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

标题：开发用于化疗药物的多药物局部递送的捕获和释放方法。 项目概要： 该提案的目标是为局部肿瘤控制建立一个新的变革范式， 分子标记物或代谢活性，允许定制的多药物给药方案。项目 满足了开发儿科肉瘤新疗法的日益增长的需求。五年生存 这种疾病的患者比例为67%，自1990年代以来一直没有改善。没有发生 在超过25年的时间里，其余三分之一的患者的治疗效果得到了重大改善。同时，只有25%的 FDA在1948年至2002年期间批准的120种新癌症药物用于儿童。拟议 一种基于材料的战略，称为“捕获和释放”，是基于生物正交逆电子需求 四嗪与反式环辛烯（TCO）之间的Diels-Alder（IEDDA）反应。的关键要素 所提出的设计是生物相容性水凝胶，用四嗪（HMT）修饰，注射在局部 肉瘤具有减弱活性和最小副作用的前药，含有可释放的TCO 部分将被全身注射。当前体药物和水凝胶接触时，生物正交组合物可以在水凝胶中形成。 代理通过IEDDA反应“捕获”有效载荷而相互反应。最后，生成的中间体 异构化自发地从水凝胶中释放活性细胞毒性化合物， 功能在当地。初步的体外数据表明，HMT在模拟生理条件下是稳定的。 条件下，并能够激活阿霉素的前药。同时，初步的体内试验证明， “捕获和释放”策略能够局部激活治疗上有意义的量的 阿霉素来治疗肉瘤。HMT的多价性允许用多剂量的HMT重复该过程。 全身给药的前药。 拟议的项目将侧重于HMT的能力，为当地激活多个剂量的不同 化疗药物具体目标1将集中在合成，以及在体外表征 本发明的目的是提供阿霉素和依托泊苷的前药组合和作为单一疗法的细胞毒性。In动力学 还将测试HMT的体外活化。具体目标2将是一项3轮单次剂量递增和递减研究 以确定最大耐受剂量（MTD）和血清药代动力学行为。MTD还将 在大鼠中施用单次静脉内剂量后，测定Aim 1前药的组合。 在特定目标3期间，我们将评价对单药治疗和联合前药的治疗反应 在小鼠中使用患者来源的异种移植物（PDX）肉瘤模型治疗一系列肉瘤类型- 2 骨肉瘤模型，横纹肌肉瘤和尤文氏肉瘤各1个模型。从长远来看，我们 目标是开发一种新的基于材料的方法来治疗局部肿瘤， 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.