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.

项目概要/摘要 虽然有许多癌症需要新的治疗方法，但小儿肉瘤属于一类 自 1990 年以来，这些患者的五年生存率一直稳定在 67% 左右，没有出现显着的变化。 此后剩余 1/3 患者的生存率有所改善，这是缺乏进展的主要原因。 市场规模有限；21 岁以下患者中仅诊断出约 12,400 例新癌症； 在美国每年都有 100 多岁的儿童参与其中。此外，针对儿科患者的药物开发需要额外的试验来考虑 针对儿童的不同解剖结构、新陈代谢、发育阶段和儿科友好型需求 这些挑战的最终结果是 120 种新的癌症。 1948 年至 2002 年间 FDA 批准的药物中，只有 30 种（微不足道的 25%）用于儿童。 为了满足这一重大需求，Shasqi, Inc. 正在将 SBIR 项目的重点放在将其药物输送技术应用于 儿童肉瘤通常采用阿霉素等化疗治疗，然后进行手术治疗。 不幸的是，化疗有严重的副作用，而且副作用可能非常严重。 导致死亡，这最终限制了它们在年轻患者中的使用。除了这些副作用之外，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） 治疗终止后，以及继发性 AML 或骨髓增生异常综合征 (MDS)，也可以 显然非常需要开发化疗药物，特别是阿霉素。 提高疗效并提高治疗指数，这将增加肿瘤切除的成功率 提高儿童肉瘤患者的生存率，同时克服这些不良事件。 Shasqi 正在开发一项正在申请专利的技术，该技术利用可植入生物材料和前药 Shasqi 的核心技术基于生物正交“捕获和释放”反应。 生物材料和前药之间，导致活性物质的局部有效负载释放 化疗，避免全身副作用。这种方法结合了注射剂的空间控制。 具有时间控制全身药物输送的生物材料，从而将全身药物转化为局部药物 在该项目下，Shasqi 将针对儿科定制其生物材料和阿霉素前药。 三项小鼠肉瘤肿瘤研究：耐受性研究、局部定量研究和异种移植功效 研究产生的数据将为 IND 研究提供关键数据，并为剂量策略提供信息。 扩大了 II 期疗效研究。