Pharmacokinetics and Immunodynamics of Immune stimulating chemotherapeuticnanoparticles for TB

结核病免疫刺激化疗纳米颗粒的药代动力学和免疫动力学

• 批准号: 10456120
• 负责人: JESSICA L REYNOLDS
• 金额: $ 43.62万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456120
• 关键词: Affect; Anti-Bacterial Agents; Antibacterial Response; Antibiotics; Binding; Biodistribution; Bronchoalveolar Lavage; Cell Culture System; Cells; Cessation of life; Chitosan; Clinical; Communicable Diseases; Data; Dependence; Disease; Dose; Drug Delivery Systems; Drug Exposure; Drug Kinetics; Drug Targeting; Drug resistance; Drug toxicity; Formulation; Future; Generations; Glucans; Glycolates; Goals; HIV; HIV-1; Immune; Immune Targeting; Immune response; Immune system; Immunization; Immunotherapy; In Vitro; Individual; Inflammatory; Inhalation; Innate Immune System; Knowledge; Letters; Ligands; Macrophage Activation; Measures; Methods; Microbe; Modeling; Mus; Mutate; Mycobacterium tuberculosis; Oropharyngeal; Oxygen; Pathogenesis; Penetration; Persons; Phagolysosome; Phagosomes; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Physiological; Play; Polymers; Production; Property; Reactive Nitrogen Species; Reactive Oxygen Species; Research; Research Personnel; Resistance; Rifampin; Risk; Role; Route; Series; Serum; Surface; System; Therapeutic; Time; Treatment outcome; Tuberculosis; Vaccines; base; beta-Glucans; biocompatible polymer; biomaterial compatibility; cytokine; dectin 1; design; dosage; drug development; immunoregulation; in silico; in vitro Model; in vivo; innovation; insight; intravenous administration; isoniazid; macrophage; microbial; mouse model; multidisciplinary; nanocarrier; nanoformulation; nanoparticle; nanoparticle drug; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pathogen; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; physiologically based pharmacokinetics; predictive modeling; prevent; receptor; resistant strain; treatment duration; tuberculosis drugs; tuberculosis treatment; uptake

Project Summary The risk of developing TB is estimated to be between 26 to 31 times greater in people living with HIV-1. TB suppresses the macrophage anti-bacterial response by preventing the maturation of phagosomes to phagolysosomes (Ca2+ dependent) and suppressing the production of intracellular reactive oxygen species and reactive nitrogen species (ROS/RNS) and pro-inflammatory cytokines. Effective antibacterial drugs against Mycobacterium tuberculosis exist (e.g., rifampin, isoniazid). However, these drugs have a major challenge with respect to entering macrophage in order to eradicate the microbe. In addition, the low intracellular drug concentrations are rapidly cleared from macrophage before the microbe has been completely eradicated. These issues have clinical implications: 1) TB treatment is lengthy in order to eradicate the microbe within the cells (minimum 6 month-treatment); and 2) poor cellular drug penetration plays a role in the generation of drug resistant strains, due to the periods of sub-optimal drug exposure of the microbe, allowing the microbe to mutate and become resistant. Thus it is necessary to develop targeted macrophage therapies in which the effects of current TB drugs act synergistically with the actions of the innate immune system to eradicate pathogens. This strategy may potentially reduce the drug dosage required, shorten the duration of treatment, and reduce the emergence of drug resistance. We have developed a macrophage targeted nanoparticle drug delivery system that is combined with immunomodulation using a single ligand, β-glucan. We designed a core-shell nanoparticle prepared from the biocompatible polymers, poly-lactic-co-glycolic acid (PLGA; core containing TB drug) and chitosan (CS; shell) with surface adsorbed β-glucan (GLU) (GLU-CS-PLGA). GLU on the nanoparticle's surface binds to Dectin-1 on macrophage, enhancing cellular uptake. This binding also activates macrophage, enhancing the production of Ca2+, ROS/RNS and cytokines. We will first determine the in vitro cellular pharmacokinetics (PK) and pharmacodynamics (PD) of the GLU-CS-PLGA nanoparticles utilizing a novel PK/PD-based macrophage cell culture system. These data will inform our in vivo mouse studies. We will next determine the PK and PD of the GLU-CS-PLGA nanoparticles in vivo in a healthy mouse model. These studies will yield the optimal dose, route of delivery, biodistribution, PK and PD of the nanoparticle. Physiologically based PK (PBPK) modeling will next be used to integrate the in vitro and in vivo data to provide key insights for future in vivo TB studies. This research represents a paradigm shift whereby nanocarrier systems may be designed based on first principles with in silico and in vitro model predictions. This approach will broaden our scientific knowledge of TB disease therapies and, by combining targeted drug delivery with immune augmentation, create new approaches that will facilitate reducing individual drug doses, shorten drug duration, reduce systemic drug toxicity and reduce the development of drug resistance.

