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.

项目摘要/摘要 艾滋病毒仍然是全球威胁目的地，联合抗逆转录病毒疗法（CART）的巨大进展。 慢性注射和免疫激活支持CART中非AID的风险增加 治疗的艾滋病毒患者。这种情况归因于各种因素，包括抗逆转录病毒（ARV）毒性和 继发性淋巴组织（SLT）中的病毒持久性与这些与低ARV渗透有关 水库站点。此外，每日抗逆转录病毒（ARV）的摄取仍然燃烧，导致不良 粘附可能导致SLT的病毒反弹。在这个项目中，我们建议开发长效 由脂质包裹的多乳酸纳米颗粒（GM3-PLA-NP）组成的“隐形”纳米成型 用非核苷逆转录酶抑制剂Rilpivirine（RPV）和整合酶抑制剂Cabotegravir （出租车）。这些GM3-Pla-NP具有创新的靶向和设计功能，可增加药物进入和 除了调节炎症反应外，在SLT中保留。确实，膜掺入 Monosialo Di-己糖基结肽（GM3）具有特定的结合与唾液酸杠杆受体CD169上的结合 髓样细胞（巨噬细胞和树突状细胞），导致非酸性膜的形成 可以防止NP降解并长期建立细胞药物沉积物的诱人。 这些NP收集室（NPCC）与先前定义的含有的病毒相同 CD169捕获HIV-1时形成的车厢（VCC）。由于VCC也参与了髓样细胞 通过病毒学突触，介导向CD4+ T细胞（转染）的HIV传播，我假设 NPCC可以通过巨噬细胞 - T细胞促进持续的ARV释放到旁观者T细胞 突触连接。我们的初步数据表明，这些GM3-PLA-NP成功 随着时间的推移，保留在CD169+巨噬细胞的NPCC中 体外月份。随后，在旁观者的Jurkat T细胞中观察到持续的病毒抑制 具有NP暴露CD169+巨噬细胞的培养。此外，我们的发现表明GM3脂质涂层 承认“隐身”特性，以抑制已加载ARV引起的非特异性免疫激活和 纳米粒子核心。在AIM 1中，我们将研究CD169+的细胞外药物释放机制 巨噬细胞到CD4+ T细胞。在AIM 2中，我们将评估GM3-的长期毒性和隐形机制 PLA-NPS。最后，我们将通过评估空间分布和隐身来确认这些结果 AIM 3中SLTS中GM3-PLA-NP的表型。这些研究将阐明一种新方法 有效地将长效疗法提供给SLT，这可能有益于预防HIV和 治疗以及其他疾病，例如转移性癌症。