Topical Microbicides: Targeted Intracellular Delivery

局部杀菌剂：靶向细胞内递送

基本信息

批准号：
8711813
负责人：
Peter A Anton
金额：
$ 59.83万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711813
关键词：
Address Adherence Anatomy Anti-Retroviral Agents Antibodies Antiviral Agents Autologous Behavior Biological Availability Blood Circulation Bypass Cells Clinical Trials Coitus Colorectal Data Diffusion Dissociation Dose Drug Delivery Systems Drug Formulations Drug Targeting Drug usage Employment Encapsulated Gel HIV HIV-1 Hepatotoxicity Human Hydrogels Immunology Incidence Infection Inflammatory Kidney Failure Lactic Acidosis Local Microbicides Modification Mucositis Mucous Membrane Oral Oral Administration Pathogenesis Persons Pharmaceutical Preparations Phase Polymer Chemistry Polymers Prevention Property Prophylactic treatment Proteins Published Comment Research Personnel Resistance Reverse Transcriptase Inhibitors Risk Route Science Site Technology Tenofovir Therapeutic Tissues Toxic effect Vaccines Vaginal Gel Viral Virus Water Woman aqueous base cell type design dosage emtricitabine high risk immunogenic interdisciplinary approach men who have sex with men microbicide mucosal site multidisciplinary nanopolymer novel particle polypeptide prevent prophylactic protein structure public health relevance response success targeted delivery theories transmission process uptake

项目摘要

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.

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 感染的提案的响应。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强调了简单凝胶方法的显着缺点，该方法依赖于间歇性应用和非特异性药物输送的被动扩散。我们组建了一个多学科研究小组来解决有效杀微生物剂所需的主要问题：强效亲脂性药物的水输送、解剖定位、相关细胞靶向、细胞内定位以及应用后的持续活性。这些问题通过三个目标来解决，重点关注 HIV-1 获得的最高风险部位（结直肠粘膜）：目标 1：具有可调特性的新型多肽水凝胶将能够持久存在并粘附于粘膜，并捕获 HIV-1颗粒。目标2：人类“金库”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，将药物有效负载在胞质内释放到相关细胞类型中。目标3：将应用高分子化学来负载水凝胶与穹窿的方式能够持续释放药物并将其输送到相关细胞类型中以获取 HIV-1。这些研究将为开发一种安全、有效且廉价的杀微生物剂来预防 HIV-1 提供途径。