Nanoformulation Uptake, Release, Toxicology and Tissue Delivery

这个项目的基础现在取决于它在制剂合成和在病毒感染的动物中进行临床疗效测试之间建立桥梁的能力。为了支持这一概念，我们现在已经实现了最有效的体外试验配方与药代动力学（PK）试验之间的联系。这大大加强了先前提交的概念，但在当前的再次提交中得到了加强，即纳米配方抗逆转录病毒药物的注射形式可以用于未来的临床应用。尽管如此，我们承认，仍需要进行大量的发展研究，才能将这一目标视为一个明确的现实。在这方面，纳米配方抗逆转录病毒疗法[nanoART；将研究因地那韦（IDV）、洛匹那韦（LPV）、依非韦伦（EFV）、阿扎那韦（ATZ）和利托那韦（RTV）在人类实验室细胞培养系统和啮齿动物体内的细胞摄取、释放和PK反应。迄今为止，在初步实验中，三种（IDV， RTV和EFV）已被单核细胞来源的巨噬细胞和

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).