Topical Microbicides: Targeted Intracellular Delivery

描述(由申请者提供)：该项目是对开发新型杀微生物剂以预防HIV-1感染的建议的响应。尽管有限的成功暗示了基于杀菌剂的预防的前景，但临床试验的混合结果突显了简单凝胶方法的重大缺点，这种方法依赖于间歇给药和被动扩散来非特异性给药。我们已经组建了一个多学科的研究团队来解决有效杀微生物剂所需的主要问题：强效脂类药物的水给药、解剖定位、相关的细胞靶向、细胞内定位和应用后的持续活性。这些问题是通过三个目标来解决的，这些目标集中在HIV-1感染的最高风险部位(大肠粘膜)：目标1：具有可调特性的新型多肽水凝胶将被改造成能够持久并附着在粘膜上，以及捕获HIV-1颗粒。目的2：人“拱顶”生物颗粒将被修饰为非极性抗逆转录病毒药物的载体，具有特定的靶向性，将药物有效载荷释放到胞浆内相关细胞类型。目标3：将应用聚合物化学来加载 将水凝胶与保险库连接，以提供药物的持续释放，并将药物输送到相关类型的细胞中，以获取艾滋病毒-1病毒。这些研究将为HIV-1预防提供一种安全、有效和廉价的杀微生物剂。

DESCRIPTION (provided by applicant): This project is a response to a call for proposals to develop novel microbicides to prevent HIV-1 infection. Although limited successes have hinted at the promise of microbicide-based prevention, the mixed results of clinical trials underscore the significant shortcomings of simple gel approaches, which depend on intermittent application and passive diffusion for nonspecific drug delivery. We have assembled a multidisciplinary team of investigators to address major issues required for an effective microbicide: aqueous delivery of potent lipophilic drugs, anatomic localization, relevant cell targeting, intracellular localizaton, and sustained activity after application. These issues are approached through three aims focused on the highest risk site of HIV-1 acquisition (the colorectal mucosa): Aim 1: Novel polypeptide hydrogels with tunable properties will be adapted to persist and adhere to mucosa, as well as capture HIV-1 particles. Aim 2: Human "vault" bioparticles will be modified as carriers for nonpolar antiretroviral drugs, with specific targeting to release the drug payload intracytoplasmically into relevant cell types. Aim 3: Polymer chemistry will be applied to load the hydrogels with the vaults in a manner to provide sustained release and delivery of drugs into the relevant cell types for HIV-1 acquisition. These studies will provide a path to a safe, effective, and inexpensive microbicide for HIV-1 prevention.