Nanoformulation, Manufacture and Characterization

项目1摘要： 该项目寻求一种健壮且可扩展的程序来制备临床可翻译的长效药物 具有最佳大小范围、表面涂层的抗逆转录病毒疗法(NanoArt)的库靶向纳米制剂 和胶体稳定性。首先，我们将开发前药(从目前的亲水性药物到疏水性药物) 具有一系列病毒作用部位，然后优化配方功能参数(制造方法， 药物载量、颗粒大小和胶体稳定性)以促进单核巨噬细胞对药物的摄取 在延长的一段时间内，细胞内持续的治疗药物浓度。的发展。 吲哚胺2，3-双加氧酶抑制剂有助于消除限制性病毒感染，将提供一个阶段 启动病毒教育战略。第二，我们将开发通用的合成程序，以 靶向配体与聚合物的偶联以促进纳米艺术对细胞HIV的修饰 水库。第三，我们将确定目标1和目标2中制定的修改是否将转化为 改善药代动力学特征。我们假设利用单核巨噬细胞作为细胞载体和 仓库将加强抗逆转录病毒跨越组织屏障和进入病毒生长部位的输送。这药是 协同的长效抗逆转录病毒疗效将在细胞培养试验中确定，并在动物身上进行验证(在 与项目2合作，H.Gendelman和3，M.Boska；Core C，L.Pluektova和H.Fox)。

Project 1 Abstract: The project seeks a robust and scalable procedure for preparation of clinically-translatable long-acting reservoir-targeted nanoformulations of antiretroviral therapy (nanoART) with optimal size range, surface coating and colloidal stability. We will, first, develop prodrugs (from what is presently hydrophilic to hydrophobic ART) with a range of viral action sites then optimize the formulation functional parameters (manufacturing methods, drug loading, particle size and colloidal stability) to facilitate drug uptake by monocyte-macrophages for sustained therapeutic drug concentrations in cells over an extended time period. The development of indoleamine 2,3-dioxygenase inhibitors to facilitate elimination of restricted viral infection would provide a stage for viral education strategies to be initiated. Second, we will develop versatile synthetic procedures for conjugation of targeting ligands to coating polymers to facilitate decorations of nanoART to cellular HIV reservoirs. Third, we will determine whether the modifications developed in aims 1 and 2 will translate into improve pharmacokinetic profiles. We posit that harnessing of monocyte-macrophages as cell carriers and depots will enhance antiretroviral delivery across tissue barriers and into sites of viral growth. The drug's synergistic long-acting antiretroviral efficacy will be determined in cell culture assays and validated in animals (in collaboration with Projects 2, H. Gendelman and 3, M. Boska; Core C, L. Poluektova and H. Fox).