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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.

项目总结