Topical Microbicides: Targeted Intracellular Delivery

描述（由申请人提供）：该项目是对开发新型杀微生物剂以预防HIV-1感染的呼吁的回应。虽然有限的成功暗示了基于杀微生物剂的预防的前景，但临床试验的混合结果强调了简单凝胶方法的重大缺点，这种方法依赖于间歇性应用和非特异性药物递送的被动扩散。我们已经组建了一个多学科的研究团队，以解决有效杀微生物剂所需的主要问题：有效亲脂性药物的水性递送、解剖定位、相关细胞靶向、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集中在HIV-1收购的最高风险网站（结直肠粘膜）：目标1：新的多肽水凝胶与可调性能将适应坚持和坚持粘膜，以及捕获HIV-1颗粒。目标二：人类“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，具有特异性靶向，以胞质内释放药物有效载荷进入相关细胞类型。目标3：聚合物化学将被应用于加载 水凝胶与拱顶的方式，以提供持续释放和药物输送到相关的细胞类型的HIV-1收购。这些研究将为预防HIV-1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.