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.

项目概要/摘要 尽管组合抗逆转录病毒疗法（cART）取得了巨大进展，但艾滋病毒仍然是全球威胁。 慢性炎症和免疫激活支持 cART 中非艾滋病合并症的风险增加 HIV 患者的这种情况归因于多种因素，包括抗逆转录病毒 (ARV) 毒性和治疗。 二级淋巴组织 (SLT) 中病毒的持续存在与这些组织中抗逆转录病毒药物的低渗透率有关 此外，每日服用抗逆转录病毒药物（ARV）仍然是一个负担，导致贫困。 坚持服用可导致 SLTS 病毒反弹。在该项目中，我们建议开发一种长效药物。 由脂质包裹的聚乳酸纳米粒子（GM3-PLA-NPs）组成的“隐形”纳米制剂 与非核苷逆转录酶抑制剂利匹韦林 (RPV) 和整合酶抑制剂卡博特韦 (Cabotegravir) 一起使用 (CAB)。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 事实上，除了调节炎症反应外，SLT 中的保留也被纳入其中。 单唾液酸二己糖神经节苷脂 (GM3) 能够与唾液酸凝集素受体 CD169 特异性结合 骨髓细胞（巨噬细胞和树突状细胞），导致非酸性膜的形成 内陷可以防止纳米粒子降解，并导致细胞药物库的长期建立。 这些 NP 收集室 (NPCC) 与之前定义的包含病毒的病毒相同 CD169 捕获 HIV-1 后形成 VCC，因为 VCC 也参与骨髓细胞。 通过病毒突触介导 HIV 传播至 CD4+ T 细胞（反式感染），我对此感到困惑 NPCC 可能会通过巨噬细胞（T 细胞）促进旁观 T 细胞持续释放 ARV 我们的初步数据表明这些 GM3-PLA-NP 是成功的。 随着时间的推移，CD169+巨噬细胞保存在NPCC中，从而延长了这些细胞的抗病毒效力 随后，观察到旁观者 Jurkat T 细胞的持续病毒抑制。 此外，我们的研究结果表明 GM3 脂质涂层。 赋予“隐形”特性，抑制加载的抗逆转录病毒药物诱导的非特异性免疫激活， 因此，在目标 1 中，我们将研究 CD169+ 的细胞外药物释放机制。 在目标 2 中，我们将评估 GM3- 的长期毒性和隐形机制。 最后，我们将通过评估空间分布和隐形性在体内确认这些结果。 目标 3 中 SLT 中 GM3-PLA-NP 的表型。这些研究将阐明一种安全、可靠的新方法 向 SLT 有效提供长效治疗药物，这可能有益于艾滋病毒预防和 治疗以及其他疾病，例如转移性癌症。