Modeling of the vitreous for in vitro prediction of drug delivery of porous silicon particles and episcleral plaques

摘要

Abstract A significant limitation in the development of nanoparticle-based therapeutics is the lack of in vitro models that can predict in vivo behavior, in particular with respect to rate of release and steady state concentration of the therapeutic. This proposal focuses on development, testing, and validation of an in vitro device that can accurately predict therapeutic levels delivered from nanomaterials injected intravitreally or placed on the back of the eye. The testbed nanomaterial we will use is based on nanostructured porous silicon (pSi) and its composites with various biocompatible polymers. Porous silicon has been identified as an ideal drug carrier for ocular therapeutics. It has demonstrated excellent biocompatibility and biodegradability in vivo and versatile surface chemistry that enables incorporation of a wide range of drug types, including antibodies, oligonucleotides, and hydrophilic or hydrophobic small molecules. Although there has been significant progress in this area, testing candidate nanotherapeutic formulations in live animal eyes poses a challenge due to low drug levels in vitreous taps or expensive and time- consuming harvesting of the entire vitreous at each time point. For this proposal, we will design and construct a simulator that will mimic the vitreous to enable a more accurate correlation with in vivo drug release profiles than has been achieved previously. Formulations of pSi will be developed in collaboration with Spinnaker Biosciences, a small California company that has expertise in fabrication and testing of pSi particles for ocular therapeutics. Crosslinked hyaluronic acid and polyvinyl alcohol mixtures and copolymers will be used in conjunction with buffer solutions to imitate the viscous environment of the vitreous. Flow characteristics, viscosity, and temperature will be systematically varied for real-time and accelerated testing conditions. We will use a range of different pSi formulations to test nanoparticle degradation, dissolution, and drug release/leaching under a variety of experimental conditions. The results will be compared with in vivo tests of the same materials in rabbits. To provide additional correlative data, we will exploit the photonic properties of pSi to monitor its degradation and temporal drug release profile. The primary goal of the research is to develop a better understanding of the key in vitro characteristics needed to accurately mimic in vivo drug delivery in the eye.