项目摘要 据估计，HIV-1感染者患结核病的风险要高出26至31倍。TB 通过阻止吞噬体的成熟来抑制巨噬细胞的抗菌反应， 吞噬溶酶体（Ca 2+依赖性）和抑制细胞内活性氧的产生， 活性氮物质（ROS/RNS）和促炎细胞因子。有效的抗菌药物 存在结核分枝杆菌（例如，利福平、异烟肼）。然而，这些药物面临着一个重大挑战， 在进入巨噬细胞以消灭微生物方面。此外，低细胞内药物 在微生物被完全根除之前，浓度被迅速从巨噬细胞中清除。这些 这些问题具有临床意义：1）为了根除细胞内的微生物，结核病治疗是漫长的 （至少6个月治疗）;和2）细胞药物渗透不良在药物生成中起作用 耐药菌株，由于微生物的次优药物暴露期，使微生物发生突变 变得有抵抗力因此，有必要开发靶向巨噬细胞疗法，其中， 目前的结核病药物与先天免疫系统协同作用以根除病原体。这 该策略可能会减少所需的药物剂量，缩短治疗时间，并减少 耐药性的出现。我们已经开发了一种巨噬细胞靶向纳米颗粒药物递送系统， 与使用单一配体β-葡聚糖的免疫调节相结合。我们设计了一种核壳纳米粒子 由生物相容性聚合物聚乳酸-羟基乙酸共聚物（PLGA;含TB药物的核心）和 壳聚糖（CS; shell）表面吸附β-葡聚糖（GLU）（GLU-CS-PLGA）。纳米颗粒表面的葡萄糖 与巨噬细胞上的Dectin-1结合，增强细胞摄取。这种结合也激活巨噬细胞， Ca ~（2+）、ROS/RNS和细胞因子的产生。我们将首先确定体外细胞药代动力学 (PK)和药效学（PD）的GLU-CS-PLGA纳米颗粒利用一种新的PK/PD为基础的 巨噬细胞培养系统。这些数据将为我们的体内小鼠研究提供信息。我们接下来将确定 GLU-CS-PLGA纳米颗粒在健康小鼠模型中的体内PK和PD。这些研究将产生 最佳剂量、递送途径、生物分布、纳米颗粒的PK和PD。基于生理学的PK（PBPK） 接下来将使用建模来整合体外和体内数据，为未来的体内TB提供关键见解 问题研究这项研究代表了一种范式转变，即纳米载体系统可以基于第一个 原理与计算机模拟和体外模型预测。这种方法将扩大我们的科学知识， 结核病疗法，并通过将靶向药物输送与免疫增强相结合， 有助于减少个体药物剂量，缩短药物持续时间，减少全身药物 毒性和减少耐药性的发展。

项目成果

Mitochondrial Dynamics in SARS-COV2 Spike Protein Treated Human Microglia: Implications for Neuro-COVID.

• DOI: 10.1007/s11481-021-10015-6
• 发表时间: 2021-12
• 期刊: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
• 作者: Clough E;Inigo J;Chandra D;Chaves L;Reynolds JL;Aalinkeel R;Schwartz SA;Khmaladze A;Mahajan SD
• 通讯作者: Mahajan SD