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

使用可植入生物材料和生物正交化学对儿童肿瘤进行材料引导的药物输送

• 批准号: 9559449
• 负责人: Sangeetha Srinivasan
• 金额: $ 29.99万
• 依托单位: TAMBO, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-26 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9559449
• 关键词: 21 year old; Adjuvant; Adjuvant Chemotherapy; Adult; Adverse effects; Adverse event; Aftercare; Alginates; Anatomy; Animals; Biocompatible Materials; Biodistribution; Cancerous; Cells; Cessation of life; Chemicals; Chemistry; Child; Childhood; Chronic; Clinical Trials; Complement; Congestive Heart Failure; Cyclooctenes; Cytotoxic Chemotherapy; Cytotoxin; Data; Development; Diagnosis; Disease; Dose; Doxorubicin; Drug Controls; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; Dysmyelopoietic Syndromes; Effectiveness; Excision; FDA approved; Formulation; Frequencies; Gel; Human; Immune system; Immunocompetent; Immunocompromised Host; Immunodeficient Mouse; Immunosuppression; Implant; Infertility; Injectable; Lead; Legal patent; Life; Liquid substance; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Medicine; Metabolism; Mouse Strains; Mucositis; Mus; Myocardial; Nausea; Necrosis; Operative Surgical Procedures; Opportunistic Infections; Patients; Pediatric Neoplasm; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Prodrugs; Quality of life; Radiation; Radiation therapy; Reaction; Recurrence; Safety; Second Primary Cancers; Serum; Site; Small Business Innovation Research Grant; Survival Rate; System; Tablets; Technology; Therapeutic; Therapeutic Effect; Therapeutic Index; Tissues; Toxic effect; Tumor Tissue; Unresectable; Xenograft procedure; base; cancer diagnosis; cancer therapy; chemotherapy; childhood sarcoma; controlled release; dosage; drug development; drug distribution; efficacy study; hearing impairment; improved; in vivo; novel anticancer drug; novel therapeutic intervention; novel therapeutics; osteosarcoma; outcome forecast; pediatric patients; pre-clinical; prevent; safety study; sarcoma; success; tumor

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.

项目摘要/摘要 虽然有许多癌症需要新的治疗方法，但小儿肉瘤正在上课 自己的。自1990年以来，这些患者的五年生存率一直保持在67％左右，没有明显的 此后，其余1/3患者的存活率得到改善。缺乏进步的主要原因 是市场规模有限；在21岁以下的患者中，只有大约12,400名新癌症 此外，每年在美国老年，儿科患者的药物开发需要进行其他试验 对于儿童的不同解剖结构，新陈代谢，发育阶段以及对小儿友好的需求 公式 - 例如液体而不是片剂。这些挑战的最终结果是，在120种新癌症中 在1948年至2002年之间，由FDA批准的药物，其中只有30个（一个微不足道的25％）用于儿童。到期的 满足了这一巨大需求，Shasqi，Inc。将这个SBIR项目集中在将其药物输送技术应用于 小儿肉瘤。肉瘤通常用阿霉素等化学疗法治疗，然后是手术 切除肿瘤。不幸的是，化学疗法具有严重的副作用，可能很严重，并且 导致死亡，最终限制了他们在年轻患者中的使用。在这些副作用之上，阿霉素可以 导致心肌毒性最终可能导致治疗期间致命的充血性心力衰竭（CHF） 终止治疗后，以及次级AML或骨髓增生综合征（MDS），也可以是 致命疾病。显然，尤其是开发化学疗法，尤其是阿霉素的必要 提高效率并提高了治疗指数，这将增加肿瘤切除的成功和 增加小儿肉瘤患者的存活率。在维护的同时克服这些不利事件 效率，Shasqi正在开发一种正在申请专利的技术，该技术利用可植入的生物材料和前药 化学治疗药。 Shasqi的核心技术基于生物正交的“捕获和释放”反应 在生物材料和前药之间导致主动的局部有效载荷释放 化学治疗性，避免全身副作用。这种方法结合了可注射的空间控制 具有全身药物递送的临时控制的生物材料，从而将全身药物转化为局部 药物。在这个项目下，Shasqi将量身定制其生物材料和阿霉素前药针对儿科 三项小鼠研究中的肉瘤肿瘤：一项耐受性研究，局部定量研究和异种移植效率 学习。由此产生的数据将为辅助研究提供关键数据，并为剂量策略提供信息 在第二阶段扩大效率研究。