Development of Sustained-Release Anti-HIV Nucleoside Phosphonate Nanoparticles

项目摘要 尽管过去20年来药物开发取得了显著进展，但抗逆转录病毒治疗的成功 并不普遍。治疗和预防性治疗中最常见的治疗失败原因 仍然是与药物依从性相关的挑战。虽然许多患者可以每天 坚持相当长的时间，治疗疲劳以及特殊困难存在的脆弱 患者人群，包括受药物滥用、精神疾病、长期远离 以及社区内的耻辱感。治疗失败往往会导致并发症。这导致 对开发抗逆转录病毒化疗剂的兴趣日益增加， 给药间隔。几种新的化合物和复合方法已经出现，表明这一点 目标是高度可实现的。在这个应用程序中，我们希望开发一种有效的方法来在全球范围内提供 使用的核苷酸，替诺福韦，可以每月一次给予的代理商的列表。 我们已经证明，烷氧基烷基侧链与母体分子的酯键大大增强了 细胞摄取，并且我们可以通过添加第二个前体基团来改变细胞内释放的速率， 剩余的膦酸酯氧。这些修饰的综合作用导致细胞快速摄取 以及替诺福韦二磷酸盐向细胞内隔室的持续“定时释放”递送。一个引线 化合物，替诺福韦的十八烷氧基乙基苄基二酯（ODE-Bn-TFV），具有单一纳摩尔抗HIV 活性和>3000的选择性指数。替诺福韦二磷酸在细胞内缓慢释放， 它在隔室中的半衰期超过一周。我们建议利用这种方法， 开发具有更大效力和细胞内半衰期的其他化合物。我们要把小说 纳米颗粒中的时间释放分子，将这些分子缓慢释放到体循环中 从肌肉注射部位。我们相信，通过使用纳米技术，首先调节释放的 前药进入体循环，然后使用合成化学方法来增强细胞摄取 并减缓细胞内的衰变，我们可以在一个月内将有效的抗病毒活性传递到病毒复制的部位， 肌肉注射后。

Project Summary Despite the remarkable progress in drug development over the past 20 years, antiretroviral treatment success is not universal. The most frequent cause of treatment failure in both therapeutic and prophylactic settings continues to be challenges associated with drug adherence. Although many patients can manage daily adherence for substantial periods of time, treatment fatigue as well as special difficulties exist for vulnerable patient populations including those challenged by substance abuse, mental illness, prolonged periods away from home and stigma within their communities. All too often treatment failure ensues. This has led to an increasing interest in the development of antiretroviral chemotherapeutic agents that can be given at prolonged dosing intervals. Several novel compounds and compounding approaches have emerged that suggest this goal is highly attainable. In this application we wish to develop an effective approach to deliver the globally used nucleotide, tenofovir, to the list of agents that can be administered at monthly intervals. We have demonstrated that ester linkage of an alkoxyalkyl side chain to the parent molecule greatly enhances cellular uptake and that we can modify the rate of intracellular release by the addition of a second promoiety at the remaining phosphonate oxygen. The combined effect of these modifications results in rapid cellular uptake and sustained “timed-release” delivery of tenofovir diphosphate to the intracellular compartment. One lead compound, the octadecyloxyethyl benzyl diester of tenofovir (ODE-Bn-TFV), has single nanomolar anti-HIV activity and a selectivity index of >3000. Tenofovir diphosphate was slowly liberated in the intracellular compartment where it maintained a half-life of more than a week. We propose to utilize this approach to develop additional compounds of even greater potency and intracellular half-life. We will compound our novel time-release molecules in nanoparticles that will slowly release these molecules into the systemic circulation from the site of intramuscular injection. We believe that by using nanotechnology to first modulate release of prodrug into the systemic circulation and then using a synthetic chemical approach to enhance cellular uptake and to slow intracellular decay that we can deliver potent antiviral activity to sites of viral replication for a month following intramuscular injection.