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）在全球最致命的单一感染剂中被排名为最致命的剂，结核病结核病（TB）紧随其后。至少有三分之一的艾滋病毒阳性患者感染了结核病，这是该患者人群死亡的主要原因。另一方面，艾滋病毒是结核病患者的主要合并症，该人群发生活性结核病的可能性是没有艾滋病毒的患者的30倍。在没有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。 HIV治疗的基础是基于单个方案中多种抗逆转录病毒药物的组合。但是，有几个因素导致治疗衰竭和耐药性的持续发展，其中包括次优的药物有效性和/或可变的药代动力学，对终身治疗的依从性不足，耐药性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种一线药物进行6至9个月的组合疗法。治疗失败和耐药性主要与治疗的持续时间，TB药物副作用和毒性，各种社会经济的约束，对治疗的依从性不佳，随访的损失，处方不充分的治疗方案，不一致的剂量和药物质量不佳的人体错误。这两种疾病的一种创新替代方法将抗菌药物作用与增强的先天免疫系统结合给放射性病原体，并克服与当前疗法相关的问题。 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 immuno Stimulatory ligand, ?-glucan, to the surface of the shell and encapsulation of drugs (HIV and/or TB) in the 核。这些纳米颗粒将特异性地向巨噬细胞递送结核病和/或HIV药物，同时诱导巨噬细胞内的细胞因子和活性氧分子的产生，目的是细胞内病原体清除率。这种创新的疗法代表了研究靶向纳米颗粒药物递送的一种新的替代方法，并使用单个配体β-葡聚糖结合了免疫调节。该研究设计利用基于物理的综合，动态，空心纤维巨噬细胞培养系统来确定这种多模式纳米粒子的药代动力学和免疫动力学。我们将确定小鼠模型中的最佳剂量和方法以及生物分布，药代动力学和免疫刺激。然后，我们将开发一个基于物理的 - 绘画模型，该模型描述了基于化学和生物学参数（体外和体内数据）的纳米颗粒分布。这种方法将扩大我们对艾滋病毒和/或结核病疾病疗法的科学知识，并通过将靶向药物递送与免疫增强结合起来，创建新方法，以减少单个药物剂量，降低全身药物毒性并降低耐药性的发展。