Quantifying drug delivery to the vascular endothelium and hippocampus: Release, distribution and biological effects of paclitaxel and brain derived neurotrophic factor.

摘要

The design of effective drug delivery devices is improved by the ability to predict how the drug will interact with the target tissue site. Quantitative understanding of drug delivery is particularly important for implanted devices, which are designed to remain in the body for long periods of time. In this thesis, the release, distribution and biological effects of sustained delivery were examined for two agents that represent two of the most important classes of drugs for controlled release (hydrophobic drugs and proteins). First, the rate of release of paclitaxel (PTx) from a vascular stent was mathematically modeled as a function of stent formulation parameters. Models accounting for release due to different physical mechanisms produced equivalent predictions, highlighting important considerations in data fitting methodology. Second, the distribution of a fluorescent analog of PTx (F-PTx) was measured in an in vitro tissue mimic. The presence of elastin fibers in agarose produced a strong reduction in the effective diffusion coefficient, but no reduction was observed in gels containing elastin-like polypeptides or degraded, extracted elastin, suggesting a source for the non-homogeneous distribution of PTx observed in intact tissue. Third, polymer devices were designed to deliver brain derived neurotrophic factor (BDNF) to the dorsal hippocampus. Delivery devices of varying composition were implanted in the rat, and behavioral and biochemical outcomes were examined as a function of delivery rate. A small dose of BDNF delivered as a single infusion or from two-day sustained-release alginate microspheres was antidepressant, whereas the same dose delivered from seven-day, sustained-release poly(ethylene-vinyl-acetate) implants did not alter behavior and produced dysregulation of neuroplasticity related pathways. Cumulatively, this dissertation has revealed tissue site-specific parameters which affect the release and distribution of drug from implantable devices, and has also demonstrated how variations in the rate of drug delivery may have profound consequences for biological outcome.