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Currently available synthetic small diameter vascular grafts reveal low patency rates due to thrombosis and intimal hyperplasia. Biofunctionalized grafts releasing nitric oxide (NO) in situ may overcome these limitations. In this study, a drug-eluting vascular graft was designed by blending polycaprolactone (PCL) with S-nitroso-human-serum-albumin (S-NO-HSA), a nitric oxide donor with prolonged half-life. PCL-S-NO-HSA grafts and patches were fabricated via electrospinning. The fabrication process was optimized. Patches were characterized in vitro for their morphology, drug release, biomechanics, inflammatory effects, cell proliferation, and expression of adhesion molecules. The selected optimized formulation (8%PCL-S-NO-HSA) had superior mechanical/morphological properties with high protein content revealing extended NO release (for 28 days). 8%PCL-S-NO-HSA patches significantly promoted endothelial cell proliferation while limiting smooth muscle cell proliferation. Expression of adhesion molecules (ICAM-1, VCAM-1) and pro-inflammatory macrophage/cytokine markers (CD80, IL-1α, TNF-α) was significantly reduced. 8%PCL-S-NO-HSA patches had superior immunomodulatory properties by up-regulating anti-inflammatory cytokines (IL-10) and M2 macrophage marker (CD163) at final time points. Grafts were further evaluated in a small rodent model as aortic implants up to 12 weeks. Grafts were assessed by magnetic resonance imaging angiography (MRI) in vivo and after retrieval by histology. All grafts remained 100 % patent with no signs of thrombosis or calcification. 8%PCL-S-NO-HSA vascular grafts supported rapid endothelialization, whereas smooth muscle cell proliferation was hampered in earlier phases. This study indicates that 8%PCL-S-NO-HSA grafts effectively support long-term in situ release of bioactive NO. The beneficial effects observed can be promising features for long-term success of small diameter vascular grafts. STATEMENT OF SIGNIFICANCE: Despite extensive research in the field of small diameter vascular graft replacement, there is still no appropriate substitute to autografts yet. Various limitations are associated with currently available synthetic vascular grafts such as thrombogenicity and intimal hyperplasia. Therefore, developing new generations of such conduits has become a major focus of research. One of the most significant signaling molecules that are involved in homeostasis of the vascular system is nitric oxide. The new designed nitric-oxide eluting vascular grafts described in this study induce rapid surface endothelialization and late migration of SMCs into the graft wall. These beneficial effects have potential to improve current limitations of small diameter vascular grafts.

In prostate cancer, hormone therapy via leuprolide acetate drug (LUP) is used to lower the level of testosterone down to castration level to effectively control the development of prostate cancer. The objective of this study was to evaluate the effective parameters in degradation and controlled release of an injectable in situ formed polymeric implant, loaded with leuprolide acetate, in order to achieve an optimum formulation for sustained drug release for 90 days with minimum burst release. The main problem associating with such implants is their high burst release. Designing an injectable implant with sustained and minimum burst release has thus become an attractive challenge in drug delivery field. Effects of type of poly(lactic-co-glycolic acid) 75:25 copolymers (RG752, RG756) and addition of nano-hydroxyapatite (HA) particles on degradation rates of the implants and release profiles were examined in vitro and in vivo in a rabbit animal model. Results showed that implants containing polymers with higher molecular weights had significantly lower weight loss and molecular weight reduction. Adding nanoparticles of hydroxyapatite into poly(lactic-co-glycolic acid) implants caused further reduction in degradation rates, leading to a more sustained drug release in vivo, with reduced burst release. Different conventional kinetic models were applied to drug release and degradation data. The degradation data fit well to the first-order degradation model. Higuchi model was the best kinetic release model fitted to the experimental in vitro release data. This study led to an optimum formulation (RG756:RG752 3:1 + 5% HA) with sustained leuprolide release and testosterone suppression over a 90-day period with significant decrease of burst release phase (50%, p

A method for generating poly(lactic-co-glycolic acid) and polycaprolactone biodegradable particles of different size and shape using a jet generated in an electric field is elucidated. These particles are suitable for use as drug carriers and the method can be developed into a mass production route. The effect of different parameters such as applied voltage, collecting distance, flow rate and polymer concentration on inducing size and shape differences in these particles was studied. It was found that the flow rate, polymer concentration and collecting distance have a significant impact on the size of the generated particles and by changing the collecting distance a systematic reduction in the particle size by at least an order of magnitude (10microm-100nm) can be achieved. By using a high polymer concentration (30 wt. %) the shape and surface morphology of these particles can also be controlled from spherical to fibrous, and smooth to irregular, respectively, which presently is an interesting strategy and concept in drug delivery. This method is very useful as a one-step generator of different sizes of drug carriers with morphological variations.

