Immunotherapeutic nanoparticles: Implications for the treatment of tuberculosis and HIV

免疫治疗纳米粒子：对结核病和艾滋病毒治疗的影响

• 批准号: 10757507
• 负责人: JESSICA L REYNOLDS
• 金额: $ 24.08万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-02 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10757507
• 关键词: Acids; Address; Adsorption; Affect; Alveolar Macrophages; Antibiotics; Bacillus; Binding; Bronchoalveolar Lavage; Cessation of life; Chitosan; Communicable Diseases; Data; Disease; Dose; Dose Limiting; Drops; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Effectiveness; Encapsulated; Formulation; Glycolates; Granuloma; HIV; HIV Envelope Protein gp120; HIV-1; HIV/TB; Histology; Human; Immune system; Immunologic Stimulation; Immunotherapeutic agent; In Situ; In Vitro; Inbred BALB C Mice; Inflammatory; Inhalation; Innate Immune System; Knowledge; Learning; Lesion; Lung; Macrophage; Methods; Modeling; Mus; Mycobacterium tuberculosis; Nature; Necrosis; Necrotic Lesion; Oropharyngeal; Oxygen; Pathogenesis; Persons; Phagolysosome; Phagosomes; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Production; Property; Proteins; Reactive Nitrogen Species; Research Personnel; Rifampin; Rifamycins; Risk; Science; Surface; TNF gene; Testing; Therapeutic; Time; Treatment Protocols; Tuberculosis; Vaccines; Viral Proteins; Virulent; alveolar epithelium; aspirate; bactericide; beta-Glucans; biocompatible polymer; biodegradable polymer; co-infection; cytokine; dectin 1; efficacy evaluation; efficacy study; experimental study; extracellular; human disease; in vivo; in vivo Model; innovation; microbial; mouse model; nanoformulation; nanoparticle; nanoparticle delivery; nanoshell; nanotechnology platform; novel; pathogen; receptor; side effect; skills; tuberculosis drugs; tuberculosis granuloma; tuberculosis treatment; uptake

The risk of developing tuberculosis (TB) is estimated to be 26 to 31 times greater in people living with Human Immunodeficiency Virus (HIV-1). The arduous treatment regimen for TB (minimum of six months on a cocktail of antibiotics with dose-limiting side-effects) has remained essentially unchanged for decades. Reducing the global TB burden has focused primarily on new antibiotics and vaccines with little focus on macrophage targeted drug delivery methods that activate the immune system to increase microbial eradication. To address this unmet need, we developed a targeted macrophage therapy with broad applications for HIV and TB. Our formulation delivers a model rifamycin drug, rifampin, loaded into β-glucan and chitosan coated poly(lactic-co-glycolic) acid (GLU-CS-PLGA) nanoparticles. Our pharmacokinetic studies found that after a single nanoparticle administration via oropharyngeal aspiration to healthy mice, rifampin was detected in the cellular fraction of the bronchoalveolar lavage up to 10 days post-dosing. Furthermore, we found a time course of release of TNFα that returns to baseline at 24 hr post administration. All nanoparticles stimulated the release of TNFα in the range of 500 to 2000 pg/ml, similar to TNFα concentrations in a TB mouse model after drug treatment. While we have demonstrated sustained delivery of rifampin to alveolar macrophage in mice using our nanoparticles, we have yet to learn how this nanoparticle functions in the setting of virulent mycobacterium tuberculosis in the lung. Furthermore, we have yet to discover how this nanoformulation affects a TB granuloma in the absence or presence of HIV viral proteins. To address this, we are taking a two-pronged approach with independent aims. Aim 1, “Determine the GLU-CS-PLGA nanoparticles in an in vitro TB granuloma model in the absence or presence of HIV proteins”, will analyze the bactericidal efficacy elicited by GLU-CS-PLGA nanoparticles in this model. We also have included an exploratory experiment to investigate the effects of HIV-1 proteins on GLU-CS-PLGA nanoparticle efficacy. Aim 2, “Determine the in vivo efficacy of GLU-CS-PLGA nanoparticles in the BALB/c TB mouse model”, will determine the bactericidal efficacy in situ in the lungs following oropharyngeal aspiration with GLU-CS-PLGA in the BALB/c TB mouse model. Therefore, this nanoplatform is broadly relevant to disorders that affect macrophage, including TB and HIV (HIV macrophage reservoirs). Determining the efficacious nature of this nanoformulation is essential to decide whether (1) we should abandon this therapeutic approach or (2) we should move forward to test it in an advanced mouse TB model that develops highly organized encapsulated necrotic lesions, i.e., granulomas, that contain large numbers of extracellular bacilli that more closely resembled human lesions and, in an HIV-TB co-infection model. This innovative proposal advances the conceptual and mechanistic knowledge of stimulation of the immune system to treat infectious diseases and this novel immune-stimulating drug delivery nanoparticle platform. By incorporating GLU onto the nanoparticle's surface, the resulting immune stimulation is independent of its therapeutic cargo.

