Pharmacology of Antiretroviral Nanoparticle Micelles

描述（由申请人提供）：抗逆转录病毒药物（ART），即高活性抗逆转录病毒疗法（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者的长期治疗。单核吞噬细胞不仅是HIV-1的早期宿主，也是HIV-1传播的载体。基于先前对茚地那韦纳米颗粒（NP）的研究，我们希望扩展我们的工作，包括联合抗逆转录病毒药物，并与药物联合制造NP。纳米制剂可以支持药物持续释放到被认为是避难所的HIV-1组织，并提供远远超过抑制商的药物浓度。我们假设联合抗逆转录病毒药物纳米配方给药系统可以被优化，从身体的限制区域根除HIV-1。使用可生物降解的聚合物（聚dl -乳酸-co 5-己内酯），联合ARV药物（利托那韦RTV，洛匹那韦LPV和依非韦伦EFV）将被包裹在纳米颗粒中，并将研究效率。将收集液相色谱，扫描电子和共聚焦显微镜以及巨噬细胞作为药物传递系统的功能研究。一个中空纤维体外模型将通过p24抗原测定和液相色谱测定ART NP药物水平来探索HIV- 1抑制的药效学。通过液相色谱法、共聚焦显微镜和透射电镜观察巨噬细胞的渗透情况。纳米制剂将被用作药物递送系统，以提高ART进入小鼠网状内皮系统（RES，脾、肝、淋巴结）的组织外显率。与游离可溶性药物和空白纳米颗粒相比，联合ARV NP的药效学和药代动力学将通过体外和体内系统在较长时间内进行测定。该建议的目的是更好地理解如何优化NP给药技术的使用，以抑制HIV-1隐藏的身体受限区域的病毒产生。这些方法为HIV-1的治疗提供了直接的患者益处。

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.