Sustained Release of Potent Antiviral Prodrugs for HIV Prevention

摘要 在遏制艾滋病毒流行病的蔓延方面取得了重要进展，但新的艾滋病毒感染 发病率超过了全球卫生组织设定的目标：2019年，估计有170万人 成为全球新的艾滋病毒感染者。需要新的艾滋病毒暴露前预防（PrEP）策略 迫切需要克服这一令人震惊的预防差距。坚持每日给药方案一直是一个关键 阻碍了以前在易感人群中使用抗逆转录病毒（ARV）药物进行的HIV PrEP临床试验的成功， 未受感染的人。这种挑战可以通过持续释放或长效抗逆转录病毒药物来缓解 将给药频率降低至每月一次或更长时间的间隔并靶向 最有可能感染艾滋病毒的异质人群。一种可注射缓释纳米粒， 抗逆转录病毒药物cabotegravir的配方最近已被美国FDA批准用于HIV PrEP，但这 该技术具有许多缺点：高初始浓度爆发;颗粒不能被 如果有不良反应，则在注射后移除; 治疗性全身药物浓度可在最后一次注射后持续超过1年。皮下 正在开发使用六个月或更长时间的植入物，用于使用单一药剂的HIV PrEP; 然而，有效的策略可能需要两种抗逆转录病毒药物。这一生物医学挑战因以下因素而加剧： 缺乏安全、有效的FDA批准的可用药物，这些药物具有足够的效力来实现可行的植入 尺寸和六个月或更长的使用期。建议的努力建立在我们以前成功的基础上 在开发持续释放药物递送生物医学技术方面取得的成就，并将测试 中心假设，一个创新的皮下植入系统提供两个新的有效的抗逆转录病毒药物， 在药物生物医药化学性质和预期使用持续时间方面证明初步可行性。在 目的1，我们将设计，合成和筛选一个新的前药库的基础上建立，FDA批准， 来自不同机械类的代理人。将使用决策树合理选择领导候选人 基于明确定义的量化规则。在目标2中，将配制有希望的前药候选物用于 持续交付使用我们的下一代皮下植入系统，这些努力将指导 在南非进行的用户偏好研究，以微调可修改的设备属性。在目标3中，我们 在小鼠和绵羊中进行PK和安全性研究，然后在人源化小鼠中进行功效研究，以确定 这些装置是否可以安全地预防阴道和直肠艾滋病毒感染。该项目建立在一个既定的 经验丰富的研究人员的合作，并将推进我们的科学知识，在许多， 预防艾滋病毒的系统、持续药物输送的相互关联方面。

ABSTRACT Important progress in curbing the progression of the HIV epidemic has been achieved, but new HIV infection rates are outpacing the targets set by global health organizations: in 2019, an estimated 1.7 million people became newly HIV infected worldwide. New HIV pre-exposure prophylaxis (PrEP) strategies are needed urgently to overcome this alarming prevention gap. Adherence to daily dosing regimens has been a critical impediment to success in previous HIV PrEP clinical trials with antiretroviral (ARV) drugs in susceptible, uninfected individuals. This challenge can be mitigated with sustained release, or long-acting, ARV formulations that reduce dosing frequency to intervals of once per month or longer and target the heterogeneous populations most at risk from contracting HIV. An injectable sustained release nanoparticle formulation of the ARV drug cabotegravir recently has been approved by the US FDA for HIV PrEP, but this technology suffers from a number of drawbacks: a high initial concentration burst; the particles cannot be removed following injection should there be an adverse reaction; pharmacokinetic (PK) tail-phase where sub- therapeutic systemic drug concentrations can persist for over 1 year after the last injection. Subdermal implants with a duration of use of six months or longer are being developed for HIV PrEP using a single agent; however, effective strategies likely will require two ARV drugs. This biomedical challenge is exacerbated by the scarcity of safe, efficacious FDA-approved available agents with sufficient potency to enable a feasible implant size and a period of use of six months, or longer. The proposed efforts build on our previous successful accomplishments in developing sustained release drug delivery biomedical technologies and will test the central hypothesis that an innovative subdermal implant system delivering two, new potent ARV agents will demonstrate initial feasibility in terms of drug biophysicochemical properties and expected duration of use. In Aim 1, we will design, synthesize, and screen a library of novel prodrugs based on established, FDA-approved agents from different mechanistic classes. Lead candidates will be selected rationally using a decision tree based on clearly defined, quantitative rules. In Aim 2, promising prodrug candidates will be formulated for sustained delivery using our next-generation subdermal implant system, and these efforts will be guided by user preference research conducted in South Africa to fine-tune modifiable device attributes. In Aim 3, we will conduct PK and safety studies in mice and sheep, followed by efficacy studies in humanized mice to determine if the devices can safely prevent vaginal and rectal HIV infection. The project builds on an established collaboration of highly experienced investigators and will advance our scientific knowledge on the many, interrelated aspects of systemic, sustained drug delivery for HIV prevention.