Nanoformulation Uptake, Release, Toxicology and Tissue Delivery

纳米制剂的吸收、释放、毒理学和组织递送

• 批准号: 8016285
• 负责人: Howard E Gendelman
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8016285
• 关键词: AIDS neuropathy; AIDS/HIV problem; Adherence; Affect; Animals; Anti-Retroviral Agents; Atazanavir; Biodistribution; Biological Assay; Biological Models; Blood - brain barrier anatomy; Brain; Cell Culture System; Cells; Cellular biology; Charge; Chemotherapy-Oncologic Procedure; Clinical; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug resistance; Epidemiology; Equus caballus; Foundations; Foxes; Friendships; Future; Genitalia; Goals; HIV; Human; In Vitro; Indinavir; Infection; Injectable; Laboratories; Laboratory Animal Models; Life; Link; Liver; Locales; Lopinavir; Lymphoid Tissue; Macaca mulatta; Maintenance; Measures; Medical center; Medicine; Mission; Morbidity - disease rate; Mus; Mutate; Nanotechnology; Natural History; Nebraska; Neuraxis; Nucleosides; Pathologist; Patients; Persons; Pharmaceutical Preparations; Philosophy; Physical Chemistry; Plasma; Regimen; Research; Rest; Reverse Transcriptase Inhibitors; Ritonavir; Rodent; Rodent Model; SIV; Safety; Screening procedure; Shapes; Solid; Spleen; System; Technology; Testing; Time; Tissues; Toxic effect; Toxicology; Translating; Translations; Treatment Efficacy; United States Food and Drug Administration; Universities; Viral; Virulent; Virus; Work; antiretroviral therapy; base; bench to bedside; clinical efficacy; clinical practice; combat; combinatorial; cytotoxicity; efavirenz; efficacy testing; improved; in vitro testing; lymph nodes; macrophage; microbial; monocyte; mortality; nanoformulation; nanomedicine; nanotoxicity; novel; particle; programs; research study; response; transmission process; uptake

The foundation of this project now rests on its abilities to bridge formulation synthesis to testing for clinical efficacy in virus-infected animals. In support of this notion, we have now achieved a linkage between the most efficient formulations for in vitro testing with pharmacokinetic (PK) testing. This serves to significantly strengthen the notion put forward in the prior submission but strengthened in the current re-submission that an injectable form of nanoformulated antiretrovirals can be achieved for future clinical use. Nonetheless we acknowledge that significant research in development still needs to be performed to see this goal as a definable reality. In this regard, nanoformulated antiretroviral therapies [nanoART; indinavir (IDV), lopinavir (LPV), efavirenz (EFV), atazanavir (ATZ) and ritonavir (RTV)] will be investigated for cell uptake, release, and PK responses in human laboratory cell culture systems and in rodents. To date three (IDV, RTV, and EFV), in preliminary experiments, have demonstrated robust uptake in monocyte-derived macrophages and drug release, measured in weeks, beyond an established plasma effective concentrationso (EC50). We posit that size, composition, coating, and charge can enhance nanoART uptake into monocytes and monocytederived macrophages and subsequent drug delivery into viral reservoirs. This includes the lymphoreticular and the central nervous systems. This project aims to test efficiency of cell-based nanoART and to explore relevant toxicities in laboratory cell systems and mice in support of antiretroviral efficacy tests in small (rodent) and large animals (rhesus macaques) (H. Fox, project 3). The project is highly interactive with project 1 (A. Kabanov) and cores A, B, and C (H. Gendelman, M. Boska and C. Fletcher).

该项目的基础现在取决于其将制剂合成与病毒感染动物临床疗效测试联系起来的能力。为了支持这一观点，我们现在已经实现了体外测试的最有效配方与药代动力学 (PK) 测试之间的联系。这大大加强了先前提交中提出的概念，但在当前重新提交中也得到了加强，即可以实现注射形式的纳米制剂抗逆转录病毒药物用于未来的临床使用。尽管如此，我们承认仍然需要进行大量的开发研究才能将这一目标视为可定义的现实。在这方面，纳米制剂抗逆转录病毒疗法[nanoART；茚地那韦 (IDV)、洛匹那韦 (LPV)、依非韦伦 (EFV)、阿扎那韦 (ATZ) 和利托那韦 (RTV)] 将在人类实验室细胞培养系统和啮齿动物中研究细胞摄取、释放和 PK 反应。迄今为止，三种（IDV、RTV 和 EFV）在初步实验中已证明单核细胞来源的巨噬细胞和 药物释放，以周为单位测量，超出既定的血浆有效浓度（EC50）。我们假设尺寸、成分、涂层和电荷可以增强单核细胞和单核细胞衍生巨噬细胞对 nanoART 的吸收，以及随后将药物递送到病毒库中。这包括淋巴网状系统和中枢神经系统。该项目旨在测试基于细胞的 nanoART 的效率，并探索实验室细胞系统和小鼠的相关毒性，以支持小型（啮齿动物）和大型动物（恒河猴）的抗逆转录病毒功效测试（H. Fox，项目 3）。该项目与项目 1（A. Kabanov）和核心 A、B 和 C（H. Gendelman、M. Boska 和 C. Fletcher）高度互动。