一种癌细胞膜原位生成并定向入核的新型抗癌纳米药物

As the second leading cause of death, cancer has long been a serious threat to human health. However chemotherapy inevitably leads to toxic side effects and damage to normal cells, it is important for anticancer drugs that target the cell nucleus to develop a novel drug delivery system which can help them into the nucleus of cancer cells. This drug delivery system will improve the anti-cancer efficiency of existing anticancer drugs and reduce their toxic side effects. Recently, Rotello group has reported that proteins synthetically modified with a simple aromatic boronate motif are actively trafficked to the nucleus via the importin α/β pathway. This work inspired us to develop a novel anticancer nanomedicine delivery system which can help not only the anticancer drugs target cancer cells, but also the in situ synthesis of anticancer nanomedicines on the surface of cell membranes. In the present of phenylboronic acid motif, the in situ formed anticancer nanomedicines further trasfer into the nucleus and kill the cancer cells effectively. Our preliminary experiment has confirmed that the peptide nanomedicine precursors with phenylboric acid motif have well enzymatic self-assembly ability. This study based on the good preliminary results and the applicant’s rich experience in peptide self-assembly has good feasibility. The implementation of the plan will provide the design of nanomedicine delivery material with new ideas and developing direction.

癌症一直严重威胁着人类的健康，是造成死亡的第二大疾病。但是化疗不可避免的给病人带来毒副作用并损伤正常细胞，因此针对作用靶点在癌细胞核内的抗癌药物，开发具有细胞核靶向的抗癌药物递送体系对提高现有可用抗癌药物的抗癌效率降低毒副作用具有重要意义。最近，Rotello课题组报道了经过芳香族硼酸盐基团简单修饰后的蛋白质通过转运蛋白转运通路能被主动运输至细胞核。受该研究成果启发，我们利用酶促自组装手段来构建一种能靶向癌细胞并在癌细胞膜表面原位自组装生成抗癌纳米药物的新型抗癌纳米药物递送体系。原位生成的抗癌纳米药物在苯硼酸基团的作用下能进一步进入细胞核内，从而高效杀死癌细胞。我们的前期预实验已证实所设计的带有苯硼酸基团的多肽纳米药物前体分子具有良好的酶促自组装能力。本研究基于良好的前期结果和申请人在多肽自组装方面积累的丰富经验具有很好的可行性，计划的实施将为纳米药物递送材料的设计提供新的思路和发展方向。

本研究计划拟利用酶促自组装手段来构建一种能靶向癌细胞并在癌细胞膜表面原位自组装生成抗癌纳米药物的新型抗癌纳米药物递送体系。在2019-2022年间，项目负责人带领研究团队按照原定计划利用酶促自组装技术能在癌症原位形成新型纳米药物的策略，设计和制备了一系列新型的多肽纳米药物，并利用多种癌细胞和小鼠肿瘤模型初步探索了这些新型纳米药物的疗效。同时，合成了一系列新型的荧光分子探针，利用表面诱导多肽自组装技术将分子探针应用到了正常癌细胞和衰老癌细胞的检测和杀伤。我们的科研工作为新型抗肿瘤纳米药物的研发提供新的思路和策略。项目执行期间一共发表了标注该基金项目的SCI收录论文3篇，申请并获得授权中国发明专利6项，培养了自组装多肽研究方面的多名优秀人才，包括5名博士生，3名硕士生。其中有3名博士生毕业后继续从事科研工作，有1名硕士继续去国外攻读博士学位。2019年获得天津市自然科学一等奖（第九完成人）。