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GM3 Nanoparticles for Sustained Delivery of Anti-Retrovirals to Lymphatic Tissues

用于将抗逆转录病毒药物持续递送至淋巴组织的 GM3 纳米颗粒

基本信息

批准号：
10056188
负责人：
SURYARAM GUMMULURU
金额：
$ 62.6万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-11-08 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056188
关键词：
Address Anti-Retroviral Agents Binding Cell membrane Cell surface Cells Clinical Research Data Dendritic Cells Development Disease Drug toxicity Encapsulated Environment Future Goals HIV HIV-1 Human In Vitro Individual Infection Inflammation Link Lymphatic Lymphatic System Lymphoid Tissue Macaca Malignant Neoplasms Membrane Membrane Fluidity Metabolic Diseases Mus Myelogenous Myeloid Cells Oral Penetration Pharmaceutical Preparations Pharmacodynamics Plasma Play Process Property Regulation Research Research Priority Residual state Role SIV Secondary to Sialic Acids Site Solid Spleen Subcutaneous Injections Surface Testing Therapeutic Time Tissues Treatment Efficacy Vaccine Antigen Viral Viral reservoir Virus Virus Replication antiretroviral therapy base design draining lymph node efficacy validation exosome extracellular humanized mouse improved in vivo intravenous injection lymph nodes macrophage mouse model nano nanoGold nanocarrier nanoparticle nanoparticle delivery nonhuman primate novel novel strategies pre-clinical preservation prevent segregation simian human immunodeficiency virus systemic toxicity targeted delivery trafficking uptake viral rebound virus development

项目摘要

PROJECT ABSTRACT Despite widespread implementation of antiretroviral therapy (ART) that effectively suppresses virus replication in the periphery, HIV persists in tissue reservoirs and accounts for the rapid plasma viral rebound in HIV- infected individuals who have discontinued ART. It is well appreciated that secondary lymphoid tissues represent a drug-privileged site that account for residual viral persistence in HIV-infected individuals on ART. Hence, effective cure and eradication strategies require development of novel approaches that specifically target lymph node-resident HIV reservoirs. An effective strategy to enhance anti-retroviral (ARV) drug concentrations in secondary lymph nodes is to formulate ARVs in carriers such as nanoparticles that promote transport of compounds via the lymphatics to the draining lymph nodes. Additionally, strategies that prevent rapid clearance and maintain inhibitory concentrations of ARVs in lymph nodes for an extended time are needed to effectively suppress persistent virus expression. Hence in this application, we are proposing to develop GM3-containing membrane encapsulated nanoparticle-based approaches to establish long-term tissue depots of ARVs in lymph nodes to suppress residual viral replication. The design of these nanoparticles is based on our recent findings that demonstrate specific capture of GM3 (α2,3-linked sialic acid containing monosialo-dihexosylganglioside) containing membrane encapsulated gold nanoparticles by CD169 expressing primary human myeloid cells such as macrophages and dendritic cells in vitro and co-localization of GM3-gold NPs with CD169+ cells in lymph nodes of mice. Interestingly, capture of GM3-gold NPs resulted in sequestration and preservation within surface accessible non-lysosomal plasma membrane invaginations in CD169+ myeloid cells. Hence, we will exploit these specific interactions between GM3-containing membrane encapsulated nanoparticles and CD169 to achieve both selective targeting of lymph node resident-myeloid cells and sequestration to specialized non-lysosomal compartments for formation of “drug depots” that achieve sustained inhibitory concentrations of ARVs. Finally, we will determine the ability of these novel ARV- containing nanocarriers to suppress virus replication in lymph nodes in a humanized mouse model of HIV-1 infection. We believe these studies are critical to development of virus-eradication strategies for eliminating persistent HIV reservoir.

项目摘要