonhwan; Lee, Jangwook; Rhim, Taiyoun; Lee, Kuen Yong

    2015-12-21

    Although chitosan and its derivatives have been frequently utilized as delivery vehicles for small interfering RNA (siRNA), it is challenging to improve the gene silencing efficiency of chitosan-based nanoparticles. In this study, we hypothesized that controlling the spacer arm length between a cell-penetrating peptide (CPP) and a nanoparticle could be critical to enhancing the cellular uptake as well as the gene silencing efficiency of conventional chitosan/siRNA nanoparticles. A peptide consisting of nine arginine units (R9) was used as a CPP, and the spacer arm length was controlled by varying the number of glycine units between the peptide (R9Gn) and the nanoparticle (n = 0, 4, and 10). Various physicochemical characteristics of R9Gn-chitosan/siRNA nanoparticles were investigated in vitro. Increasing the spacing arm length did not significantly affect the complex formation between R9Gn-chitosan and siRNA. However, R9G10-chitosan was much more effective in delivering genes both in vitro and in vivo compared with non-modified chitosan (without the peptide) and R9-chitosan (without the spacer arm). Chitosan derivatives modified with oligoarginine containing a spacer arm can be considered as potential delivery vehicles for various genes.

  9. Accurate quantum chemical calculations

    NASA Technical Reports Server (NTRS)

    Bauschlicher, Charles W., Jr.; Langhoff, Stephen R.; Taylor, Peter R.

    1989-01-01

    An important goal of quantum chemical calculations is to provide an understanding of chemical bonding and molecular electronic structure. A second goal, the prediction of energy differences to chemical accuracy, has been much harder to attain. First, the computational resources required to achieve such accuracy are very large, and second, it is not straightforward to demonstrate that an apparently accurate result, in terms of agreement with experiment, does not result from a cancellation of errors. Recent advances in electronic structure methodology, coupled with the power of vector supercomputers, have made it possible to solve a number of electronic structure problems exactly using the full configuration interaction (FCI) method within a subspace of the complete Hilbert space. These exact results can be used to benchmark approximate techniques that are applicable to a wider range of chemical and physical problems. The methodology of many-electron quantum chemistry is reviewed. Methods are considered in detail for performing FCI calculations. The application of FCI methods to several three-electron problems in molecular physics are discussed. A number of benchmark applications of FCI wave functions are described. Atomic basis sets and the development of improved methods for handling very large basis sets are discussed: these are then applied to a number of chemical and spectroscopic problems; to transition metals; and to problems involving potential energy surfaces. Although the experiences described give considerable grounds for optimism about the general ability to perform accurate calculations, there are several problems that have proved less tractable, at least with current computer resources, and these and possible solutions are discussed.

  10. Tumor pHe-triggered charge-reversal and redox-responsive nanoparticles for docetaxel delivery in hepatocellular carcinoma treatment

    NASA Astrophysics Data System (ADS)

    Chen, Fengqian; Zhang, Jinming; Wang, Lu; Wang, Yitao; Chen, Meiwan

    2015-09-01

    The insufficient cellular uptake of nanocarriers and their slow drug release have become major obstacles for achieving satisfactory anticancer outcomes in nano-medicine therapy. Because of the slightly acidic extracellular environment (pHe ~ 6.5) and a higher glutathione (GSH) concentration (approximately 10 mM) in tumor tissue/cells, we firstly designed a novel d-α-tocopheryl polyethylene glycol 1000-poly(β-amino ester) block copolymer containing disulfide linkages (TPSS). TPSS nanoparticles (NPs) with pH- and redox-sensitive behaviors were developed for on-demand delivery of docetaxel (DTX) in hepatocellular carcinoma. DTX/TPSS NPs exhibited sensitive surface charge reversal from -47.6 +/- 2.5 mV to +22.5 +/- 3.2 mV when the pH decreased from 7.4 to 6.5, to simulate the pHe. Meanwhile, anabatic drug release of DTX/TPSS NPs was observed in PBS buffer (pH 6.5, 10 mM GSH). Due to the synergism between the pHe-triggered charge reversal and the redox-triggered drug release, enhanced drug uptake and anticancer efficacy were observed in HepG2 and SMMC 7721 cells treated with DTX/TPSS NPs. The positively charged NPs exhibited a stronger inhibitory effect on cell proliferation, promoted cell cycle arrest in the G2/M phase, and increased the rate of apoptosis. More importantly, based on the higher tumor accumulation of TPSS vehicles in vivo, a significant suppression of tumor growth, but without side-effects, was observed when DTX/TPSS NPs were injected intravenously into HepG2 xenograft tumor-bearing mice. Collectively, these results demonstrate that the newly developed dual-functional TPSS copolymer may be utilized as a drug delivery system for anticancer therapy.The insufficient cellular uptake of nanocarriers and their slow drug release have become major obstacles for achieving satisfactory anticancer outcomes in nano-medicine therapy. Because of the slightly acidic extracellular environment (pHe ~ 6.5) and a higher glutathione (GSH) concentration (approximately 10 m

  11. Evaluation of the biological differences of canine and human factor VIII in gene delivery: Implications in human hemophilia treatment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The canine is the most important large animal model for testing novel hemophilia A(HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, the different biological properties between cFVIII and human FVII...

  12. Systematic measurements of whole-body dose distributions for various treatment machines and delivery techniques in radiation therapy

    SciTech Connect

    Haelg, Roger A.; Besserer, Juergen; Schneider, Uwe

    2012-12-15

    Purpose: Contemporary radiotherapy treatment techniques, such as intensity-modulated radiation therapy and volumetric modulated arc therapy, could increase the radiation-induced malignancies because of the increased beam-on time, i.e., number of monitor units needed to deliver the same dose to the target and the larger volume irradiated with low doses. In this study, whole-body dose distributions from typical radiotherapy patient plans using different treatment techniques and therapy machines were measured using the same measurement setup and irradiation intention. Methods: Individually calibrated thermoluminescent dosimeters were used to measure absorbed dose in an anthropomorphic phantom at 184 locations. The dose distributions from 6 MV beams were compared in terms of treatment technique (3D-conformal, intensity-modulated radiation therapy, volumetric modulated arc therapy, helical TomoTherapy, stereotactic radiotherapy, hard wedges, and flattening filter-free radiotherapy) and therapy machine (Elekta, Siemens and Varian linear accelerators, Accuray CyberKnife and TomoTherapy). Results: Close to the target, the doses from intensity-modulated treatments (including flattening filter-free) were below the dose from a static treatment plan, whereas the CyberKnife showed a larger dose by a factor of two. Far away from the treatment field, the dose from intensity-modulated treatments showed an increase in dose from stray radiation of about 50% compared to the 3D-conformal treatment. For the flattening filter-free photon beams, the dose from stray radiation far away from the target was slightly lower than the dose from a static treatment. The CyberKnife irradiation and the treatment using hard wedges increased the dose from stray radiation by nearly a factor of three compared to the 3D-conformal treatment. Conclusions: This study showed that the dose outside of the treated volume is influenced by several sources. Therefore, when comparing different treatment techniques

  13. Promising practices for delivery of court-supervised substance abuse treatment: Perspectives from six high-performing California counties operating Proposition 36

    PubMed Central

    Evans, Elizabeth; Anglin, M. Douglas; Urada, Darren; Yang, Joy

    2010-01-01

    Operative for nearly a decade, California's voter-initiated Proposition 36 program offers many offenders community-based substance abuse treatment in lieu of likely incarceration. Research has documented program successes and plans for replication have proliferated, yet very little is known about how the Proposition 36 program works or practices for achieving optimal program outcomes. In this article, we identify policies and practices that key stakeholders perceive to be most responsible for the successful delivery of court-supervised substance abuse treatment to offenders under Proposition 36. Data was collected via focus groups conducted with 59 county stakeholders in six high-performing counties during 2009. Discussion was informed by seven empirical indicators of program performance and outcomes and was focused on identifying and describing elements contributing to success. Program success was primarily attributed to four strategies, those that: (1) fostered program engagement, monitored participant progress, and sustained cooperation among participants; (2) cultivated buy-in among key stakeholders; (3) capitalized on the role of the court and the judge; and (4) created a setting which promoted a high-quality treatment system, utilization of existing resources, and broad financial and political support for the program. Goals and practices for implementing each strategy are discussed. Findings provide a “promising practices” resource for Proposition 36 program evaluation and improvement and inform the design and study of other similar types of collaborative justice treatment efforts. PMID:20965568

  14. A case study using a patient satisfaction survey to improve the delivery and effectiveness of drug addiction treatment services: marketing implications and organizational impact.

