Dual antiretroviral loaded nanoparticles for long-acting suppressive HIV therapy

用于长效抑制艾滋病毒治疗的双重抗逆转录病毒纳米粒子

• 批准号: 10548482
• 负责人: Josiane Fofana
• 金额: $ 4.68万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-28 至 2025-02-27
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548482
• 关键词: AIDS prevention; Address; Adherence; Anti-Retroviral Agents; Binding; Biodistribution; Biotin; CD4 Positive T Lymphocytes; Cell Survival; Cell membrane; Cell surface; Cells; Chronic; Coculture Techniques; Data; Dendritic Cells; Development; Disease; Disseminated Malignant Neoplasm; Dose; Dyes; Exposure to; Failure; Flow Cytometry; G(M3) Ganglioside; Goals; HIV; HIV therapy; HIV-1; Image Cytometry; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Injections; Integrase Inhibitors; Label; Lead; Lectin Receptors; Ligase; Link; Lipid Bilayers; Lipids; Lymphoid Tissue; Measures; Mediating; Membrane; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Oral; Patients; Penetration; Pharmaceutical Preparations; Phenotype; Plasma; Polymers; Prevention; Property; Protein-Protein Interaction Map; Regimen; Reverse Transcriptase Inhibitors; Risk; Role; Secondary to; Sialic Acids; Site; Spatial Distribution; Synapses; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toxic effect; Viral; Virus; antiretroviral therapy; combinatorial; comorbidity; cytokine; design; extracellular; immune activation; immunoregulation; in vivo; innovation; live cell imaging; macrophage; monocyte; nanoformulation; nanoparticle; nanotherapeutic; non-nucleoside reverse transcriptase inhibitors; nonhuman primate; novel strategies; poly(lactic acid); preservation; prevent; response; targeted delivery; transmission process; uptake; viral rebound; viral transmission; virological synapse

PROJECT SUMMARY/ABSTRACT HIV remains a global threat despite the tremendous progress of combinatorial antiretroviral therapy (cART). Chronic inflammation and immune activation support an increased risk of non-AIDS co-morbidities in cART- treated HIV patients. This condition is attributed to various factors including antiretroviral (ARV) toxicity and viral persistence in secondary lymphoid tissues (SLTs) which has been linked to low ARV penetration in these reservoir sites. Furthermore, uptake of daily antiretrovirals (ARVs) remains a burden resulting in poor adherence that can lead to viral rebound from the SLTS. In this project, we propose to develop a long-acting “stealth” nanoformulation composed of lipid wrapped poly-lactic acid nanoparticles (GM3-PLA-NPs) loaded with a non-nucleoside reverse transcriptase inhibitor, Rilpivirine (RPV) and integrase inhibitor, Cabotegravir (CAB). These GM3-PLA-NPs have innovative targeting and design features that will increase drug entry and retention in SLTs, in addition to modulating inflammatory responses. Indeed, the membrane incorporated monosialo di-hexosylganglioside (GM3) enables specific binding to the sialic acid lectin receptor CD169 on myeloid cells (macrophages and dendritic cells), leading to the formation of non-acidic membrane invaginations which can prevent NP degradation, and lead to long-term establishment of cellular drug depots. These NP collecting compartments (NPCCs) are identical to the previously defined virus containing compartments (VCCs) formed upon capture of HIV-1 by CD169. Since VCCs are also involved in myeloid cell- mediated HIV transmission to CD4+ T cells (trans-infection) through the virological synapse, I hypothesize that NPCCs could potentially promote sustained ARV release to bystander T cells through macrophage – T cell synaptic junctions. Our preliminary data have demonstrated that these GM3-PLA-NPs are successfully preserved in NPCCs of CD169+ macrophages over time which extended anti-viral potency in these cells for a month in vitro. Subsequently, sustained viral inhibition in bystander Jurkat T cells was observed upon co- culture with NP-exposed CD169+ macrophages. Additionally, our findings suggest that the GM3 lipid coating confers “stealth” properties to suppress non-specific immune activation induced by loaded ARVs and nanoparticle core. Thus, in aim 1, we will investigate the extracellular drug release mechanism from CD169+ macrophages to CD4+ T cells. In aim 2, we will assess the long-term toxicity and stealth mechanism of GM3- PLA-NPs. Finally, we will confirm these results in vivo by assessing the spatial distribution and stealth phenotype of GM3-PLA-NPs in SLTs in aim 3. These studies will elucidate a new approach for safe and effective delivery of long-acting therapeutics to SLTs which could be beneficial for HIV prevention and treatment as well as other diseases such as metastatic cancer.

项目总结/文摘