plga-nanoparticles-formed-single-or-double-emulsion-with-vitamin-e

PLGA Nanoparticles Formed by Single- or Double-emulsion with Vitamin E-TPGS

Poly(lactic-co-glycolic acid) (PLGA) is a biocompatible member of the aliphatic polyester family of biodegradable polymers. PLGA has long been a popular ...

Barrow Neurological Institute

Paclitaxel (PTx) is reported to have an nonuniform steady-state concentration profile in the arterial wall. We utilized epifluorescence microscopy to make precise measurements of fluorescently-labeled PTx (F-PTx) distribution through an in vitro tissue mimic which contained varying concentrations of fibrin, elastin, soybean oil, palmitic acid, and solid glass beads. As little as 0.5 mg/mL of elastin in agarose produced a 50% drop in the measured diffusion coefficient, while as much as 10 mg/mL of fibrin in agarose was required for the same reduction in rate of transport. Because no reduction in the measured diffusion coefficient was observed for solubilized, extracted elastin or unassembled elastin-like polypeptides, the effect was specific to elastic fibers that closely resembled the native elastin network. Collectively, this work identifies a potential source for the high degree of partitioning observed for PTx in native tissue and further develops an in vitro technique for exploring complex tissue-drug interactions.

Effect of extracellular matrix elements on the transport of paclitaxel through an arterial wall tissue mimic.

The TAXUS Express coronary artery stent delivers a sustained dose of a hydrophobic drug (paclitaxel) from a hydrophobic polymer coating (poly(styrene-isobutylene-styrene), SIBS). It is known that particles of concentrated drug are dispersed throughout the polymer coating, however, the mechanism by which drug exits the polymer matrix is not fully characterized. In this work, mathematical models were applied to in vitro controlled release data obtained from 8.8, 25 and 35% loadings of drug in polymer. Models that accounted for release by different mechanisms were tested. It was observed that Fickian diffusion, dissolution and osmotic gradient models were capable of fitting the data equally well. It was also possible to fit the data with a variety of parameter combinations, even if the values of some parameters were unlikely. We use the example of Paclitaxel release from the SIBS matrix to discuss important considerations in fitting controlled release data with mechanistic models.

Parameter estimation methodology in a model of hydrophobic drug release from a polymer coating.

Brain-derived neurotrophic factor (BDNF) is closely linked with neuronal survival and plasticity in psychiatric disorders. In this work, we engineered degradable, injectable alginate microspheres and non-degradable, implantable poly(ethylene vinyl acetate) matrices to continuously deliver BDNF to the dorsal hippocampus of rats for two days or more than a week, respectively. The antidepressant-like behavioral effects of BDNF delivery were examined in the Porsolt forced swim test. Rats were sacrificed 10days after surgery and tissue samples were analyzed by western blot. A small dose of BDNF delivered in a single infusion, or from a two-day sustained-release alginate implant, produced an antidepressant-like behavior, whereas the same dose delivered over a longer period of time to a larger tissue region did not produce antidepressant-like effects. Prolonged delivery of BDNF resulted in a dysregulation of plasticity-related functions: increased dose and duration of BDNF delivery produced increased levels of TrkB, ERK, CREB, and phosphorylated ERK, while also producing decreased phosphorylated CREB. It is evident from this work that both duration and magnitude of BDNF dosing are of critical importance in achieving functional outcome.

The behavioral and biochemical effects of BDNF containing polymers implanted in the hippocampus of rats.

Our goal was to use positron emission tomography (PET) to analyze the movement of radiolabeled agents in tissue to enable direct measurement of drug delivery to the brain.

Direct, quantitative, and noninvasive imaging of the transport of active agents through intact brain with positron emission tomography.

Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

Article	Year
Effect of extracellular matrix elements on the transport of paclitaxel through an arterial wall tissue mimic. Biomacromolecules\| PubMed ID: 18785771	2008
Parameter estimation methodology in a model of hydrophobic drug release from a polymer coating. Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 19958804	2010
The behavioral and biochemical effects of BDNF containing polymers implanted in the hippocampus of rats. Brain research\| PubMed ID: 20096671	2010
Direct, quantitative, and noninvasive imaging of the transport of active agents through intact brain with positron emission tomography. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging\| PubMed ID: 23624949	2013
Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 23818631	2013

Rachael W. Sirianni

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