    PubMed

    Hogan, Beth; Hershey, Lewis; Ritchey, Steven

    2007-01-01

    Drug abuse and addiction continues to negatively impact many lives in this country. The United States health care system has grappled with how to best serve this vulnerable population. Since the personal and societal costs of addiction are high, all recent iterations of the United States strategic health plans (such as Healthy People 2010) have prioritized this area for improvement. At the local level, health care providers who care for those with addictions are challenged with shrinking insurance coverage for services, a difficult patient population, lack of treatment options, growing ranks of indigent patients, as well as a plethora of additional management challenges. It is known that successful treatment is integrally linked with patient satisfaction with services. The most critical factors in successful addiction treatment (from a patient's perspective) are (1) their belief that the counselor cares about them and, (2) their belief that they can recover. This paper reports a case study in the use of a patient satisfaction survey as a quality management/service refinement tool within a methadone treatment setting. Results indicate that the use of the survey itself provides patients with a tangible cue supporting the presence of the critical success factors. Further, the use of a survey provides a baseline for future measurements and trending. The paper concludes with a discussion of the marketing and organizational implications of incorporating the patient satisfaction survey into the ongoing delivery program for addiction services.

  15. Forceps Delivery

    MedlinePlus

    ... provider might limit the amount of time you push. Your baby is facing the wrong direction. A forceps delivery might be needed if your baby is facing up (occiput posterior position) rather than down (occiput anterior ...

  16. Delivery presentations

    MedlinePlus

    ... page: //medlineplus.gov/ency/patientinstructions/000621.htm Delivery presentations To use the sharing features on this page, ... baby by cesarean birth (C-section) . Less Common Presentations With the brow-first position, the baby's head ...

  17. Accurate spectral color measurements

    NASA Astrophysics Data System (ADS)

    Hiltunen, Jouni; Jaeaeskelaeinen, Timo; Parkkinen, Jussi P. S.

    1999-08-01

    Surface color measurement is of importance in a very wide range of industrial applications including paint, paper, printing, photography, textiles, plastics and so on. For a demanding color measurements spectral approach is often needed. One can measure a color spectrum with a spectrophotometer using calibrated standard samples as a reference. Because it is impossible to define absolute color values of a sample, we always work with approximations. The human eye can perceive color difference as small as 0.5 CIELAB units and thus distinguish millions of colors. This 0.5 unit difference should be a goal for the precise color measurements. This limit is not a problem if we only want to measure the color difference of two samples, but if we want to know in a same time exact color coordinate values accuracy problems arise. The values of two instruments can be astonishingly different. The accuracy of the instrument used in color measurement may depend on various errors such as photometric non-linearity, wavelength error, integrating sphere dark level error, integrating sphere error in both specular included and specular excluded modes. Thus the correction formulas should be used to get more accurate results. Another question is how many channels i.e. wavelengths we are using to measure a spectrum. It is obvious that the sampling interval should be short to get more precise results. Furthermore, the result we get is always compromise of measuring time, conditions and cost. Sometimes we have to use portable syste or the shape and the size of samples makes it impossible to use sensitive equipment. In this study a small set of calibrated color tiles measured with the Perkin Elmer Lamda 18 and the Minolta CM-2002 spectrophotometers are compared. In the paper we explain the typical error sources of spectral color measurements, and show which are the accuracy demands a good colorimeter should have.

  18. Optimal control of hepatitis C antiviral treatment programme delivery for prevention amongst a population of injecting drug users.

    PubMed

    Martin, Natasha K; Pitcher, Ashley B; Vickerman, Peter; Vassall, Anna; Hickman, Matthew

    2011-01-01

    In most developed countries, HCV is primarily transmitted by injecting drug users (IDUs). HCV antiviral treatment is effective, and deemed cost-effective for those with no re-infection risk. However, few active IDUs are currently treated. Previous modelling studies have shown antiviral treatment for active IDUs could reduce HCV prevalence, and there is emerging interest in developing targeted IDU treatment programmes. However, the optimal timing and scale-up of treatment is unknown, given the real-world constraints commonly existing for health programmes. We explore how the optimal programme is affected by a variety of policy objectives, budget constraints, and prevalence settings. We develop a model of HCV transmission and treatment amongst active IDUs, determine the optimal treatment programme strategy over 10 years for two baseline chronic HCV prevalence scenarios (30% and 45%), a range of maximum annual budgets (£50,000-300,000 per 1,000 IDUs), and a variety of objectives: minimising health service costs and health utility losses; minimising prevalence at 10 years; minimising health service costs and health utility losses with a final time prevalence target; minimising health service costs with a final time prevalence target but neglecting health utility losses. The largest programme allowed for a given budget is the programme which minimises both prevalence at 10 years, and HCV health utility loss and heath service costs, with higher budgets resulting in greater cost-effectiveness (measured by cost per QALY gained compared to no treatment). However, if the objective is to achieve a 20% relative prevalence reduction at 10 years, while minimising both health service costs and losses in health utility, the optimal treatment strategy is an immediate expansion of coverage over 5-8 years, and is less cost-effective. By contrast, if the objective is only to minimise costs to the health service while attaining the 20% prevalence reduction, the programme is deferred

  19. Multi-point injection: A general purpose delivery system for treatment and containment of hazardous and radiological waste

    SciTech Connect

    Kauschinger, J.L.; Kubarewicz, J.; Van Hoesen, S.D.

    1997-12-31

    The multi-point injection (MPI) technology is a proprietary jetting process for the in situ delivery of various agents to treat radiological and/or chemical wastes. A wide variety of waste forms can be treated, varying from heterogeneous solid waste dumped into shallow burial trenches, bottom sludge (heel material) inside of underground tanks, and contaminated soils with widely varying soil composition (gravel, silts/clays, soft rock). The robustness of the MPI system is linked to the use of high speed mono-directional jets to deliver various types of agents for a variety of applications, such as: pretreatment of waste prior to insitu vitrification, solidification of waste for creating low conductivity monoliths, oxidants for insitu destruction of organic waste, and grouts for creating barriers (vertical, inclined, and bottom seals). The only strict limitation placed upon the MPI process is that the material can be pumped under high pressure. This paper describes the procedures to inject ordinary grout to form solidified monoliths of solid wastes.

  20. In situ delivery of thermosensitive gel-mediated 5-fluorouracil microemulsion for the treatment of colorectal cancer

    PubMed Central

    Wang, Lu-Lu; Huang, Shuai; Guo, Hui-Hui; Han, Yan-Xing; Zheng, Wen-Sheng; Jiang, Jian-Dong

    2016-01-01

    In situ administration of 5-fluorouracil (5FU) “thermosensitive” gel effectively reduced systemic side effects in treating colon rectal cancer; however, the penetration efficacy of the formulation was considerably low due to the poor lipid solubility of 5FU. The aim of this study was to develop thermosensitive gel-mediated 5FU water-in-oil microemulsion (TG-5FU-ME) for improving the infiltration of 5FU. An in vitro release test showed that TG-5FU-ME sustained the drug’s release up to 10 hours. TG-5FU-ME exhibited good stability, and the microemulsion entrapped did not show any change in morphology and 5FU content during the 4-month storage. Transportation test in the Caco-2 cell monolayer showed that TG-5FU-ME had a permeability 6.3 times higher than that of 5FU thermosensitive gel, and the intracellular uptake of 5FU increased by 5.4-fold compared to that of 5FU thermosensitive gel. In vivo tissue distribution analysis exhibited that the TG-5FU-ME group had drug levels in rectal tissue and mesenteric lymph nodes, which were significantly higher than those of 5FU thermosensitive gel group, with very low blood levels of 5FU in both groups. Furthermore, TG-5FU-ME was not associated with detectable morphological damage to the rectal tissue. Conclusively, TG-5FU-ME might be an efficient rectal delivery system to treat colorectal cancer. PMID:27660416

  1. Probiotics for the prevention and treatment of allergies, with an emphasis on mode of delivery and mechanism of action.

