Material guided drug delivery for pediatric tumors using an implantable biomaterial and bio-orthogonal chemistry

项目摘要/摘要 虽然有许多癌症需要新的治疗方法，但儿童肉瘤是一类 他们自己的。自1990年以来，这些患者的五年存活率一直稳定在67%左右，没有明显的 从那时起，其余三分之一的患者的存活率有所改善。缺乏进展的一个主要原因 是市场的有限规模；在21岁以下的患者中，只有大约12,400名新诊断的癌症 此外，针对儿科患者的药物开发需要额外的试验，以说明 针对不同的儿童解剖、代谢、发育阶段及对儿科友好的需求 制剂--如液体而不是片剂。这些挑战的最终结果是，在120种新癌症中 FDA在1948年至2002年期间批准的药物中，只有30种-微不足道的25%-用于儿童。到期 为了满足这一重大需求，沙斯基公司将这一SBIR项目的重点放在将其药物输送技术应用于 儿科肉瘤。肉瘤通常用阿霉素等化疗药物治疗，其次是外科手术。 切除肿瘤。不幸的是，化疗有严重的副作用，可能非常严重和 导致死亡，这最终限制了它们在年轻患者中的使用。除了这些副作用，阿霉素还可以 引起心肌毒性，最终可能在治疗期间或数年内导致致命的充血性心力衰竭(CHF) 终止治疗后，以及继发性AML或骨髓增生异常综合征(MDS)，这也可以是 致命的疾病。显然非常需要开发化疗药物--特别是阿霉素-- 提高疗效和改善治疗指数，这将增加肿瘤切除和治疗的成功率 提高儿童肉瘤患者的存活率。为了克服这些不利事件，同时保持 功效，沙斯基正在开发一项正在申请专利的技术，该技术利用一种可植入的生物材料和前药 化疗药物。沙斯基公司的核心技术是基于生物正交化的“捕捉和释放”反应 在生物材料和前药之间，导致活性物质的局部有效载荷释放 化疗，避免全身副作用。该方法结合了注射器的空间控制。 全身性给药时间控制的生物材料，使全身性药物本地化 药物。根据该项目，沙奇将为儿科医生量身定做其生物材料和阿霉素前体药物。 三项小鼠肉瘤研究：耐受性研究、局部量化研究和异种移植疗效 学习。由此产生的数据将为IND支持研究提供关键数据，并为 第二阶段的扩大疗效研究。

Project Summary/Abstract While there are many cancers that are in need of new therapeutic approaches, pediatric sarcomas are in a class of their own. Five-year survival rates in these patients has held steady around 67% since 1990, without significant improvements in the survival of the remaining 1/3 of patients since then. A major reason for the lack of progress is the limited size of the market; there are only around 12,400 new cancers diagnosed in patients under 21 years old each year in the U.S. In addition, drug development for pediatric patients require additional trials that account for the different anatomy of children, metabolism, developmental stage and need for pediatric-friendly formulations—such as liquid instead of tablets. The end result of these challenges is that out of 120 new cancer drugs approved by the FDA between 1948 and 2002, only 30 of them—a paltry 25%—are used in children. Due to this significant need, Shasqi, Inc. is focusing this SBIR project on applying its drug delivery technology towards pediatric sarcomas. Sarcomas are typically treated with chemotherapies like doxorubicin, followed by surgical resection of the tumor. Unfortunately, chemotherapies have severe side effects that can be quite severe and result in death, which ultimately limits their use in young patients. On top of these side effects, doxorubicin can cause myocardial toxicity that may ultimately lead to fatal congestive heart failure (CHF) during therapy or years after termination of therapy, as well as secondary AML or myelodysplastic syndrome (MDS), which can also be fatal diseases. There is clearly a great need to develop chemotherapies—and doxorubicin in particular—with improved efficacy and improved therapeutic index, which would increase the success of tumor resection and increase the survival of pediatric sarcoma patients. To overcome these adverse events while maintaining efficacy, Shasqi is developing a patent-pending technology that utilizes an implantable biomaterial and prodrugs of chemotherapeutics. Shasqi’s core technology is based on a bio-orthogonal ‘catch and release’ reaction between the biomaterial and the prodrug that results in a localized payload release of the active chemotherapeutic, avoiding systemic side effects. This approach combines the spatial control of injectable biomaterials with the temporal control of systemic drug delivery, thus turning systemic drugs into localized medicines. Under this project, Shasqi will tailor its biomaterial and doxorubicin prodrug towards pediatric sarcoma tumors in three mouse studies: A tolerability study, a local quantification study, and a xenograft efficacy study. The resulting data will provide critical data for IND-enabling studies as well as inform dosing strategies in expanded efficacy studies in Phase II.