Development of prodrug approaches for long-acting nanoformulations of emtricitabine-based regimens

项目摘要 目前用于艾滋病毒治疗和预防的抗逆转录病毒(ARV)药物需要终生每日服用 服药，这可能会导致患者因服药疲劳而减少依从性，从而增加了 因为治疗失败。长效(LA)抗逆转录病毒药物将允许减少给药频率，改善 坚持不懈。尽管成功地开发了用于非核苷的LA制剂 逆转录酶抑制剂(NNRTI)利培韦林和整合酶抑制剂卡波替格韦 用于生产它们的纳米研磨技术与核素(T)反转不兼容 转录酶抑制剂(NRTI)由于其高度的水溶性。最新的ARV组合 治疗方法包括NRTI的管理。因此，为了生产完整的LA剂量 方案，需要非限制性内科药物的LA配方。使生产疏水固体成为可能 药物纳米粒(SDN)，我们提出了一系列的设计、合成和评价 可调节的恩曲他滨(FTC)前药，掩蔽关键的亲水性基团并制造这些药物 与SDN制定方法兼容。将测量前药激活动力学 在各种生理相关条件下模拟 通过肌肉内仓库实施完整的治疗方案。此外，将对前药进行分析 对于亲脂性和抗病毒活性的情况下，它很可能会达到和通过 靶细胞中的激活。最有希望的候选者将被用来生成SDN。这个 这些制剂的药代动力学和疗效益处将在体外和在 体内模型系统，以电子生理学为基础的药代动力学模型 与利物浦大学的合作。总体而言，这项研究有望加速 开发完整的LA-ARV方案，显著提高依从性。

Project Summary Current antiretroviral (ARV) medications for HIV treatment and prevention require lifelong daily dosing, which can lead to reduced patient adherence due to pill fatigue, increasing the likelihood for treatment failure. Long-acting (LA) ARVs would allow less frequent administration, improving adherence. Despite success in the development of LA formulations for the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine and the integrase inhibitor cabotegravir, the nanomilling technologies used to produce them are incompatible with the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) due to their high water solubility. Most current ARV combination therapies include administration of the NRTIs. Thus, in order to produce a complete LA dosing regimen, LA formulations of NRTIs are required. To enable the production of hydrophobic solid drug nanoparticles (SDNs), we propose the design, synthesis, and evaluation of a series of tunable emtricitabine (FTC) prodrugs that mask key hydrophilic groups and make these drugs compatible with SDN formulation approaches. Prodrug activation kinetics will be measured under a variety of physiologically relevant conditions to mimic those encountered by the complete regimen administered via intramuscular depot. In addition, prodrugs will be analyzed for lipophilicity and antiviral activity in cases where it is likely prodrugs will reach and undergo activation in target cells. The most promising candidates will be used to generate SDNs. The pharmacokinetic and efficacy benefits of these formulations will be tested with in vitro and in vivo model systems, guided by in silico physiologically-based pharmacokinetic modeling in collaboration with the University of Liverpool. Overall, this research is expected to accelerate the development of complete LA-ARV regimens to significantly improve adherence.