    PubMed

    Prakash, Satya; Tomaro-Duchesneau, Catherine; Saha, Shyamali; Rodes, Laetitia; Kahouli, Imen; Malhotra, Meenakshi

    2014-01-01

    Allergy, also termed type I hypersensitivity, is defined as a "disease following a response by the immune system to an otherwise innocuous antigen". The prevalence of allergies is high and escalating, with almost half the populations of North America and Europe having allergies to one or more common environmental antigens. Although rarely life-threatening allergies cause much distress and pose an important economic burden. Recent studies demonstrate the importance of the commensal bacteria of the gastrointestinal tract, termed the microbiota, in stimulating and modulating the immune system. This goes hand-in-hand with the hygiene hypothesis, proposed by Strachan in 1989. With this in mind, the use of pre- and probiotics has gained interest to prevent and treat allergies through modulation of the gut microbiota and the immune system. Probiotics, namely Lactobacilli and Bifidobacteria, are live microorganisms that can be incorporated in the diet in the form of functional foods or dietary supplements to beneficially influence the host. In recent studies, probiotic formulations demonstrated the capability to successfully modulate allergic rhinitis, atopic disorders and food-related allergies. A number of probiotic mechanisms of action are involved in controlling hypersensitivity responses, many of which are still not yet understood. Microencapsulation has gained importance as a device for the oral delivery of probiotic cells and may play an important role in the development of a successful probiotic formulation to treat and prevent allergies. Despite the promising research on probiotic biotherapeutics, further investigations are required to develop a successful therapeutic to treat and prevent allergies.

  2. Transmucosal delivery of linagliptin for the treatment of type- 2 diabetes mellitus by ultra-thin nanofibers.

    PubMed

    Modgill, Vedant; Garg, Tarun; Goyal, Amit K; Rath, Goutam

    2015-01-01

    The objective of the present research was to cultivate an oral formulation of an anti-diabetic drug using polymeric nanofiber. A biodegradable polymer i.e. poly (vinyl alcohol) (PVA) nanofiber loaded linagliptin was prepared using electro spinning technique. The drug entrapment in the developed nanofibers was confirmed by scanning electron microscopy and X-ray diffraction. The in vivo study was performed on male Wistar rats to establish the pharmacodynamics behavior of developed formulation. The mucoadhesive strength results confirmed that the drug loaded PVA nanofiber patch had the highest mucoadhesion strength compare to PVA film and blank PVA nanofiber, due to its higher water holding capacity and surface area. The in vitro release study suggested that controlled release array of the drug from the nanofiber patch. In vivo activity validated the fact that linagliptin was delivered in its active state and showed visible results when compared to the commercial formulation. Additionally an encapsulation efficacy of 92% of the experimental formulation provides sufficient suggestion that the nanofibers serve as an ideal carrier for the delivery of linagliptin via the sublingual route.

  3. Intranasal delivery of antipsychotic drugs.

    PubMed

    Katare, Yogesh K; Piazza, Justin E; Bhandari, Jayant; Daya, Ritesh P; Akilan, Kosalan; Simpson, Madeline J; Hoare, Todd; Mishra, Ram K

    2016-11-29

    Antipsychotic drugs are used to treat psychotic disorders that afflict millions globally and cause tremendous emotional, economic and healthcare burdens. However, the potential of intranasal delivery to improve brain-specific targeting remains unrealized. In this article, we review the mechanisms and methods used for brain targeting via the intranasal (IN) route as well as the potential advantages of improving this type of delivery. We extensively review experimental studies relevant to intranasal delivery of therapeutic agents for the treatment of psychosis and mental illnesses. We also review clinical studies in which intranasal delivery of peptides, like oxytocin (7 studies) and desmopressin (1), were used as an adjuvant to antipsychotic treatment with promising results. Experimental animal studies (17) investigating intranasal delivery of mainstream antipsychotic drugs have revealed successful targeting to the brain as suggested by pharmacokinetic parameters and behavioral effects. To improve delivery to the brain, nanotechnology-based carriers like nanoparticles and nanoemulsions have been used in several studies. However, human studies assessing intranasal delivery of mainstream antipsychotic drugs are lacking, and the potential toxicity of nanoformulations used in animal studies has not been explored. A brief discussion of future directions anticipates that if limitations of low aqueous solubility of antipsychotic drugs can be overcome and non-toxic formulations used, IN delivery (particularly targeting specific tissues within the brain) will gain more importance moving forward given the inherent benefits of IN delivery in comparison to other methods.

  4. Optimal Control of Hepatitis C Antiviral Treatment Programme Delivery for Prevention amongst a Population of Injecting Drug Users

    PubMed Central

    Vickerman, Peter; Vassall, Anna; Hickman, Matthew

    2011-01-01

    In most developed countries, HCV is primarily transmitted by injecting drug users (IDUs). HCV antiviral treatment is effective, and deemed cost-effective for those with no re-infection risk. However, few active IDUs are currently treated. Previous modelling studies have shown antiviral treatment for active IDUs could reduce HCV prevalence, and there is emerging interest in developing targeted IDU treatment programmes. However, the optimal timing and scale-up of treatment is unknown, given the real-world constraints commonly existing for health programmes. We explore how the optimal programme is affected by a variety of policy objectives, budget constraints, and prevalence settings. We develop a model of HCV transmission and treatment amongst active IDUs, determine the optimal treatment programme strategy over 10 years for two baseline chronic HCV prevalence scenarios (30% and 45%), a range of maximum annual budgets (50,000–300,000 per 1,000 IDUs), and a variety of objectives: minimising health service costs and health utility losses; minimising prevalence at 10 years; minimising health service costs and health utility losses with a final time prevalence target; minimising health service costs with a final time prevalence target but neglecting health utility losses. The largest programme allowed for a given budget is the programme which minimises both prevalence at 10 years, and HCV health utility loss and heath service costs, with higher budgets resulting in greater cost-effectiveness (measured by cost per QALY gained compared to no treatment). However, if the objective is to achieve a 20% relative prevalence reduction at 10 years, while minimising both health service costs and losses in health utility, the optimal treatment strategy is an immediate expansion of coverage over 5–8 years, and is less cost-effective. By contrast, if the objective is only to minimise costs to the health service while attaining the 20% prevalence reduction, the programme is deferred

  5. Microemulsion as a tool for the transdermal delivery of ondansetron for the treatment of chemotherapy induced nausea and vomiting.

    PubMed

    Al Abood, Raid M; Talegaonkar, Sushama; Tariq, Mohammad; Ahmad, Farhan J

    2013-01-01

    The main objective of this study was to develop a microemulsion (ME) formulation for transdermal delivery of ondansetron for chemotherapy induced nausea and vomiting (CINV). For the formulation development oil was selected on the basis of drug solubility in it while the surfactants and co-surfactants (S(mix)) were screened on the basis of their capacity to solubilize the oil as well as their efficiency to provide the microemulsion area. The microemulsion existence ranges were defined through the construction of the pseudo-ternary phase diagram and various formulations were developed. Effect of surfactant and cosurfactant mass ratio (S(mix)) on the microemulsion formation and its permeation through excised rat skin was studied. A significant increase in permeability parameters such as steady-state flux (J(ss)), permeability coefficient (K(p)), and enhancement ratio (ER) was observed in ME. Formulation B4 which consisted of 0.5% (w/w) of ondansetron, 5% (w/w) of oleic acid, 30% (w/w) S(mix) (2:1, Tween 20 and PEG 400) and 64.5% (w/w) of distilled water showed the best permeability profile. The formulation B4 was subjected to various in vitro attributes and converted to microemulsion gel (OMG). In order to predict the efficacy, pharmacokinetic studies were performed and pharmacokinetic profile was compared with ondansetron conventional gel (OCG) and oral marketed syrup (ONDANZ). The absorption of ondansetron from OMG resulted in 6.03 fold increase in bioavailability as compared to oral conventional syrup and 9.66 times with reference to the OCG gel. The future perspective includes preclinical, toxicological and clinical studies for developing clinically viable formulation.

