Pharmacokinetics and immunodynamics of multimodal nanoparticles for HIV and TB

HIV 和 TB 多模式纳米粒子的药代动力学和免疫动力学

基本信息

批准号：
8868387
负责人：
PARAS N. PRASAD
金额：
$ 11.9万
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：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8868387
关键词：
Acquired Immunodeficiency Syndrome Acute Adherence Adverse drug effect Adverse effects Anti-Retroviral Agents Binding Biodistribution Biological Breathing Cell Culture System Cell Culture Techniques Cells Cessation of life Chemicals Chitosan Chronic Combined Modality Therapy Communicable Diseases Comorbidity Complex Data Developing Countries Development Disease Dose Drug Delivery Systems Drug Formulations Drug Kinetics Drug Targeting Drug resistance Drug toxicity Drug usage Encapsulated Event FDA approved Fiber Foundations Generations Glucans Glycolates Goals HIV Health Human Immune Immune response Immune system Immunotherapy In Vitro Individual Infectious Agent Inflammatory Innovative Therapy Interleukin-12 Intravenous Knowledge Laboratories Lead Ligands Malaria Measures Methods Morbidity - disease rate Mus Mycobacterium tuberculosis Nitrogen Oral Oxygen Patients Performance Phagocytosis Pharmaceutical Preparations Pharmacotherapy Physiological Population Prevention Production Reactive Nitrogen Species Reactive Oxygen Species Regimen Reporting Research Design Serum Surface System Techniques Time Tissue Sample Toxic effect Treatment Failure Treatment outcome Tuberculosis Vaccines World Health Organization antimicrobial drug base biocompatible polymer biodegradable polymer chemokine cytokine dectin 1 design dosage drug efficacy drug quality effective therapy experience follow-up global health immunoregulation in vitro Model in vivo in vivo Model in vivo imaging innovation liquid chromatography mass spectroscopy macrophage mortality mouse model nanomedicine nanoparticle novel novel strategies novel therapeutic intervention particle pathogen patient population pharmacokinetic model receptor response socioeconomics targeted delivery treatment duration tuberculosis drugs uptake

项目摘要

DESCRIPTION: Human Immunodeficiency Virus (HIV) is ranked globally as the deadliest single most infectious agent, with Mycobacterium tuberculosis (TB) following a close second. At least one-third of HIV-positive people are infected with TB and it is a major cause of mortality among this patient population. On the other hand, HIV is a major co- morbidity in patients with TB, with this population 30 times more likely to develop active TB disease than people without HIV. In the absence of vaccines against these diseases, drug therapy approaches remain the only effective treatment options. The foundation of HIV therapy is based on the combination of multiple antiretroviral agents in a single regimen. However, several factors contribute to the continuing development of treatment failure and drug resistance, among them are suboptimal drug efficacy and/or variable pharmacokinetics, inadequate adherence to lifelong therapy, pre-existing drug resistance and acute or chronic drug toxicities. Standard TB management involves combination therapy for 6 to 9 months using 4 first-line drugs. Treatment failure and drug resistance are primarily related to the long duration of treatment, TB drug side effects and toxicity, various socioeconomic constraints, poor adherence to treatment, loss to follow up, human errors in prescribing inadequate regimens, inconsistent dosing and poor quality of drugs. An innovative alternative for both of these diseases would combine the antimicrobial drug effects with an augmented innate immune system to eradicate pathogens and overcome the problems associated with current therapies. We utilize nanoparticle carriers prepared from FDA approved, biodegradable and biocompatible polymers, with poly(lactic-co-glycolic) acid (PLGA) as the core and chitosan as the shell in a core-shell configuration that allows attachment of the immune stimulatory ligand, ?-glucan, to the surface of the shell and encapsulation of drugs (HIV and/or TB) in the core. These nanoparticles will deliver TB and/or HIV drugs specifically to macrophages while concomitantly inducing the production of cytokines and reactive oxygen molecules within the macrophage, with the goal of intracellular pathogen clearance. This innovative therapy represents a new and practical alternative to study targeted nanoparticle drug delivery combined with immunomodulation using a single ligand, β-glucan. The study design utilizes an integrated physiologically-based, dynamic, hollow fiber macrophage cell culture system to determine the pharmacokinetics and immune-dynamics of this multi-modal nanoparticle. We will determine the optimal dose and method of delivery and the bio-distribution, pharmacokinetics and immune stimulation in a mouse model. We will then develop a physiological based-pharmacokinetic model that describes nanoparticle distribution based on chemical and biological parameters (in vitro and in vivo data). This approach will broaden our scientific knowledge of HIV and/or TB disease therapies and, by combining targeted drug delivery with immune augmentation, create new approaches that will facilitate reducing individual drug doses, reduce systemic drug toxicity and reduce the development of drug resistance.

描述：人类免疫缺陷病毒 (HIV) 被列为全球最致命的单一传染性病原体，结核分枝杆菌 (TB) 紧随其后，至少有三分之一的艾滋病毒阳性者感染了结核病，这是一个主要原因。另一方面，艾滋病毒是结核病患者的主要合并症，该人群患活动性结核病的可能性是非结核病患者的 30 倍。在缺乏针对这些疾病的疫苗的情况下，药物治疗方法仍然是唯一有效的治疗选择，其基础是在单一治疗方案中联合使用多种抗逆转录病毒药物。治疗失败和耐药性，其中包括药物疗效欠佳和/或药代动力学变化、终身治疗依从性不足、预先存在的耐药性以及急性或慢性药物毒性。标准结核病管理涉及使用 4 个药物进行 6 至 9 个月的联合治疗。一线药物治疗。失败和耐药性主要与治疗时间长、结核病药物副作用和毒性、各种社会限制、治疗依从性差、失访、处方不充分的人为错误、剂量不一致和药物质量差有关。针对这两种疾病的创新替代方案是将抗菌药物作用与增强的先天免疫系统结合起来，以根除病原体并克服与当前疗法相关的问题。我们利用由 FDA 批准的、可生物降解和生物相容性聚合物制备的纳米颗粒载体。聚乳酸-乙醇酸 (PLGA) 作为核心，壳聚糖作为壳，采用核-壳结构，允许免疫刺激配体 β-葡聚糖附着到壳表面并封装药物。这些纳米粒子将特异性地将结核病和/或艾滋病毒药物递送至巨噬细胞，同时诱导巨噬细胞内细胞因子和活性氧分子的产生，以达到目标。这种创新疗法代表了一种新的、实用的替代方案，用于研究靶向纳米颗粒药物递送与使用单一配体 β-葡聚糖的免疫调节相结合。为了确定这种多模式纳米粒子的药代动力学和免疫动力学，我们将确定最佳剂量和给药方法以及小鼠模型中的生物分布、药代动力学和免疫刺激。基于化学和生物参数（体外和体内数据）描述纳米颗粒分布的药代动力学模型将拓宽我们对艾滋病毒和/或结核病治疗的科学知识，并通过将靶向药物输送与免疫增强相结合，创建。新方法将有助于减少个体药物剂量、降低全身药物毒性并减少耐药性的发展。