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.

患有人类的人的结核病（TB）的风险估计是26至31倍 免疫缺陷病毒（HIV-1）。 TB的艰苦治疗方案（鸡尾酒至少六个月 数十年来，具有限制剂量的副作用的抗生素基本保持不变。减少 全球结核Burnen主要集中于新的抗生素和疫苗，几乎没有针对巨噬细胞的目标 激活免疫系统以增加微生物消除的药物输送方法。解决这个尚未满足的 需要，我们开发了针对艾滋病毒和结核病的广泛应用的靶向巨噬细胞疗法。我们的公式 输入rifamycin模型，利福平，加载到β-葡聚糖和壳聚糖涂层的聚（乳酸 - 乙醇酸）酸中 （glu-cs-plga）纳米颗粒。我们的药代动力学研究发现，在一个纳米颗粒之后 通过对健康小鼠的口咽术进行给药，在细胞的细胞分数中检测到利福平 剂量后10天的支气管肺泡灌洗。此外，我们发现了TNFα的释放时间过程 邮政管理后24小时返回基线。所有纳米颗粒都刺激了TNFα在该范围内的释放 在药物治疗后，在TB小鼠模型中，在500至2000 pg/mL中，类似于TNFα浓度。而我们有 使用纳米颗粒证明了利福平持续递送至小鼠肺泡巨噬细胞，我们有 然而，要了解该纳米颗粒在有毒的分枝杆菌结核病的情况下如何发挥作用 肺。此外，我们尚未发现这种纳米成型在不存在的情况下如何影响结核病 或HIV病毒蛋白的存在。为了解决这个问题，我们正在以独立 目标。 AIM 1，“在不存在或 HIV蛋白的存在”将分析GLU-CS-PLGA纳米颗粒引起的细菌有效性 模型。我们还包括了一个探索性实验，以研究HIV-1蛋白的影响 GLU-CS-PLGA纳米颗粒效率。 AIM 2，“确定GLU-CS-PLGA纳米颗粒的体内效率 BALB/C TB小鼠模型”将确定肺部原位的杀菌效率 在BALB/C TB小鼠模型中使用GLU-CS-PLGA进行口咽抽吸。因此，这个纳米板是 与影响巨噬细胞的疾病广泛相关，包括结核病和艾滋病毒（HIV巨噬细胞储量）。 确定这种纳米成型的有效性对于决定（1）我们应该放弃是否应 这种理论方法或（2）我们应该向前迈进，以发展的高级鼠标结核病模型进行测试 高度有条理的封装坏死病变，即肉芽瘤，其中包含大量细胞外的 在HIV-TB共感染模型中，细菌更像人类病变。这种创新 提案提高了免疫系统刺激的概念和机理知识 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 GLU在纳米颗粒表面上，产生的免疫刺激与其治疗货物无关。