  6. Anthracycline Drugs on Modified Surface of Quercetin-Loaded Polymer Nanoparticles: A Dual Drug Delivery Model for Cancer Treatment

    PubMed Central

    Saha, Chabita; Kaushik, Agrima; Das, Asmita; Pal, Sandip; Majumder, Debashis

    2016-01-01

    Polymer nanoparticles are vehicles used for delivery of hydrophobic anti-cancer drugs, like doxorubicin, paclitaxel or chemopreventors like quercetin (Q). The present study deals with the synthesis and characterisation of nano formulations (NFs) from Q loaded PLGA (poly lactic-co-glycolic acid) nano particles (NPs) by surface modification. The surface of Q-loaded (NPs) is modified by coating with biopolymers like bovine serum albumin (BSA) or histones (His). Conventional chemotherapeutic drugs adriamycin (ADR) and mitoxantrone (MTX) are bound to BSA and His respectively before being coated on Q-loaded NPs to nano formulate NF1 and NF2 respectively. The sizes of these NFs are in the range 400–500 nm as ascertained by SEM and DLS measurements. Encapsulation of Q in polymer NPs is confirmed from shifts in FT-IR, TGA and DSC traces of Q-loaded NPs compared to native PLGA and Q. Surface modification in NFs is evidenced by three distinct regions in their TEM images; the core, polymer capsule and the coated surface. Negative zeta potential of Q-loaded NPs shifted to positive potential on surface modification in NF1 and NF2. In vitro release of Q from the NFs lasted up to twenty days with an early burst release. NF2 is better formulation than NF1 as loading of MTX is 85% compared to 23% loading of ADR. Such NFs are expected to overcome multi-drug resistance (MDR) by reaching and treating the target cancerous cells by virtue of size, charge and retention. PMID:27196562

  7. SW43-DOX ± loading onto drug-eluting bead, a potential new targeted drug delivery platform for systemic and locoregional cancer treatment – An in vitro evaluation

    PubMed Central

    Ludwig, Johannes M.; Gai, Yongkang; Sun, Lingyi; Xiang, Guangya; Zeng, Dexing; Kim, Hyun S.

    2016-01-01

    Treatment of unresectable primary cancer and their distant metastases, with the liver representing one of the most frequent location, is still plagued by insufficient treatment success and poor survival rates. The Sigma-2 receptor is preferentially expressed on many tumor cells making it an appealing target for therapy. Thus, we developed a potential targeted drug conjugate consisting of the Sigma-2 receptor ligand SW43 and Doxorubicin (SW43-DOX) for systemic cancer therapy and for locoregional treatment of primary and secondary liver malignancies when loaded onto drug-eluting bead (DEB) which was compared in vitro to the treatment with Doxorubicin alone. SW43-DOX binds specifically to the Sigma-2 receptor expressed on hepatocellular (Hep G2, Hep 3B), pancreatic (Panc-1) and colorectal (HT-29) carcinoma cell lines with high affinity and subsequent early specific internalization. Free SW43-DOX showed superior concentration and time depended cancer toxicity than treatment with Doxorubicin alone. Action mechanisms analysis revealed an apoptotic cell death with increased caspase 3/7 activation and reactive oxygen species (ROS) production. Only ROS scavenging with α-Tocopherol, but not the caspase inhibition (Z-VAD-FMK), partly reverted the effect. SW43-DOX could successfully be loaded onto DEB and showed prolonged eluting kinetics compared to Doxorubicin. SW43-DOX loaded DEB vs. Doxorubicin loaded DEB showed a significantly greater time dependent toxicity in all cell lines. In conclusion, the novel conjugate SW43-DOX ± loading onto DEB is a promising drug delivery platform for targeted systemic and locoregional cancer therapy. PMID:27262893

  8. On-line quality assurance of rotational radiotherapy treatment delivery by means of a 2D ion chamber array and the Octavius phantom

    SciTech Connect

    Esch, Ann van; Clermont, Christian; Devillers, Magali; Iori, Mauro; Huyskens, Dominique P.

    2007-10-15

    For routine pretreatment verification of innovative treatment techniques such as (intensity modulated) dynamic arc therapy and helical TomoTherapy, an on-line and reliable method would be highly desirable. The present solution proposed by TomoTherapy, Inc. (Madison, WI) relies on film dosimetry in combination with up to two simultaneous ion chamber point dose measurements. A new method is proposed using a 2D ion chamber array (Seven29, PTW, Freiburg, Germany) inserted in a dedicated octagonal phantom, called Octavius. The octagonal shape allows easy positioning for measurements in multiple planes. The directional dependence of the response of the detector was primarily investigated on a dual energy (6 and 18 MV) Clinac 21EX (Varian Medical Systems, Palo Alto, CA) as no fixed angle incidences can be calculated in the Hi-Art TPS of TomoTherapy. The array was irradiated from different gantry angles and with different arc deliveries, and the dose distributions at the level of the detector were calculated with the AAA (Analytical Anisotropic Algorithm) photon dose calculation algorithm implemented in Eclipse (Varian). For validation on the 6 MV TomoTherapy unit, rotational treatments were generated, and dose distributions were calculated with the Hi-Art TPS. Multiple cylindrical ion chamber measurements were used to cross-check the dose calculation and dose delivery in Octavius in the absence of the 2D array. To compensate for the directional dependence of the 2D array, additional prototypes of Octavius were manufactured with built-in cylindrically symmetric compensation cavities. When using the Octavius phantom with a 2 cm compensation cavity, measurements with an accuracy comparable to that of single ion chambers can be achieved. The complete Octavius solution for quality assurance of rotational treatments consists of: The 2D array, two octagonal phantoms (with and without compensation layer), an insert for nine cylindrical ion chambers, and a set of inserts of

  9. Zonisamide-loaded triblock copolymer nanomicelles as a novel drug delivery system for the treatment of acute spinal cord injury

    PubMed Central

    Li, JingLun; Deng, JiaoJiao; Yuan, JinXian; Fu, Jie; Li, XiaoLing; Tong, AiPing; Wang, YueLong; Chen, YangMei; Guo, Gang

    2017-01-01

    Spinal cord injury (SCI) commonly leads to lifelong disability due to the limited regenerative capacity of the adult central nervous system. Nanomicelles can be used as therapeutic systems to provide effective treatments for SCI. In this study, a novel triblock monomethyl poly(ethylene glycol)-poly(l-lactide)-poly(trimethylene carbonate) copolymer was successfully synthesized. Next, polymeric nanomicelles loaded with zonisamide (ZNS), a Food and Drug Administration-approved antiepileptic drug, were prepared and characterized. The ZNS-loaded micelles (ZNS-M) were further utilized for the treatment of SCI in vitro and in vivo. The obtained ZNS-M were ~50 nm in diameter with good solubility and dispersibility. Additionally, these controlled-release micelles showed significant antioxidative and neuron-protective effects in vitro. Finally, our results indicated that ZNS-M treatment could promote motor function recovery and could increase neuron and axon density in a hemisection SCI model. In summary, these results may provide an experimental basis for the use of ZNS-M as a clinically applicable therapeutic drug for the treatment of SCI in the future.

  10. Uniformity of Evidence-Based Treatments in Practice? Therapist Effects in the Delivery of Cognitive Processing Therapy for PTSD

    ERIC Educational Resources Information Center

    Laska, Kevin M.; Smith, Tracey L.; Wislocki, Andrew P.; Minami, Takuya; Wampold, Bruce E.

    2013-01-01

    Objective: Various factors contribute to the effective implementation of evidence-based treatments (EBTs). In this study, cognitive processing therapy (CPT) was administered in a Veterans Affairs (VA) posttraumatic stress disorder (PTSD) specialty clinic in which training and supervision were provided following VA implementation guidelines. The…

  11. Efficacy of a combined intracerebral and systemic gene delivery approach for the treatment of a severe lysosomal storage disorder.

    PubMed

    Spampanato, Carmine; De Leonibus, Elvira; Dama, Paola; Gargiulo, Annagiusi; Fraldi, Alessandro; Sorrentino, Nicolina Cristina; Russo, Fabio; Nusco, Edoardo; Auricchio, Alberto; Surace, Enrico M; Ballabio, Andrea

    2011-05-01

    Multiple sulfatase deficiency (MSD), a severe autosomal recessive disease is caused by mutations in the sulfatase modifying factor 1 gene (Sumf1). We have previously shown that in the Sumf1 knockout mouse model (Sumf1(-/-)) sulfatase activities are completely absent and, similarly to MSD patients, this mouse model displays growth retardation and early mortality. The severity of the phenotype makes MSD unsuitable to be treated by enzyme replacement or bone marrow transplantation, hence the importance of testing the efficacy of novel treatment strategies. Here we show that recombinant adeno-associated virus serotype 9 (rAAV9) vector injected into the cerebral ventricles of neonatal mice resulted in efficient and widespread transduction of the brain parenchyma. In addition, we compared a combined, intracerebral ventricles and systemic, administration of an rAAV9 vector encoding SUMF1 gene to the single administrations-either directly in brain, or systemic alone -in MSD mice. The combined treatment resulted in the global activation of sulfatases, near-complete clearance of glycosaminoglycans (GAGs) and decrease of inflammation in both the central nervous system (CNS) and visceral organs. Furthermore, behavioral abilities were improved by the combined treatment. These results underscore that the "combined" mode of rAAV9 vector administration is an efficient option for the treatment of severe whole-body disorders.

