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）：此项目是对提案的呼吁的回应，以开发新型菌心，以防止HIV-1感染。尽管成功的有限暗示了基于杀菌剂的预防的希望，但临床试验的混合结果强调了简单凝胶方法的重大缺点，这些方法取决于间歇性应用和非特异性药物递送的被动扩散。我们组建了一个多学科研究人员团队，以解决有效的杀菌剂所需的重大问题：有效的亲脂性药物的水性输送，解剖学定位，相关的细胞靶向，细胞内局部局部化以及应用后的持续活动。这些问题通过三个目的来解决HIV-1采集的最高风险部位（结直肠粘膜）：AIM 1：具有可调特性的新型多肽水凝胶将适应持久并粘附在粘膜上，并捕获HIV-1颗粒。 AIM 2：人类的“金库”生物颗粒将被修饰为非极性抗逆转录病毒药物的携带者，其特异性靶向将药物有效载荷内部内部释放到相关的细胞类型中。 AIM 3：聚合物化学将用于加载与金库的水凝胶以一种方式，以持续释放和将药物递送到相关的细胞类型中以获取HIV-1。这些研究将为预防HIV-1的安全，有效且廉价的菌心提供一条途径。