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，感染人类免疫缺陷病毒的人患结核病的风险要高出26至31倍