Pharmacokinetics and Immunodynamics of Immune stimulating chemotherapeutic nanoparticles 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: 9764250
• 负责人: JESSICA L REYNOLDS
• 金额: $ 47.85万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764250
• 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; Computer Simulation; 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; 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 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携带者患结核病的风险要高出26到31倍。结核病 通过阻止吞噬小体成熟来抑制巨噬细胞的抗细菌反应 吞噬溶酶体(依赖于钙离子)和抑制细胞内活性氧的产生和 活性氮(ROS/RNS)和促炎细胞因子。有效的抗菌药物对 存在结核分枝杆菌(如利福平、异烟肼)。然而，这些药物面临着一个重大挑战 关于进入巨噬细胞以根除微生物。此外，低价细胞内药物 在微生物被完全根除之前，巨噬细胞中的浓度会被迅速清除。这些 这些问题具有临床意义：1)结核病治疗需要很长时间才能根除细胞内的微生物。 (至少治疗6个月)；和2)细胞药物渗透性差在药物产生中起作用 耐药菌株，由于微生物处于次优药物暴露时期，允许微生物发生突变 变得有抵抗力。因此，有必要开发靶向巨噬细胞疗法，在这种疗法中， 目前的结核病药物与先天免疫系统的作用协同作用，以根除病原体。这 策略可能会潜在地减少所需的药物剂量，缩短治疗时间，并减少 出现抗药性。我们已经开发出一种巨噬细胞靶向纳米粒给药系统， 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 由生物相容聚合物聚乳酸-乙醇酸(PLGA；含有结核病药物的核心)和 壳聚糖(CS；壳)与表面吸附β-葡聚糖(GLU)(GLU-CS-PLGA)。纳米颗粒表面的谷氨酸 结合巨噬细胞上的Dectin-1，增强细胞摄取。这种结合还激活巨噬细胞，增强 钙离子、ROS/RNS和细胞因子的产生。我们将首先测定细胞的体外药代动力学 基于新型PK/PD的GLU-CS-PLGA纳米粒的PK和药效学研究 巨噬细胞培养系统。这些数据将为我们的活体小鼠研究提供信息。接下来我们将确定 GLU-CS-PLGA纳米粒在健康小鼠模型中的PK和PD这些研究将产生 纳米粒的最佳剂量、给药途径、生物分布、pK和pD。基于生理的PK(PBPK) 接下来将使用建模来整合体外和体内数据，以提供对未来体内结核病的关键见解 学习。这项研究代表了一种范式的转变，即纳米载体系统可以基于第一个 电子计算机和体外模型预测的原理。这种方法将扩大我们对 结核病治疗，并通过将靶向药物输送与免疫增强相结合，创造新的 有助于减少个人用药剂量、缩短用药持续时间、减少全身用药的方法 毒性和减少抗药性的发展。