Pharmacology of Antiretroviral Nanoparticle Micelles

抗逆转录病毒纳米颗粒胶束的药理学

• 批准号: 7495257
• 负责人: CHRISTOPHER J DESTACHE
• 金额: $ 22.47万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495257
• 关键词: Active Sites; Address; Adverse effects; Affect; Animals; Anti-Retroviral Agents; Antigens; Area; Biochemical; Biological Assay; Biological Availability; Bioreactors; Cell Culture System; Cells; Clinical; Confocal Microscopy; Coumarins; Daily; Data; Dialysis procedure; Disease; Dose; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug usage; Electrons; Fiber; Fluorescent Dyes; Future; HIV; HIV-1; High Pressure Liquid Chromatography; Highly Active Antiretroviral Therapy; Histology; Human; In Vitro; Inbred BALB C Mice; Indinavir; Intracellular Membranes; Intraperitoneal Injections; Intravenous; Kidney; Laboratory Animals; Liquid Chromatography; Liver; Lopinavir; Lopinavir/Ritonavir; Lung; Macrophage Cell Biology; Measures; Membrane; Micelles; Modeling; Mononuclear; Mus; Particle Size; Patients; Penetrance; Penetration; Peripheral; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phospholipids; Physical Dialysis; Plasma; Production; Property; Rate; Reporting; Reticuloendothelial System; Ritonavir; Sampling; Scanning; Scanning Electron Microscopy; Shapes; Simulate; Spleen; System; Technology; Testing; Time; Tissues; Toxicology; Transmission Electron Microscopy; Travel; Treatment Failure; Viral; Virus; Work; alpha benzopyrone; antiretroviral therapy; attenuation; base; biodegradable polymer; caprolactone; controlled release; cytokine; drug distribution; efavirenz; extracellular; human disease; improved; in vitro Model; in vivo; intraperitoneal; intravenous administration; lymph nodes; macrophage; monocyte; mortality; nanoformulation; nanoparticle; novel; particle; poly(DL-lactide); polycaprolactone; pressure; research study; size; uptake; zeta potential

DESCRIPTION (provided by applicant): The use of anti-retroviral agents (ART), namely highly active anti-retroviral therapy (HAART) has significantly diminished the mortality associated with human immunodeficiency virus type-1 (HIV-1) disease. However, treatment failures, dosing complexities, and adverse effects all limit the long-term therapy in infected peoples. Mononuclear phagocytes serve as not only as early reservoirs but also vehicles for dissemination for HIV-1. Based on previous work with indinavir nanoparticles (NP) we want to extend our work to include combination ARV agents and fabricate NP with combinations of drugs. Nanoformulations can support sustained drug release to HIV-1 tissues considered sanctuaries and deliver drug concentrations that far exceed the inhibitory quotient. We hypothesize that combination ARV nanoformulated drug delivery system can be optimized to eradicate HIV-1 from restricted areas of the body. Using a biodegradable polymer (poly (DL-lactide-co 5-caprolactone)), combined ARV agents (ritonavir RTV, lopinavir LPV, and efavirenz EFV) will be entrapped into a nanoparticle and efficiency will be investigated. Liquid chromatography, scanning electron and confocal microscopy, and functional studies in macrophages as a drug delivery system will be gathered. A hollow fiber in vitro model will explore the pharmacodynamics of HIV- 1 inhibition as measured by p24 antigen assay and ART NP drug levels measured by liquid chromatography. Penetration into macrophages will be assessed by liquid chromatography and confocal and transmission electron microscopy. The nanoformulations will be used as a drug delivery system to improve tissue penetrance of ART into the reticuloendothelial system (RES; spleen, liver, lymph nodes) in mice. The pharmacodynamics and pharmacokinetics of combination ARV NP will be determined using in vitro and in vivo systems over extended time periods as compared to free soluble drugs as well as blank nanoparticles. The aims of this proposal are a better understanding of how to optimize the use of NP drug delivery technology to inhibit the production of virus from restricted areas of the body where HIV-1 hides. These approaches offer direct patient benefit for the treatment of HIV-1. PUBLIC HELATH RELEVANCE: This application will investigate the pharmacology of combination antiretrovirals (ritonavir, lopinavir, and efavirenz) fabricated into nanoparticles both in cell culture systems and in animals. The nanoparticles will be delivered to HIV-1 sanctuaries (spleen, liver, lymph nodes). Due to the nanoparticle small size, the particles will stay in tissue longer and allow for less frequent dosing. This nanoparticle delivery system could affect the future of HIV- 1 treatment.

描述（由申请人提供）：抗逆转录病毒药物（ART），即高效抗逆转录病毒疗法（HAART）的使用显著降低了与人类免疫缺陷病毒1型（HIV-1）疾病相关的死亡率。然而，治疗失败，剂量复杂性和不良反应都限制了感染人群的长期治疗。单核细胞吞噬细胞不仅是HIV-1的早期宿主，也是HIV-1传播的载体。基于先前的茚地那韦纳米粒（NP）的工作，我们希望将我们的工作扩展到包括组合ARV药物和制造NP与药物的组合。纳米制剂可以支持药物持续释放到被认为是庇护所的HIV-1组织，并提供远远超过抑制商数的药物浓度。我们假设，组合抗逆转录病毒纳米制剂药物递送系统可以被优化，以消除HIV-1从身体的限制区域。使用可生物降解的聚合物（聚（DL-丙交酯-co 5-己内酯）），将组合的ARV药物（利托那韦RTV、洛匹那韦LPV和依法韦仑EFV）包埋到纳米颗粒中，并研究其效率。液相色谱法，扫描电子显微镜和共聚焦显微镜，以及巨噬细胞作为药物输送系统的功能研究将被收集。中空纤维体外模型将探索通过p24抗原测定测量的HIV- 1抑制的药效学和通过液相色谱法测量的ART NP药物水平。将通过液相色谱、共聚焦和透射电子显微镜评估巨噬细胞的渗透。纳米制剂将用作药物递送系统，以改善ART进入小鼠网状内皮系统（RES;脾、肝、淋巴结）的组织渗透率。与游离可溶性药物以及空白纳米颗粒相比，将使用体外和体内系统在延长的时间段内确定组合ARV NP的药效学和药代动力学。该提案的目的是更好地了解如何优化NP药物递送技术的使用，以抑制HIV-1隐藏的身体限制区域的病毒产生。这些方法为治疗HIV-1提供了直接的患者益处。 公共卫生相关性：本申请将研究组合抗逆转录病毒药物（利托那韦，洛匹那韦和依法韦仑）制成纳米颗粒在细胞培养系统和动物中的药理学。纳米颗粒将被递送到HIV-1保护区（脾、肝、淋巴结）。由于纳米颗粒尺寸小，颗粒将在组织中停留更长时间，并允许较低频率的给药。这种纳米颗粒输送系统可能会影响HIV- 1治疗的未来。