超分子化疗：降低对正常细胞的毒性与提高抗肿瘤生物活性

Chemotherapy is a vital method for tumor therapy, but traditional chemotherapy exists problems in low targeted and high side-effect, which limits tumor therapy. During the study of supramolecular drug delivery systems in several years, supramolecular chemotherapy provides the possibility to achieve both high bioactivity and low side-effect of anti-tumor drugs. To this end, the research is aimed to develop the "Disguise and Exposure" systems for drug delivery: based on host-guest interactions, cucurbituril/lobaplatin and cucurbituril-poly(ethylene glycol) alternating copolymers will be used to loading eptaplatin and oxaliplatin complexes. Cucurbituril and cucurbituril-poly(ethylene glycol) alternating copolymers can decrease the cytotoxicity of drugs in normal cells through complexation ("Disguise"). Overexpressed tumor biomarker in tumor microenvironment, spermine, is capable of competitive complexation with cucurbituril, thus releasing the anti-tumor drug from drug delivery system; with spermine consuming, cooperative enhancement of anti-tumor activity, thus increasing the toxicity of drugs to tumor cells ("Exposure"). The safety, drug release effect and anti-tumor bioactivity of the drug delivery system will be evaluated by cell and animal experiment, and its mechanism will be studied. It is highly anticipated that the research will establish a novel system for supramolecular drug delivery, and provide a new way for clinical tumor therapy, and achieve low side-effect as well as high efficiency of clinical chemotherapeutics delivery system, thus advancing supramolecular chemotherapy.

化疗是肿瘤治疗的重要手段，但传统化疗存在靶向性差和副作用大的问题，影响肿瘤治疗。近年超分子药物递送体系研究中超分子化疗为实现抗肿瘤药物的高药效和低副作用提供了可能。本研究提出“伪装-去伪装”策略，并据此构建药物递送新体系：基于主客体相互作用，利用葫芦脲与洛铂、以及葫芦脲-聚乙二醇交替共聚物与依铂和奥沙利铂形成主客体复合物，构建超分子洛铂递送体系和超分子共聚物双药递送体系。利用葫芦脲和葫芦脲-聚乙二醇交替共聚物的包覆降低药物对正常细胞的毒性（“伪装”）。利用肿瘤微环境中过表达的肿瘤标志物精胺对药物递送体系中药物的竞争释放，协同精胺消耗，提高药物的抗肿瘤活性（“去伪装”）。通过细胞及动物实验评价药物递送体系的安全性、释药效果和对肿瘤的杀伤效果，并研究其作用机制。本研究构建的可控的超分子药物递送新体系，有利于发展“超分子化疗”和构建高效低毒的临床化疗药物递送体系，为提高临床肿瘤治疗提供新的途径。

临床上晚期肿瘤患者常用的治疗方法依旧是化疗，但传统化疗药物存在毒副作用大和靶向性差的问题。本项目的研究目标为设计高效低毒的超分子化疗药物和发展超分子“伪装去伪装”策略，项目按照研究计划顺利进行，已按要求完成项目内容。葫芦脲(CB[n])具有刚性空腔的立体分子结构、化学稳定性优异和生物毒性低。因此，我们以葫芦脲为主体分子，通过主客体相互作用，将葫芦脲的空腔包合抗肿瘤药物，构建了超分子抗肿瘤药物递送体系。我们制备的超分子化疗药物包括洛铂@葫芦脲[7]、依铂@葫芦脲[7]、阿霉素@葫芦脲[7]、洛铂+依铂@葫芦脲[8]和奥沙利铂+阿霉素@葫芦脲[8]。通过肠道/肺肿瘤微环境中多胺的竞争置换，多胺与葫芦脲的结合能力强于化疗药物和葫芦脲，和/或肿瘤微环境中高浓度多胺推动解组装反应，实现了超分子化疗药物在肿瘤细胞中可控释放。通过葫芦脲的包覆、肿瘤细胞内多胺消耗和超分子药物被动靶向释放，不同非共价键间协同作用，超分子化疗药物既实现了降低化疗药物在正常细胞中毒性，又实现了提高化疗药物抗肿瘤生物活性。项目研究成果为高效低毒的抗肿瘤超分子化疗药物研究与开发开辟了新的思路。