  12. 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

  13. Rotational IMRT delivery using a digital linear accelerator in very high dose rate 'burst mode'

    NASA Astrophysics Data System (ADS)

    Salter, Bill J.; Sarkar, Vikren; Wang, Brian; Shukla, Himanshu; Szegedi, Martin; Rassiah-Szegedi, Prema

    2011-04-01

    Recently, there has been a resurgence of interest in arc-based IMRT, through the use of 'conventional' multileaf collimator (MLC) systems that can treat large tumor volumes in a single, or very few pass(es) of the gantry. Here we present a novel 'burst mode' modulated arc delivery approach, wherein 2000 monitor units per minute (MU min-1) high dose rate bursts of dose are facilitated by a flattening-filter-free treatment beam on a Siemens Artiste (Oncology Care Systems, Siemens Medical Solutions, Concord, CA, USA) digital linear accelerator in a non-clinical configuration. Burst mode delivery differs from continuous mode delivery, used by Elekta's VMAT (Elekta Ltd, Crawley, UK) and Varian's RapidArc (Varian Medical Systems, Palo Alto, CA, USA) implementations, in that dose is not delivered while MLC leaves are moving. Instead, dose is delivered in bursts over very short arc angles and only after an MLC segment shape has been completely formed and verified by the controller. The new system was confirmed to be capable of delivering a wide array of clinically relevant treatment plans, without machine fault or other delivery anomalies. Dosimetric accuracy of the modulated arc platform, as well as the Prowess (Prowess Inc., Concord, CA, USA) prototype treatment planning version utilized here, was quantified and confirmed, and delivery times were measured as significantly brief, even with large hypofractionated doses. The burst mode modulated arc approach evaluated here appears to represent a capable, accurate and efficient delivery approach.

  14. Rotational IMRT delivery using a digital linear accelerator in very high dose rate 'burst mode'.

    PubMed

    Salter, Bill J; Sarkar, Vikren; Wang, Brian; Shukla, Himanshu; Szegedi, Martin; Rassiah-Szegedi, Prema

    2011-04-07

    Recently, there has been a resurgence of interest in arc-based IMRT, through the use of 'conventional' multileaf collimator (MLC) systems that can treat large tumor volumes in a single, or very few pass(es) of the gantry. Here we present a novel 'burst mode' modulated arc delivery approach, wherein 2000 monitor units per minute (MU min(-1)) high dose rate bursts of dose are facilitated by a flattening-filter-free treatment beam on a Siemens Artiste (Oncology Care Systems, Siemens Medical Solutions, Concord, CA, USA) digital linear accelerator in a non-clinical configuration. Burst mode delivery differs from continuous mode delivery, used by Elekta's VMAT (Elekta Ltd, Crawley, UK) and Varian's RapidArc (Varian Medical Systems, Palo Alto, CA, USA) implementations, in that dose is not delivered while MLC leaves are moving. Instead, dose is delivered in bursts over very short arc angles and only after an MLC segment shape has been completely formed and verified by the controller. The new system was confirmed to be capable of delivering a wide array of clinically relevant treatment plans, without machine fault or other delivery anomalies. Dosimetric accuracy of the modulated arc platform, as well as the Prowess (Prowess Inc., Concord, CA, USA) prototype treatment planning version utilized here, was quantified and confirmed, and delivery times were measured as significantly brief, even with large hypofractionated doses. The burst mode modulated arc approach evaluated here appears to represent a capable, accurate and efficient delivery approach.

  15. Measurements of the neutron dose equivalent for various radiation qualities, treatment machines and delivery techniques in radiation therapy

    NASA Astrophysics Data System (ADS)

    Hälg, R. A.; Besserer, J.; Boschung, M.; Mayer, S.; Lomax, A. J.; Schneider, U.

    2014-05-01

    In radiation therapy, high energy photon and proton beams cause the production of secondary neutrons. This leads to an unwanted dose contribution, which can be considerable for tissues outside of the target volume regarding the long term health of cancer patients. Due to the high biological effectiveness of neutrons in regards to cancer induction, small neutron doses can be important. This study quantified the neutron doses for different radiation therapy modalities. Most of the reports in the literature used neutron dose measurements free in air or on the surface of phantoms to estimate the amount of neutron dose to the patient. In this study, dose measurements were performed in terms of neutron dose equivalent inside an anthropomorphic phantom. The neutron dose equivalent was determined using track etch detectors as a function of the distance to the isocenter, as well as for radiation sensitive organs. The dose distributions were compared with respect to treatment techniques (3D-conformal, volumetric modulated arc therapy and intensity-modulated radiation therapy for photons; spot scanning and passive scattering for protons), therapy machines (Varian, Elekta and Siemens linear accelerators) and radiation quality (photons and protons). The neutron dose equivalent varied between 0.002 and 3 mSv per treatment gray over all measurements. Only small differences were found when comparing treatment techniques, but substantial differences were observed between the linear accelerator models. The neutron dose equivalent for proton therapy was higher than for photons in general and in particular for double-scattered protons. The overall neutron dose equivalent measured in this study was an order of magnitude lower than the stray dose of a treatment using 6 MV photons, suggesting that the contribution of the secondary neutron dose equivalent to the integral dose of a radiotherapy patient is small.

  16. Measurements of the neutron dose equivalent for various radiation qualities, treatment machines and delivery techniques in radiation therapy.

    PubMed

    Hälg, R A; Besserer, J; Boschung, M; Mayer, S; Lomax, A J; Schneider, U

    2014-05-21

    In radiation therapy, high energy photon and proton beams cause the production of secondary neutrons. This leads to an unwanted dose contribution, which can be considerable for tissues outside of the target volume regarding the long term health of cancer patients. Due to the high biological effectiveness of neutrons in regards to cancer induction, small neutron doses can be important. This study quantified the neutron doses for different radiation therapy modalities. Most of the reports in the literature used neutron dose measurements free in air or on the surface of phantoms to estimate the amount of neutron dose to the patient. In this study, dose measurements were performed in terms of neutron dose equivalent inside an anthropomorphic phantom. The neutron dose equivalent was determined using track etch detectors as a function of the distance to the isocenter, as well as for radiation sensitive organs. The dose distributions were compared with respect to treatment techniques (3D-conformal, volumetric modulated arc therapy and intensity-modulated radiation therapy for photons; spot scanning and passive scattering for protons), therapy machines (Varian, Elekta and Siemens linear accelerators) and radiation quality (photons and protons). The neutron dose equivalent varied between 0.002 and 3 mSv per treatment gray over all measurements. Only small differences were found when comparing treatment techniques, but substantial differences were observed between the linear accelerator models. The neutron dose equivalent for proton therapy was higher than for photons in general and in particular for double-scattered protons. The overall neutron dose equivalent measured in this study was an order of magnitude lower than the stray dose of a treatment using 6 MV photons, suggesting that the contribution of the secondary neutron dose equivalent to the integral dose of a radiotherapy patient is small.

  17. From cancer screening to treatment: service delivery and referral in the National Breast and Cervical Cancer Early Detection Program.

