肿瘤响应富集的精准化疗药物在膀胱癌灌注化疗中的应用

Bladder perfusion chemotherapy is the most important method of postoperative adjuvant treatment of bladder cancer. This project aims to overcome the key disadvantages of bladder perfusion chemotherapy, in terms of low therapeutic efficacy and high side toxicity. This project plans to endow the currently available drugs that are clinically used for bladder perfusion chemotherapy with specific tumor targeting ability, increase the drug retention in bladder tumor tissues to decrease the frequency of perfusion, reduce the side toxicity, and thus realize the precise chemotherapy of bladder perfusion. In this proposal, we will design and synthesis small-molecule peptide prodrug on the basis of three clinically utilized drugs, Epirubicin, Gemcitabine and Hydroxycamptothecine, respectively. The prodrug possesses dual tumor targeting/responsive ability, which is able to selectively self-assemble into nanomedicine in bladder cancer cells and subsequently release the active drugs in a sustained manner. We will also establish the in situ bladder tumor rat model, which will be used to evaluate the antitumor efficacy of the prepared prodrug after intravesical instillation administration. This project combines the advantages of nanotechnology and self-assembling peptides with bladder perfusion chemotherapy, which is expected to provide new materials and new insights for the precise chemotherapy of bladder perfusion.

膀胱灌注化疗是目前膀胱癌术后辅助治疗的最主要方式。本项目针对目前膀胱癌灌注化疗低效高毒的缺点，致力于赋予现有临床上膀胱灌注化疗药物以肿瘤特异靶向性，增加药物在膀胱肿瘤组织中的滞留时间以降低灌注频次，减小膀胱灌注化疗所带来的不良反应，从而实现膀胱灌注的精准化疗。本项目拟制备基于临床上常用的膀胱灌注化疗药物（表柔比星、吉西他滨与羟基喜树碱）的多肽小分子前药，其具备对膀胱癌细胞的“双重靶向”能力(同时具备膀胱肿瘤组织靶向能力以及肿瘤细胞微环境响应能力)，能够特异性地在膀胱肿瘤细胞中自组装形成纳米药物并随后对活性药物进行缓释。本项目还将建立大鼠膀胱癌原位瘤动物模型，探讨所制备的多肽小分子前药通过膀胱灌注的给药方式对于大鼠原位膀胱癌的治疗效果。课题将纳米科技、多肽超分子自组装的优势有机地与膀胱灌注化疗相结合，有望为膀胱灌注的精准化疗提供新材料和新思路。

化疗是治疗膀胱癌的主要方式，但由于膀胱这一器官的特殊性（尿液从膀胱排出）以及化疗药物分子量小的特点，导致膀胱中化疗药物的生物利用度低，并且药物在膀胱肿瘤组织中的滞留时间短，因而不得不提高化疗药物的给药频次和剂量。但是，化疗药物给药的剂量和频率与其所带来的不良反应的严重程度正相关。在项目的资助下，项目组针对以上关键科学问题制备了基于临床上常用膀胱灌注化疗药物的多肽小分子前药，其不仅能够特异性地靶向膀胱肿瘤，还能够响应膀胱肿瘤微环境从而形成纳米纤维药物，从而长期滞留在膀胱肿瘤细胞中，并对化疗药物进行长时间缓释。采用膀胱癌荷瘤小鼠模型的体内实验表明，多肽小分子前药能够在肿瘤组织中自组装形成纳米纤维药物，并且相比于化疗药物对膀胱肿瘤具有更好的治疗效果。本项目为膀胱癌的精准化疗提供了一种新的思路，也为今后开发新型的膀胱癌化疗系统提供了理论依据和实践指导。在本项目的资助下，项目组在4年项目执行期内共发表了12篇通讯作者SCI论文。依托本项目的研究内容，项目组于2019年获得了天津市科技进步二等奖，刘谦为第一完成人，杨志谋为第三完成人。