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

基本信息

批准号：
9974460
负责人：
JESSICA L REYNOLDS
金额：
$ 47.05万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
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/9974460
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 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

项目摘要

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 HIV-1患者估计患结核病的风险估计在26至31倍之间。 TB 通过防止吞噬体的成熟来抑制巨噬细胞抗细菌反应吞噬症（Ca2+依赖性），并抑制细胞内活性氧和反应性氮种（ROS/RN）和促炎细胞因子。有效的抗菌药物结核分枝杆菌存在（例如，利福平，异烟肼）。但是，这些药物面临着重大挑战尊重进入巨噬细胞以消除微生物。另外，细胞内药物在微生物完全消除之前，从巨噬细胞中迅速清除了浓度。这些问题具有临床意义：1）结核病治疗是为了消除细胞内的微生物的长度（至少6个月治疗）； 2）细胞药物渗透不良在药物的产生中起作用抗性菌株，由于微生物的亚最佳药物暴露时期，使微生物突变并变得抗药性。有必要开发有针对性的巨噬细胞疗法，其中当前的结核病药物与先天免疫系统对放射性病原体的作用协同作用。这策略可能有可能减少所需的药物剂量，缩短治疗持续时间，并减少耐药性的出现。我们已经开发了一种巨噬细胞的靶向纳米颗粒药物输送系统使用单个配体β-葡聚糖与免疫调节结合。我们设计了一个核心纳米颗粒由生物相容性聚合物，多乳酸 - 乙醇酸（PLGA；含TB药物的核心）和带有表面吸附的β-葡聚糖（GLU）（GLU-CS-PLGA）的壳聚糖（CS;壳）。纳米颗粒表面上的glu 与巨噬细胞上的Dectin-1结合，增强细胞摄取。这种结合还激活巨噬细胞，增强 Ca2+，ROS/RN和细胞因子的产生。我们将首先确定体外细胞药代动力学 GLU-CS-PLGA纳米颗粒的（PK）和药效学（PD），利用新型基于PK/PD 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。接下来，我们将确定健康小鼠模型中的Glu-CS-Plga纳米颗粒的PK和PD。这些研究将产生纳米颗粒的最佳剂量，递送途径，生物分布，PK和PD。基于生理的PK（PBPK）接下来，建模将用于整合体外和体内数据，以为未来的体内TB提供关键见解研究。这项研究代表了范式转变，纳米载体系统可以基于首先设计在计算机和体外模型预测中的原理。这种方法将扩大我们对结核病疾病疗法，并通过将靶向药物输送与免疫增强结合起来，创建新的可以促进减少单个药物剂量的方法，缩短药物持续时间，减少全身药物毒性并降低耐药性的发展。