    PubMed

    Miller, Jacqueline W; Hanson, Vivien; Johnson, Gale D; Royalty, Janet E; Richardson, Lisa C

    2014-08-15

    The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) provides breast and cervical cancer screening and diagnostic services to low-income and underserved women through a network of providers and health care organizations. Although the program serves women 40-64 years old for breast cancer screening and 21-64 years old for cervical cancer screening, the priority populations are women 50-64 years old for breast cancer and women who have never or rarely been screened for cervical cancer. From 1991 through 2011, the NBCCEDP provided screening and diagnostic services to more than 4.3 million women, diagnosing 54,276 breast cancers, 2554 cervical cancers, and 123,563 precancerous cervical lesions. A critical component of providing screening services is to ensure that all women with abnormal screening results receive appropriate and timely diagnostic evaluations. Case management is provided to assist women with overcoming barriers that would delay or prevent follow-up care. Women diagnosed with cancer receive treatment through the states' Breast and Cervical Cancer Treatment Programs (a special waiver for Medicaid) if they are eligible. The NBCCEDP has performance measures that serve as benchmarks to monitor the completeness and timeliness of care. More than 90% of the women receive complete diagnostic care and initiate treatment less than 30 days from the time of their diagnosis. Provision of effective screening and diagnostic services depends on effective program management, networks of providers throughout the community, and the use of evidence-based knowledge, procedures, and technologies.

  18. An innovative matrix controlling drug delivery produced by thermal treatment of DC tablets containing polycarbophil and ethylcellulose.

    PubMed

    Caviglioli, Gabriele; Baldassari, Sara; Cirrincione, Paola; Russo, Eleonora; Parodi, Brunella; Gatti, Paolo; Drava, Giuliana

    2013-12-15

    An innovative matrix, produced by thermal treatment on direct compression (DC) tablets containing polycarbophil (POL) and ethylcellulose (EC), identified as matrix forming polymers, and able to control the release of diltiazem hydrochloride, was developed. At pH 7.2, 72 ± 1.2% (w/w) of drug loaded was released in 25 h, mostly at constant rate. This swellable and unerodible matrix controls drug release by an anomalous transport mechanism. The modifications induced by the thermal treatment are irreversible and can be used to control and characterize the matrix. A 3-component constrained mixture design allowed the investigation of the experimental domain in which the matrix forms and the computation of a mathematical model that can be used to optimize the formulation properties. The release rate can be modulated (0.032-0.064% drug released/min) through the choice of suitable treatment conditions and tablet composition. The maximum amount of diltiazem hydrochloride released by zero-order kinetics, at the lowest release rate, occurs for POL:EC ratio in the range of 1:1-2:3 with 20-30% of diluent. The tablets are able to load up to 50% (w/w) of diltiazem hydrochloride without losing their properties. A stability study performed on a selected formulation containing DTZ showed stability for at least 2.7 years at RT conditions.

  19. Sci—Thur PM: Planning and Delivery — 03: Automated delivery and quality assurance of a modulated electron radiation therapy plan

    SciTech Connect

    Connell, T; Papaconstadopoulos, P; Alexander, A; Serban, M; Devic, S; Seuntjens, J

    2014-08-15

    Modulated electron radiation therapy (MERT) offers the potential to improve healthy tissue sparing through increased dose conformity. Challenges remain, however, in accurate beamlet dose calculation, plan optimization, collimation method and delivery accuracy. In this work, we investigate the accuracy and efficiency of an end-to-end MERT plan and automated-delivery workflow for the electron boost portion of a previously treated whole breast irradiation case. Dose calculations were performed using Monte Carlo methods and beam weights were determined using a research-based treatment planning system capable of inverse optimization. The plan was delivered to radiochromic film placed in a water equivalent phantom for verification, using an automated motorized tertiary collimator. The automated delivery, which covered 4 electron energies, 196 subfields and 6183 total MU was completed in 25.8 minutes, including 6.2 minutes of beam-on time with the remainder of the delivery time spent on collimator leaf motion and the automated interfacing with the accelerator in service mode. The delivery time could be reduced by 5.3 minutes with minor electron collimator modifications and the beam-on time could be reduced by and estimated factor of 2–3 through redesign of the scattering foils. Comparison of the planned and delivered film dose gave 3%/3 mm gamma pass rates of 62.1, 99.8, 97.8, 98.3, and 98.7 percent for the 9, 12, 16, 20 MeV, and combined energy deliveries respectively. Good results were also seen in the delivery verification performed with a MapCHECK 2 device. The results showed that accurate and efficient MERT delivery is possible with current technologies.

  20. Delivery systems for brachytherapy.

    PubMed

    de la Puente, Pilar; Azab, Abdel Kareem

    2014-10-28

    Brachytherapy is described as the short distance treatment of cancer with a radioactive isotope placed on, in, or near the lesions or tumor to be treated. The main advantage of brachytherapy compared with external beam radiation (EBR) is the improved localized delivery of dose to the target volume of interest, thus normal tissue irradiation is reduced. The precise and targeted nature of brachytherapy provides a number of key benefits for the effective treatment of cancer such as efficacy, minimized risk of side effects, short treatment times, and cost-effectiveness. Brachytherapy devices have yielded promising results in preclinical and clinical studies. However, brachytherapy can only be used in localized and relatively small tumors. Although the introduction of new delivery devices allows the treatment of more complex tumor sites, with wider range of dose rate for improving treatment efficacy and reduction of side effects, a better understanding about the safety, efficacy, and accuracy of these systems is required, and further development of new techniques is warranted. Therefore, this review focuses on the delivery devices for brachytherapy and their application in prostate, breast, brain, and other tumor sites.

  1. Oral administration of a curcumin-phospholipid delivery system for the treatment of central serous chorioretinopathy: a 12-month follow-up study

    PubMed Central

    Mazzolani, Fabio; Togni, Stefano

    2013-01-01

    Background The therapeutic effects of Meriva®, a curcumin-phospholipid (lecithin) delivery system (formulated as Norflo® tablets), on visual acuity and retinal thickness in patients with acute and chronic central serous chorioretinopathy was previously investigated in a six-month open-label study. Methods In this follow-up study, visual acuity was again assessed by ophthalmologic evaluation and retinal thickness by optical coherence tomography (OCT). Norflo tablets were administered twice daily to patients with central serous chorioretinopathy. The study group consisted of 12 patients (total 18 eyes) who completed 12 months of follow-up. The primary endpoint was change in visual acuity before and after treatment with Norflo, and change in neuroretinal or retinal pigment epithelium detachment on OCT was the secondary endpoint. Results After 12 months of therapy, no eyes showed further reduction in visual acuity, 39% showed stabilization, and 61% showed statistically significant improvement (P = 0.0001 by Student’s t-test and P = 0.0005 by Wilcoxon signed rank test). Ninety-five percent of eyes showed a reduction in neuroretinal or retinal pigment epithelium detachment and 5% showed stabilization. The difference in retinal thickness after 12 months was statistically significant (P = 0.0001 by Student’s t-test and P = 0.0004 by Wilcoxon signed rank test). Conclusion These results, albeit preliminary, confirm our previous finding that this curcumin delivery system is effective in the management of central serous chorioretinopathy. When administered in a bioavailable formulation, curcumin is worth considering as a therapeutic agent for the management of inflammatory and degenerative eye conditions involving activation of retinal microglial cells. PMID:23723686

  2. Development of intramammary delivery systems containing lasalocid for the treatment of bovine mastitis: impact of solubility improvement on safety, efficacy, and milk distribution in dairy cattle

    PubMed Central

    Wang, Wen; Song, Yunmei; Petrovski, Kiro; Eats, Patricia; Trott, Darren J; Wong, Hui San; Page, Stephen W; Perry, Jeanette; Garg, Sanjay

    2015-01-01

    Background Mastitis is a major disease of dairy cattle. Given the recent emergence of methicillin-resistant Staphylococcus aureus as a cause of bovine mastitis, new intramammary (IMA) treatments are urgently required. Lasalocid, a member of the polyether ionophore class of antimicrobial agents, has not been previously administered to cows by the IMA route and has favorable characteristics for development as a mastitis treatment. This study aimed to develop an IMA drug delivery system (IMDS) of lasalocid for the treatment of bovine mastitis. Methods Minimum inhibitory concentrations (MICs) were determined applying the procedures recommended by the Clinical and Laboratory Standards Institute. Solid dispersions (SDs) of lasalocid were prepared and characterized using differential scanning calorimetry and Fourier transform infrared spectroscopy. IMDSs containing lasalocid of micronized, nano-sized, or as SD form were tested for their IMA safety in cows. Therapeutic efficacy of lasalocid IMDSs was tested in a bovine model involving experimental IMA challenge with the mastitis pathogen Streptococcus uberis. Results Lasalocid demonstrated antimicrobial activity against the major Gram-positive mastitis pathogens including S. aureus (MIC range 0.5–8 μg/mL). The solubility test confirmed limited, ion-strength-dependent water solubility of lasalocid. A kinetic solubility study showed that SDs effectively enhanced water solubility of lasalocid (21–35-fold). Polyvinylpyrrolidone (PVP)-lasalocid SD caused minimum mammary irritation in treated cows and exhibited faster distribution in milk than either nano or microsized lasalocid. IMDSs with PVP-lasalocid SD provided effective treatment with a higher mastitis clinical and microbiological cure rate (66.7%) compared to cloxacillin (62.5%). Conclusion Lasalocid SD IMDS provided high cure rates and effectiveness in treating bovine mastitis with acceptable safety in treated cows. PMID:25653501

