Material-guided delivery and local activation of bioorthogonal prodrugs

摘要 全身应用小分子疗法治疗疾病可能无效，甚至是危险的， 因为药物在体内分布广泛。这种缺乏部位特异性意味着大剂量的全身性 需要在病变组织中达到有效浓度，但这些高剂量通常会导致非 特定毒性。大约每20名住院患者中就有一人经历药物不良事件(ADE)，而且在整个 在美国医疗体系中，每年报告的ADE超过100万例。这些意外的后果 药物治疗使死亡风险增加一倍，并增加住院时间，其经济损失 远远超过每年100美元。此外，ADE对我们的治疗武器库有严重的间接影响。 大约25%的药物开发项目在第二阶段研究完成之前失败，原因是 临床安全性。研究小组的回应是开发药物输送系统，以优化本地化的 和及时提供治疗，然而，使用的方法有重大限制。例如，毒品 与抗体结合以实现其目标特异性的分子可引起免疫反应，而它们的 有限的药物释放可能会影响治疗效果。其他研究人员正在将药物嵌入到 生物相容聚合物，这使得它们可以被植入需要的地方，但技术缺乏能力 用于重复、最佳剂量，而无需植入物移除和更换的侵入性循环。沙斯基正在发展中 一种高效、模块化的药物输送平台技术，可实现精确的时空定位 治疗学，一种可以在不引起全身副作用的情况下对抗局部疾病的疗法，并允许 药物释放的调控。它围绕着一种生物相容的凝胶建造，这种凝胶可以在目标部位停留3个月。 依靠生物正交化学将全身性前药(修改为静止的药物)集中在它们 并将其转化为治疗形式。我们的生物可降解凝胶可以在 活组织检查或手术，不需要额外的侵入性程序来进行额外的治疗或切除。 在未来，我们的凝胶可以被设计成具有双附着化学物质来“捕捉”前体药物，从而允许 用于联合治疗的受控释放(空间和时间)。虽然有市场需求，但 我们在许多治疗领域的技术，沙斯基最初专注于开发化疗药物 有可能接受手术干预的肿瘤患者。为了实现这些目标，我们将致力于 通过拟议的快速通道项目实现的七个具体目标。在第一阶段，我们将优化凝胶的用量 与一种使用荷瘤小鼠进行癌症治疗的前药联合使用。我们还将开发经过验证的 方法适用于预期的IND研究，并扩大我们的前药库。在第二阶段，我们会进行 以最大耐受量(MTD)数据为指导的犬中期(28天)毒性研究 在大鼠身上的实验和药代动力学工作。我们还将优化前药配方，以确保稳定性和 药物产品的包装，然后生产GMP级凝胶，用于I最终的第一阶段临床试验。

ABSTRACT Systemic administration of small molecule therapeutics to treat disease can be ineffective, and even hazardous, because the drugs distribute widely in the body. This lack of site-specificity means large systemic doses are needed to achieve effective concentrations in the diseased tissues, but these high doses often result in non- specific toxicity. Roughly 1 in 20 hospitalized patients experience adverse drug events (ADEs) and, throughout the U.S. healthcare system, over a million ADEs are reported every year. These unintended consequences of drug therapy double the risk of mortality and increase the length of hospital stays, with an economic toll that greatly exceeds $100 annually. In addition, ADEs have a crippling indirect effect on our therapeutic arsenal. Roughly 25% of drug development programs fail before completion of Phase II studies due to problems with clinical safety. Research groups have responded by developing drug delivery systems to optimize the localized and timely delivery of therapeutics, however, the approaches used have major limitations. For example, drugs that are conjugated to antibodies to achieve their target specificity can cause immune responses, and their therapeutic efficacy can be compromised by limited drug release. Other researchers are embedding drugs in biocompatible polymers, which allows them to be implanted where needed, but the technologies lack the capacity for repeated, optimal dosing without an invasive cycle of implant removal and replacement. Shasqi is developing a platform technology for efficient and modular drug-delivery that enables precise spatiotemporal localization of therapeutics, one that can combat localized diseases without causing systemic side effects, and that allows for the modulation of drug release. Built around a biocompatible gel that remains at the target site for >3 months, it relies on bio-orthogonal chemistry to concentrate systemic prodrugs (drugs modified to be quiescent) where they are needed and convert them to their therapeutic form. Our biodegradable gel can be implanted at the time of biopsy or surgery and would not require an additional invasive procedure for additional treatments or removal. In the future, our gel can be designed to have dual attachment chemistries for “catching” prodrugs, thus allowing for the controlled release (spatially and temporally) of combination therapies. While there is a market need for our technology in many therapeutic areas, Shasqi is initially focusing on developing chemotherapeutics for patients with neoplasms that are candidates for surgical intervention. To achieve these goals, we will pursue seven specific aims through the proposed Fast Track project. In Phase I, we will optimize gel dosage in combination with a prodrug for cancer treatment using tumor-bearing mice. We will also develop validated methods suitable for anticipated IND studies and expand our prodrug arsenal. In Phase II, we will conduct medium term (28 days) toxicity studies in canines guided by data from maximum tolerated dose (MTD) experiments and pharmacokinetics work in rats. We will also optimize prodrug formulation for stability and packaging of the drug product then manufacture GMP-grade gel for I eventual Phase 1 clinical trials.