Pharmacokinetics and immunodynamics of multimodal nanoparticles for HIV and TB

描述：人类免疫缺陷病毒(HIV)是全球最致命的单一最具传染性的病原体，紧随其后的是结核分枝杆菌(TB)。至少三分之一的艾滋病毒阳性者感染了结核病，这是这类患者死亡的一个主要原因。另一方面，艾滋病毒是结核病患者的主要共同发病率，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结合多种抗逆转录病毒药物。然而，几个因素导致治疗失败和耐药性的持续发展，其中包括次佳的药物疗效和/或可变的药代动力学，对终身治疗的坚持不足，先前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、失去随访、人为错误地开出不适当的方案、剂量不一致和药物质量差有关。针对这两种疾病的一种创新选择是将抗菌药物的效果与增强的先天免疫系统相结合，以根除病原体并克服与现有疗法相关的问题。我们利用由FDA批准的可生物降解和生物相容的聚合物制备的纳米载体，以聚(乳酸-羟基乙酸)酸(PLGA)为核心，壳聚糖为壳-壳结构，允许将免疫刺激配体β-葡聚糖附着到壳的表面，并将药物(HIV和/或TB)包裹在核心中。这些纳米粒子将专门向巨噬细胞输送结核病和/或艾滋病毒药物，同时诱导巨噬细胞内产生细胞因子和活性氧分子，以清除细胞内病原体。这种创新的疗法代表了一种新的实用的替代方案，用于研究靶向纳米药物输送和使用单一配体β-葡聚糖的免疫调节。这项研究设计利用一个基于生理的、动态的、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。我们将确定最佳的给药剂量和方法，以及在小鼠模型中的生物分布、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，该模型基于化学和生物参数(体外和体内数据)描述纳米颗粒的分布。这一方法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，创造新的方法，有助于减少个人药物剂量，减少全身药物毒性，并减少耐药性的发展。

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.