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

• 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
• 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

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.

产品说明：人类免疫缺陷病毒（HIV）是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，结核病是这一患者群体死亡的主要原因。另一方面，艾滋病毒是结核病患者的主要并发症，这一人群患活动性结核病的可能性是未感染艾滋病毒的人的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。艾滋病毒治疗的基础是在单一方案中组合多种抗逆转录病毒药物。然而，有几个因素导致治疗失败和耐药性的持续发展，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、预先存在的耐药性和急性或慢性药物毒性。标准的结核病管理包括使用4种一线药物进行6至9个月的联合治疗。治疗失败和耐药性主要与治疗持续时间长、结核病药物副作用和毒性、各种社会经济制约因素、治疗依从性差、失访、处方不当方案中的人为错误、剂量不一致和药物质量差有关。这两种疾病的创新替代方案将联合收割机与增强的先天免疫系统相结合，以消除病原体并克服与当前疗法相关的问题。我们利用由FDA批准的生物可降解和生物相容性聚合物制备的纳米颗粒载体，以聚（乳酸-羟基乙酸）（PLGA）为核，壳聚糖为壳，形成核-壳结构，允许连接免疫刺激配体？葡聚糖，并将药物（HIV和/或TB）包封在核中。这些纳米颗粒将特异性地向巨噬细胞递送TB和/或HIV药物，同时伴随诱导巨噬细胞内细胞因子和活性氧分子的产生，目的是清除细胞内病原体。这种创新的疗法代表了一种新的和实用的替代研究靶向纳米颗粒药物输送结合免疫调节使用单一配体，β-葡聚糖。该研究设计利用基于生理学的动态中空纤维巨噬细胞培养系统来确定这种多模式纳米颗粒的药代动力学和免疫动力学。我们将在小鼠模型中确定最佳剂量和递送方法以及生物分布、药代动力学和免疫刺激。然后，我们将开发一个基于生理的药代动力学模型，该模型根据化学和生物学参数（体外和体内数据）描述纳米颗粒分布。这种方法将扩大我们对艾滋病毒和/或结核病治疗的科学知识，并通过将靶向药物递送与免疫增强相结合，创造新的方法，有助于减少个体药物剂量，减少全身药物毒性，并减少耐药性的发展。