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

摘要 基于纳米颗粒的治疗剂的开发中的一个显著限制是缺乏对纳米颗粒的抑制。 可以预测体内行为，特别是关于释放速率的体外模型， 治疗剂的稳态浓度。该提案侧重于开发、测试、 和验证一种体外装置，该装置可以准确地预测从 玻璃体内注射或放置在眼睛后部的纳米材料。纳米材料试验台 我们将使用的是基于纳米结构多孔硅（pSi）及其复合材料与各种 生物相容性聚合物。多孔硅是眼用药物的理想载体 治疗学它在体内表现出优异的生物相容性和生物降解性， 多功能表面化学，能够掺入各种药物类型，包括 抗体、寡核苷酸和亲水或疏水小分子。虽然 在这一领域取得了重大进展， 动物眼睛由于玻璃体水龙头中的药物水平低或昂贵和时间而构成挑战， 在每个时间点消耗整个玻璃体的收获。对于这一建议，我们将设计 并构建一个模拟玻璃体的模拟器， 在体内药物释放曲线比以前已经实现。pSi的配方将是 这是与Spinnaker Biosciences合作开发的，Spinnaker Biosciences是一家加州的小公司， 在制造和测试用于眼部治疗的pSi颗粒方面的专业知识。交联 透明质酸和聚乙烯醇的混合物和共聚物将与 缓冲溶液以模拟玻璃体的粘性环境。流动特性，粘度， 并且温度将针对实时和加速测试条件而系统地变化。 我们将使用一系列不同的pSi制剂来测试纳米颗粒的降解、溶解， 以及在各种实验条件下的药物释放/浸出。结果将 与相同材料的家兔体内试验相比。提供额外的相关信息 数据，我们将利用pSi的光子特性来监测其降解和时间药物 释放剖面。研究的主要目标是更好地理解 准确模拟眼睛中的体内药物递送所需的体外特性。

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.