Prodrug Formulations Create Sustained Release Antiretrovirals

摘要 该提案寻求资金，将现有的抗逆转录病毒药物(ARV)转化为可扩展的长效药物。 提供了一种循序渐进的方法，并定义了“去不去”的标准。第一个是核苷反转。 转录酶和整合酶抑制剂(S)转化为亲脂性前药纳米晶。这些转换是专门设计的 用于在当前良好的制造实践下进行简单、安全和可扩展的生产。紧随其后的是 生产ARV纳米晶，第二步将在维持药物的同时优化CD4+T细胞的摄取 巨噬细胞中的储存库。ARV从前体药物中的释放将通过受控水解实现持续 抗逆转录病毒的效力。第三种方法将促进前体药物纳米晶在肠道相关淋巴组织中的分布。 淋巴组织、泌尿生殖系统和中枢神经系统组织。第四，将完成旨在 限制靶向毒性(S·科恩)通过在细胞和细胞中筛选亲、天然和纳米晶药物配方 组织分析。这些扩展的毒理学测试将用于调查任何或没有随后的不良事件 细胞和组织中ARV水平增加。我们的目标是生产安全、耐久、动作缓慢的 有效的释放抗逆转录病毒疗法，“假定”剂量间隔长达每六个月一次。这个 设计将为暴露前的预防和治疗方案提供最大的有效性。具体目标 得到了广泛发布的数据集的支持。为了完成这项拟议的研究，双方建立了伙伴关系 由药物和聚合物化学家(B Edagwa)和病毒学家、细胞生物学家和免疫学家组成 (H·詹德尔曼)这种合作将加速短期抗逆转录病毒药物向长效抗逆转录病毒药物的转变。生物学 测试将在细胞和动物模型的产品开发之后进行。配方安全将通过以下方式实现 在良好的实验室和当前良好的情况下对复制的短效天然抗逆转录病毒制剂的持续测试 制造实践设施。抗逆转录病毒纳米晶的发展道路将向前推进 连续的去不去的标准。药物选择，制剂稳定性，药物组合，组织和细胞靶向， 毒理学、药代动力学(PK)和药效学(PD)简介遵循行动计划。有几个人 “到手”的毒品制造。这些实验的结果可以减少药物的毒性，改善治疗方案 粘附性，并提供增强的病毒预防进入组织储存库。这项研究建立在一个已经存在的 在细胞靶向纳米医学方面有良好的记录。抗逆转录病毒反应和内体贩运将是 测试过。PK和PD小鼠屏幕(S·戈兰特拉)将验证这一发现。总的来说，我们的长期目标是 将现有的抗逆转录病毒治疗方案转变为长效疗法。

Abstract This proposal seeks funds to translate existing antiretroviral drugs (ARVs) into scalable long acting medicines. A step-wise approach is offered with defined “go no go” criteria. The first is conversion of nucleoside reverse transcriptase and an integrase inhibitor(s) into lipophilic prodrug nanocrystals. These conversions are designed for simple, safe and scalable productions under current good manufacturing practices. Following the production of ARV nanocrystals, the second step will optimize CD4+ T cell uptake while sustaining drug depots in macrophages. ARV release from prodrugs will occur by controlled hydrolysis enabling sustained antiretroviral potency. The third will facilitate distribution of prodrug nanocrystals into lymphoid, gut associated lymphoid tissue, genitourinary and central nervous system tissues. The fourth, will complete tests designed to limit off target toxicity (S Cohen) by screening pro-, native- and nanocrystal- drug formulations in cell and tissue assays. These extended toxicology tests will serves to investigate any or no adverse events that follow increased ARV levels in cells and tissues. Our goal is the production of safe well-tolerated long acting slow effective release antiretroviral therapies with “putative” dosing intervals of up to once every six months. The design will offer maximal effectiveness for pre-exposure prophylaxis and treatment regimens. The specific aims are supported by extensive published data sets. To accomplish the proposed research, a partnership was made between a medicinal and polymer chemist (B Edagwa) and a virologist, cell biologist, and immunologist (H Gendelman). This collaboration will accelerate transformation of short- to long-acting ARVs. Biological testing will follow product development in cell and animal models. Formulation safety will be realized by continuous testing of replicate short-acting native ARV formulations in good laboratory and current good manufacturing practice facilities. The pathway for ARV nanocrystal development will move forward by sequential Go No Go criteria. Drug choices, formulation stability, drug combinations, tissue and cell targeting, toxicology, pharmacokinetics (PK), and pharmacodynamics (PD) profiles follow the action plan. Several have “reached” drug manufacture. The outcome of these experiments can reduce drug toxicities, improve regimen adherence, and provide enhanced viral prevention into tissue reservoirs. The research builds on an already strong track record in cell-targeted nanomedicines. Antiretroviral responses and endosomal trafficking will be tested. PK and PD mouse screens (S Gorantla) will validate the findings. Overall, our long-term goal is to transform existing antiretroviral treatment regimens into long acting therapies.