Background: Drug-loaded poly(lactide-co-glycolide) particles (100–4500 nm in diameter) were prepared via the electrospraying method. An extensive study was then carried out to determine the parameters affecting the release profile of estradiol (the drug or active pharmaceutical ingredient) in order to facilitate minimum initial burst release of estradiol. Results and discussion: The three most important factors affecting estradiol release were identified as: particle size, coating of the particles with chitosan/gelatin and the concentration of the coating agent. It was shown that coating the particles with chitosan significantly reduced the burst and initial release without affecting the subsequent release profile. Conclusions: This work demonstrates a powerful method of generating drug-loaded polymeric particles with modified release behavior and control over the initial release phase. The surface-modified particles may be useful in controlled therapeutic delivery systems to minimize undesirable side effects.

In this investigation, biodegradable polycaprolactone polymeric particles (300–4500 nm in diameter) were prepared by jetting a solution in an electric field. An extensive study has been carried out to determine how the size and size distribution of the particles generated can be controlled by systematically varying the polymer concentration in solution (and thereby its viscosity and electrical conductivity), and also the selected flow rate (2–50 µl min −1 ) and applied voltage (0–15 kV) during particle generation. Change in these parameters affects the mode of jetting, and within the stable cone-jet mode window, an increase in the applied voltage (approx. 15 kV) resulted in a reduction in particle size and this was more pronounced at high flow rates (such as; 30, 40 and 50 µl min −1 ) in the same region. The carrier particles were more polydisperse at the peripheral regions of the stable cone-jet mode, as defined in the applied voltage-flow rate parametric map. The effect of loading a drug on the particle size, size distribution and encapsulation efficiency was also studied. Release from drug-loaded particles was investigated using UV spectrophotometry over 45 days. This work demonstrates a powerful method of generating drug-loaded polymeric particles, with the ability to control size and polydispersivity, which has great potential in several categories of biotechnology requiring carrier particles, such as drug delivery and gene therapy.

In this research poly (d,l-lactide-coglycolide acid) (PLGA) as polymeric nanospheres, poly(vinyl alcohol) (PVA) with 87-89% hydrolysis degree as surfactant and distilled water as suspending medium were used. The encapsulated drug was Bethametasone. The nanospheres were prepared by an emulsion-solvent evaporation method. The nanospheres characterized by photon correlation spectroscopy (PCS) and scanning electron microscopy (SEM). The amount of drug release was determined by HPLC. In emulsion-solvent evaporation technique, time of ultrasound exposure, surfactant content in the formulation and evaporation rate of organic solvents were considered as formulation variables.

A poly (lactide-co-glycolide) (PLGA) implant was used to control the release profile of leuprolide acetate (LA) drug. The system is an in-situ polymeric precipitation system. And the formulation consisted of PLGA polymer, LA drug and N-methyl-2-pyrrolidon solvent with no additives. First, the formulation was injected into PBS solution for in-vitro studies and then it was administered to the animal models (female rats) for in-vivo release studies. The release profiles of leuprolide acetate were measured by UV spectrophotometry for a period of 28 days. The initial burst release of LA was 14% in in-vitro whereas it was 7% in in-vivo. In-vitro and in-vivo release profiles of LA had similar trends after 72 hours. However, the rate of LA release was slower in-vivo. This might be attributed to the limited diffusion process of solvent and the drug molecules. This could be due to presence of an additional pressure caused by the surrounding tissue and also the presence of small amount of water between cells in the subcutaneous site. Cross-section and surface of the implants were studied via scanning electron microscopy. Morphology of both in-vitro and in-vivo implants confirmed the release behaviours. No toxicity effects were reported in the histopathological assay. Furthermore, the pharmacological analysis showed more inactive ovaries due to release of LA.