  3. Sensitivity of an Elekta iView GT a-Si EPID model to delivery errors for pre-treatment verification of IMRT fields.

    PubMed

    Herwiningsih, Sri; Hanlon, Peta; Fielding, Andrew

    2014-12-01

    A Monte Carlo model of an Elekta iViewGT amorphous silicon electronic portal imaging device (a-Si EPID) has been validated for pre-treatment verification of clinical IMRT treatment plans. The simulations involved the use of the BEAMnrc and DOSXYZnrc Monte Carlo codes to predict the response of the iViewGT a-Si EPID model. The predicted EPID images were compared to the measured images obtained from the experiment. The measured EPID images were obtained by delivering a photon beam from an Elekta Synergy linac to the Elekta iViewGT a-Si EPID. The a-Si EPID was used with no additional build-up material. Frame averaged EPID images were acquired and processed using in-house software. The agreement between the predicted and measured images was analyzed using the gamma analysis technique with acceptance criteria of 3 %/3 mm. The results show that the predicted EPID images for four clinical IMRT treatment plans have a good agreement with the measured EPID signal. Three prostate IMRT plans were found to have an average gamma pass rate of more than 95.0 % and a spinal IMRT plan has the average gamma pass rate of 94.3 %. During the period of performing this work a routine MLC calibration was performed and one of the IMRT treatments re-measured with the EPID. A change in the gamma pass rate for one field was observed. This was the motivation for a series of experiments to investigate the sensitivity of the method by introducing delivery errors, MLC position and dosimetric overshoot, into the simulated EPID images. The method was found to be sensitive to 1 mm leaf position errors and 10 % overshoot errors.

  4. Nanomedicine in pulmonary delivery

    PubMed Central

    Mansour, Heidi M; Rhee, Yun-Seok; Wu, Xiao

    2009-01-01

    The lung is an attractive target for drug delivery due to noninvasive administration via inhalation aerosols, avoidance of first-pass metabolism, direct delivery to the site of action for the treatment of respiratory diseases, and the availability of a huge surface area for local drug action and systemic absorption of drug. Colloidal carriers (ie, nanocarrier systems) in pulmonary drug delivery offer many advantages such as the potential to achieve relatively uniform distribution of drug dose among the alveoli, achievement of improved solubility of the drug from its own aqueous solubility, a sustained drug release which consequently reduces dosing frequency, improves patient compliance, decreases incidence of side effects, and the potential of drug internalization by cells. This review focuses on the current status and explores the potential of colloidal carriers (ie, nanocarrier systems) in pulmonary drug delivery with special attention to their pharmaceutical aspects. Manufacturing processes, in vitro/in vivo evaluation methods, and regulatory/toxicity issues of nanomedicines in pulmonary delivery are also discussed. PMID:20054434

  5. Bioactive borate glass scaffolds: in vitro and in vivo evaluation for use as a drug delivery system in the treatment of bone infection.

    PubMed

    Liu, Xin; Xie, Zongping; Zhang, Changqing; Pan, Haobo; Rahaman, Mohamed N; Zhang, Xin; Fu, Qiang; Huang, Wenhai

    2010-02-01

    The objective of this work was to evaluate borate bioactive glass scaffolds (with a composition in the system Na(2)O-K(2)O-MgO-CaO-B(2)O(3)-P(2)O(5)) as devices for the release of the drug Vancomycin in the treatment of bone infection. A solution of ammonium phosphate, with or without dissolved Vancomycin, was used to bond borate glass particles into the shape of pellets. The in vitro degradation of the pellets and their conversion to a hydroxyapatite-type material in a simulated body fluid (SBF) were investigated using weight loss measurements, chemical analysis, X-ray diffraction, and scanning electron microscopy. The results showed that greater than 90% of the glass in the scaffolds degraded within 1 week, to form poorly crystallized hydroxyapatite (HA). Pellets loaded with Vancomycin provided controlled release of the drug over 4 days. Vancomycin-loaded scaffolds were implanted into the right tibiae of rabbits infected with osteomyelitis. The efficacy of the treatment was assessed using microbiological examination and histology. The HA formed in the scaffolds in vivo, resulting from the conversion of the glass, served as structure to support the growth of new bone and blood vessels. The results in this work indicate that bioactive borate glass could provide a promising biodegradable and bioactive material for use as both a drug delivery system and a scaffold for bone repair.

  6. Ethosomes® and transfersomes® containing linoleic acid: physicochemical and technological features of topical drug delivery carriers for the potential treatment of melasma disorders.

    PubMed

    Celia, Christian; Cilurzo, Felisa; Trapasso, Elena; Cosco, Donato; Fresta, Massimo; Paolino, Donatella

    2012-02-01

    Two vesicular colloidal carriers, ethosomes® and transfersomes® were proposed for the topical delivery of linoleic acid, an active compound used in the therapeutic treatment of hyperpigmentation disorders, i.e. melasma, which is characterized by an increase of the melanin production in the epidermis. Dynamic light scattering was used for the physicochemical characterization of vesicles and mean size, size distribution and zeta potential were evaluated. The stability of formulations was also evaluated using the Turbiscan Lab® Expert based on the analysis of sample transmittance and photon backscattering. Ethosomes® and transfersomes® were prepared using Phospholipon 100 G®, as the lecithin component, and ethanol and sodium cholate, as edge activator agents, respectively. Linoleic acid at 0.05% and 0.1% (w/v) was used as the active ingredient and entrapped in colloidal vesicles. Technological parameters, i.e. entrapment efficacy, drug release and permeation profiles, were also investigated. Experimental findings showed that physicochemical and technological features of ethosomes® and transfersomes® were influenced by the lipid composition of the carriers. The percutaneous permeation experiments of linoleic acid-loaded ethosomes® and transfersomes® through human stratum corneum-epidermidis membranes showed that both carriers are accumulated in the skin membrane model as a function of their lipid compositions. The findings reported in this investigation showed that both vesicular carriers could represent a potential system for the topical treatment of hyperpigmentation disorders.

  7. Forelimb Treatment in a Large Cohort of Dystrophic Dogs Supports Delivery of a Recombinant AAV for Exon Skipping in Duchenne Patients

    PubMed Central

    Le Guiner, Caroline; Montus, Marie; Servais, Laurent; Cherel, Yan; Francois, Virginie; Thibaud, Jean-Laurent; Wary, Claire; Matot, Béatrice; Larcher, Thibaut; Guigand, Lydie; Dutilleul, Maeva; Domenger, Claire; Allais, Marine; Beuvin, Maud; Moraux, Amélie; Le Duff, Johanne; Devaux, Marie; Jaulin, Nicolas; Guilbaud, Mickaël; Latournerie, Virginie; Veron, Philippe; Boutin, Sylvie; Leborgne, Christian; Desgue, Diana; Deschamps, Jack-Yves; Moullec, Sophie; Fromes, Yves; Vulin, Adeline; Smith, Richard H; Laroudie, Nicolas; Barnay-Toutain, Frédéric; Rivière, Christel; Bucher, Stéphanie; Le, Thanh-Hoa; Delaunay, Nicolas; Gasmi, Mehdi; Kotin, Robert M; Bonne, Gisèle; Adjali, Oumeya; Masurier, Carole; Hogrel, Jean-Yves; Carlier, Pierre; Moullier, Philippe; Voit, Thomas

