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，患有结核病的人患结核病的风险要高出26至31倍。 免疫缺陷病毒（HIV-1）。结核病的艰苦治疗方案（鸡尾酒疗法至少六个月 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的抗生素和疫苗上，很少关注靶向巨噬细胞 激活免疫系统以增加微生物根除的药物递送方法。为了解决这一未满足的问题， 根据需要，我们开发了一种靶向巨噬细胞疗法，广泛应用于艾滋病毒和结核病。我们的配方 将模型利福霉素药物利福平装载到β-葡聚糖和壳聚糖涂层聚（乳酸-羟基乙酸）酸中 （GLU-CS-PLGA）纳米颗粒。我们的药代动力学研究发现， 通过口咽抽吸向健康小鼠施用利福平，在细胞的细胞部分中检测到利福平。 支气管肺泡灌洗直至给药后10天。此外，我们发现TNFα释放的时间过程， 在给药后24小时恢复至基线。所有纳米颗粒刺激TNFα的释放， 500至2000 pg/ml，与药物治疗后TB小鼠模型中的TNFα浓度相似。虽然我们已经 我们证明了使用我们的纳米颗粒将利福平持续递送到小鼠肺泡巨噬细胞， 目前还不清楚这种纳米颗粒在结核病的致病分支杆菌中的作用， 肺。此外，我们还没有发现这种纳米制剂如何影响结核肉芽肿， 或HIV病毒蛋白的存在。为了解决这个问题，我们采取了双管齐下的方法， 目标。目的1，“在不存在或不存在GLU-CS-PLGA纳米颗粒的情况下， 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，以研究HIV-1蛋白对 GLU-CS-PLGA纳米颗粒功效。目的2，“确定GLU-CS-PLGA纳米颗粒在小鼠体内的功效， BALB/c TB小鼠模型”，将在肺中原位测定杀菌功效， 在BALB/c TB小鼠模型中用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TB和HIV（HIV巨噬细胞储库）。 确定这种纳米制剂的有效性对于决定（1）我们是否应该放弃 这种治疗方法或（2）我们应该向前迈进，在一个先进的小鼠结核病模型中进行测试， 高度组织化的包裹性坏死病变，即，肉芽肿，含有大量的细胞外 杆菌，更接近人类病变，并在艾滋病毒-结核病合并感染模型。这一创新 该提案提出了刺激免疫系统治疗的概念和机制知识， 感染性疾病和这种新型免疫刺激药物递送纳米颗粒平台。通过并入 GLU的纳米颗粒的表面上，所产生的免疫刺激是独立的治疗货物。