Development of Catch and Release Approach for Multi-Drug Local Delivery of Chemotherapies

标题：多种药物局部给药的捕捉和释放方法的发展。 项目总结： 这项提议的目标是建立一种新的变革性的局部肿瘤控制范式，独立于 分子标志物或代谢活性，这允许量身定做的多药给药方案。该项目 解决了开发儿童肉瘤新疗法的日益增长的需求。五年的生存 该病的患病率为67%，自20世纪90年代S以来一直没有改善。 在超过25年的时间里，其余三分之一的患者的治疗取得了重大进展。与此同时，只有25%的人 FDA在1948年至2002年期间批准了120种新的抗癌药物用于儿童。建议数 以材料为基础的策略，称为“捕捉和释放”，是基于生物正交逆电子需求 四嗪与反式环辛烯的Diels-Alder(IEDDA)反应。该计划的关键要素 建议的设计是生物相容水凝胶，用四嗪(HMT)修饰，注射在附近的局部 肉瘤。活性减弱且副作用最小的前体药物，含有可释放的TCO 部分将被系统地注入。当前药物和水凝胶接触时，生物正交化 代理之间通过IEDDA反应“捕捉”有效载荷进行反应。最后，生成的中间件 异构体自发地从水凝胶中释放出活性细胞毒性化合物来进行治疗 在当地发挥作用。初步的体外数据表明，HMT在模拟生理条件下是稳定的 条件，并能够激活阿霉素的前体药物。同时，初步的体内测试证明 “捕捉并释放”策略能够局部激活大量具有治疗意义的 阿霉素治疗肉瘤。HMT的多价性允许使用多剂量的HMT重复该过程 系统管理的亲药物。 拟议的项目将侧重于HMT对不同剂量不同剂量的局部激活的能力 化疗药物。具体目标1将集中在合成以及体外表征 阿霉素和依托泊苷联合和单独用药的细胞毒性。In的动力学 还将测试HMT的体外激活作用。具体目标2将是一项三轮单剂上下研究 测定最大耐受量(MTD)和血药动学行为。MTDS也将是 在大鼠单次静脉给药后测定Aim-1前体药物的组合。 在具体目标3中，我们将评估单一治疗和联合前药治疗的疗效。 患者源性异种(PDX)肉瘤模型治疗多种肉瘤类型的实验研究 横纹肌肉瘤和尤文氏肉瘤各1只。从长远来看，我们的 目标是开发一种基于材料的新方法来治疗局部肿瘤，这种方法具有较低的副作用- 影响和最小限度地改变常规癌症治疗工作流程。

Title: Development of catch and release approach for multi-drug local delivery of chemotherapeutics. Project Summary: The goal of this proposal is to establish a new transformative paradigm for local tumor control, independent of molecular markers or metabolic activity, that allows tailored multi-drug dosing regimens. The project addresses the increasing need of developing new treatments of pediatric sarcomas. The five-year survival rates of patients with this ailment are at 67% and have not improved since the 1990's. There have been no major therapeutic improvements for the remaining third of patients in over 25 years. Meanwhile, only 25% of 120 new cancer drugs approved by the FDA between 1948 and 2002 are used in children. The proposed materials-based strategy termed `catch and release' is based on bio-orthogonal inverse-electron demand Diels-Alder (IEDDA) reaction between tetrazine and trans-cyclooctene (TCO). The key element of the proposed design is biocompatible hydrogel, modified with tetrazine (HMT), injected in the vicinity of a local sarcoma tumor. Pro-drugs with attenuated activity and minimal side effects, containing a releasable TCO moiety will be systemically injected. When the pro-drug and the hydrogel come in contact, the bio-orthogonal agents react with each other through IEDDA reaction `catching' the payload. Finally, the resulting intermediate isomerizes spontaneously releasing the active cytotoxic compound from the hydrogel to perform its therapeutic function locally. Preliminary in vitro data has shown that HMT is stable under simulated physiological conditions and capable of activating a pro-drug of doxorubicin. Meanwhile, preliminary in vivo testing proved that the `catch and release' strategy is capable of local activation of therapeutically meaningful quantities of doxorubicin to treat sarcoma. Multivalency of HMT allows for the process to be repeated with multiple doses of the systemically administered pro-drugs. The proposed project will focus on the ability of HMT for local activation of multiple doses of different chemotherapeutic drugs. Specific aim 1 will focus on the synthesis, as well as in vitro characterization of cytotoxicity of the pro-drugs of doxorubicin and etoposide in combination and as a mono-therapy. Kinetics of in vitro activation by HMT will also be tested. The Specific aim 2 will be a 3-round single dose up-and-down study to determine the maximum tolerated dose (MTD) and serum pharmacokinetic behavior. MTDs will also be determined for combinations of the Aim 1 pro-drugs after administration of a single intravenous dose in rats. During Specific Aim 3, we will evaluate the therapeutic response to mono-therapy and combination pro-drug treatment in a range of sarcoma types using patient-derived xenograft (PDX) sarcoma model in mice – 2 models of osteosarcoma, and 1 model each of rhabdomyosarcoma and Ewing's sarcoma. In the long term, our goal is to develop a new materials-based approach for treatment of local tumors that will have lower side- effects and minimally alter the regular cancer treatment workflow.