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder caused by mutations in the dystrophin gene, without curative treatment yet available. Our study provides, for the first time, the overall safety profile and therapeutic dose of a recombinant adeno-associated virus vector, serotype 8 (rAAV8) carrying a modified U7snRNA sequence promoting exon skipping to restore a functional in-frame dystrophin transcript, and injected by locoregional transvenous perfusion of the forelimb. Eighteen Golden Retriever Muscular Dystrophy (GRMD) dogs were exposed to increasing doses of GMP-manufactured vector. Treatment was well tolerated in all, and no acute nor delayed adverse effect, including systemic and immune toxicity was detected. There was a dose relationship for the amount of exon skipping with up to 80% of myofibers expressing dystrophin at the highest dose. Similarly, histological, nuclear magnetic resonance pathological indices and strength improvement responded in a dose-dependent manner. The systematic comparison of effects using different independent methods, allowed to define a minimum threshold of dystrophin expressing fibers (>33% for structural measures and >40% for strength) under which there was no clear-cut therapeutic effect. Altogether, these results support the concept of a phase 1/2 trial of locoregional delivery into upper limbs of nonambulatory DMD patients. PMID:25200009

  8. Delivery of sFIT-1 engineered MSCs in combination with a continuous low-dose doxorubicin treatment prevents growth of liver cancer

    PubMed Central

    Niu, Jian; Wang, Yue; Wang, Ji; Liu, Bin; Hu, Xin

    2016-01-01

    One important process in liver cancer growth and progression is angiogenesis. Vascular endothelial growth factor (VEGF) has the significant role in liver cancer angiogenesis. sFlt1 (soluble Fms-like tyrosine kinase-1) is the promising inhibitor of VEGF and can be used as the new method of inhibiting angiogenesis. MSCs (Mesenchymal stem cells) can infiltrate into tumor tissue and function as the efficient transgene delivery mediator. Here, we engineered murine MSCs to express sFlt1 and examined the anti-tumor effect of MSC- sFlt1 in combination with continues low-dose doxorubicin treatment. We found that this combination therapy significantly inhibited liver cancer cells proliferation. Above all, HepG2 xenografts treated with this combination therapy went into remission. It is of note that this inhibition effect was not p53 binding and by increasing caspase8. This study suggests that this combination treatment has novel therapeutic potential for liver cancer because of significantly inhibiting cancer cells growth and anti-angiogenesis in vitro and in vivo. PMID:28039440

  9. Nanoparticle delivery of HIF1α siRNA combined with photodynamic therapy as a potential treatment strategy for head-and-neck cancer

    PubMed Central

    Chen, Wei-Hua; Lecaros, Rumwald Leo G.; Tseng, Yu-Cheng; Huang, Leaf; Hsu, Yih-Chih

    2016-01-01

    Combination therapy has become a major strategy in cancer treatment. We used anisamide-targeted lipid–calcium–phosphate (LCP) nanoparticles to efficiently deliver HIF1α siRNA to the cytoplasm of sigma receptor-expressing SCC4 and SAS cells that were also subjected to photodynamic therapy (PDT). HIF1α siRNA nanoparticles effectively reduced HIF1α expression, increased cell death, and significantly inhibited cell growth following photosan-mediated photodynamic therapy in cultured cells. Intravenous injection of the same nanoparticles into human SCC4 or SAS xenografted mice likewise resulted in concentrated siRNA accumulation and reduced HIF1α expression in tumor tissues. When combined with photodynamic therapy, HIF1α siRNA nanoparticles enhanced the regression in tumor size resulting in a ~40% decrease in volume after 10 days. Combination therapy was found to be substantially more effective than either HIF1α siRNA or photodynamic therapy alone. Results from caspase-3, TUNEL, and CD31 marker studies support this conclusion. Our results show the potential use of LCP nanoparticles for efficient delivery of HIF1α siRNA into tumors as part of combination therapy along with PDT in the treatment of oral squamous cell carcinoma. PMID:25596376

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

    PubMed Central

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

    2017-01-01

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

  11. Gold nanoparticles based imaging technique and drug delivery for the detection and treatment of atherosclerotic vascular disease

    NASA Astrophysics Data System (ADS)

    Ankri, Rinat; Leshem-Lev, Dorit; Lev, Eli I.; Motiei, Menachem; Hochhauser, Edith; Fixler, Dror

    2016-03-01

    In our study we aim to develop a new, simple and non-invasive method to detect and to treat atherosclerosis. We use gold nanoparticles (GNPs) combined with the diffusion reflection (DR) method to demonstrate the detection of vulnerable atherosclerotic plaques. Our method is based on the fact that macrophages are a major component in the vulnerable plaque and are able to uptake metal nanoparticles that can be discovered by the DR system. Moreover, it is well known that high density lipoprotein (HDL) reduces ASVD by inhibiting pro-inflammatory factors, enabling the specific treatment of atherosclerosis.

  12. Birth delivery trauma and malocclusion.

    PubMed

    Cattaneo, Ruggero; Monaco, Annalisa; Streni, Oriana; Serafino, Vittorio; Giannoni, Mario

    2005-01-01

    The aim of the investigation was to determine the dynamic of birth delivery and relate to dental occlusion among a group of adult subjects. The group studied was made up of 106 subjects (57 females and 49 males) referred for dental diagnosis and treatment. The average age was 26 with a range 22 to 30 years. In data collection and analysis the following were used as measures: dental occlusion (Angle Class I, II div 1, II div 2 and III) and type of delivery (normal, short, long, caesarean and other). Results showed that among 106 subjects 72 (68%) had malocclusion versus 34 (32%) with normal occlusion; 24 subjects (22.6%) have been normal delivery versus 82 (77.4%) with non-normal delivery. Class I is present in 34 subjects (32%), class II division 1 in 26 (24%), class II division 2 in 22. (20%), class III in 16 (14%), and 8 subjects (6%) fall in the section "other". Among 24 subjects with normal delivery 100% presented class I occlusion. However, among 82 subjects with non-normal delivery 10 subjects had a class I (12.2%) and the 72 (87.8%) had in the other classes, are distributed in the various subgroups of non-normal labor/delivery. None of the subjects with a malocclusion have a normal labor/delivery. Better understanding of the connections among osteopathic theory, craniosacral treatment and the outcomes upon dental occlusion, more rigorous evaluations are warranted.

  13. Topical delivery and in vivo antileishmanial activity of paromomycin-loaded liposomes for treatment of cutaneous leishmaniasis.

    PubMed

    Carneiro, Guilherme; Santos, Delia C M; Oliveira, Monica C; Fernandes, Ana P; Ferreira, Luciana S; Ramaldes, Gilson A; Nunan, Elziria A; Ferreira, Lucas A M

    2010-03-01

    The present study aimed to evaluate the potential of liposomes loaded with paromomycin (PA), an aminoglycoside antibiotic associated with poor skin penetration, for the topical treatment of cutaneous leishmaniasis (CL). Fluid liposomes were prepared and characterized for particle size, zeta potential, and drug entrapment. Permeation studies were performed with two in vitro models: intact and stripped skin. The antileishmanial activity of free and liposomal PA was evaluated in BALB/c mice infected by Leishmania (L.) major. Drug entrapment ranged from 10 to 14%, and the type of vesicle had little influence on this parameter. Particle size and polydispersity index of the vesicles composed by phosphatidylcholine (PC) and PC/cholesterol (Chol) ranged from of 516 to 362 nm and 0.7 to 0.4, respectively. PA permeation across intact skin was low, regardless of the formulation tested, while drug penetration into skin (percent of the applied dose) from PC (7.2 +/- 0.2%) and PC/Chol (4.8 +/- 0.2%) liposomes was higher than solution (1.9 +/- 0.1%). PA-loaded liposomes enhanced in vitro drug permeation across stripped skin and improved the in vivo antileishmanial activity in experimentally infected mice. Our findings suggest that the liposomes represent a promising alternative for the topical treatment of CL using PA.

  14. Chitosan and gelatin based prototype delivery systems for the treatment of oral mucositis: from material to performance in vitro.

    PubMed

    Perchyonok, V Tamara; Zhang, Shengmiao; Oberholzer, Theunis

    2013-02-01

    In this study we developed and evaluated a prototype of an effective occlusive mucoadhesive system for prophylaxis and/or treatment of oral mucositis based on chitosan and gelatine models together with nystatin as a prophylactic agent incorporated into the formulation and investigated drug release in-vitro. Results of in vitro studies showed that chitosan and gelatine based gels posses properties that makes them excellent candidates for treatment of oral mucositis. These properties include not only the palliative effects of an occlusive dressing but also the potential for delivering therapeutic compounds with chitosan gels providing drug concentrations above thei