据估计，患有人类结核病的人患结核病 (TB) 的风险高出 26 至 31 倍。 免疫缺陷病毒（HIV-1）。结核病的艰苦治疗方案（至少六个月的鸡尾酒疗法） 具有剂量限制性副作用的抗生素）几十年来基本保持不变。减少 全球结核病负担主要集中在新抗生素和疫苗上，很少关注针对巨噬细胞的治疗 激活免疫系统以增加微生物根除的药物输送方法。为了解决这个未满足的问题 根据需要，我们开发了一种针对艾滋病毒和结核病具有广泛应用的靶向巨噬细胞疗法。我们的配方 提供一种模型利福霉素药物利福平，负载到 β-葡聚糖和壳聚糖包被的聚（乳酸-乙醇酸）酸中 (GLU-CS-PLGA) 纳米粒子。我们的药代动力学研究发现，单个纳米颗粒后 通过口咽抽吸对健康小鼠给药，在其细胞部分中检测到利福平 给药后 10 天进行支气管肺泡灌洗。此外，我们发现 TNFα 释放的时间过程 给药后 24 小时恢复至基线。所有纳米颗粒均刺激该范围内 TNFα 的释放 500 至 2000 pg/ml，与药物治疗后结核病小鼠模型中的 TNFα 浓度相似。虽然我们有 证明使用我们的纳米颗粒将利福平持续递送至小鼠的肺泡巨噬细胞，我们已经 尚未了解这种纳米颗粒如何在有毒力的结核分枝杆菌环境中发挥作用 肺。此外，我们尚未发现这种纳米制剂如何在不存在的情况下影响结核肉芽肿 或存在 HIV 病毒蛋白。为了解决这个问题，我们正在采取双管齐下的方法， 目标。目标 1，“在不存在或不存在的情况下确定体外结核肉芽肿模型中的 GLU-CS-PLGA 纳米粒子 HIV 蛋白的存在”，将分析 GLU-CS-PLGA 纳米颗粒在这种情况下引起的杀菌功效 模型。我们还进行了一项探索性实验来研究 HIV-1 蛋白对 GLU-CS-PLGA 纳米颗粒功效。目标 2，“确定 GLU-CS-PLGA 纳米颗粒在体内的功效” BALB/c TB 小鼠模型”将在肺部原位测定杀菌功效 在 BALB/c TB 小鼠模型中使用 GLU-CS-PLGA 进行口咽抽吸。因此，这个纳米平台是 与影响巨噬细胞的疾病广泛相关，包括结核病和艾滋病毒（艾滋病毒巨噬细胞储存库）。 确定这种纳米制剂的有效性质对于决定 (1) 我们是否应该放弃至关重要 这种治疗方法或（2）我们应该继续在先进的小鼠结核病模型中进行测试，该模型开发出 高度组织化的包裹性坏死病变，即肉芽肿，含有大量细胞外物质 与人类病变更加相似的杆菌，并且在 HIV-TB 共感染模型中。这种创新的 该提案推进了刺激免疫系统治疗的概念和机制知识 传染病和这种新型免疫刺激药物输送纳米颗粒平台。通过合并 将 GLU 附着到纳米颗粒的表面上，产生的免疫刺激与其治疗货物无关。