中性粒细胞膜包覆的仿生纳米药物靶向循环肿瘤细胞与前转移病灶的治疗策略研究

The major challenge of current cancer treatment lies in metastasis, in which the highly aggressive and mobile tumor circulating cells (CTC) that originate from the primary tumor and metastasize via the blood circulation are the most important drug target. However, CTC-targeting therapy are still challenging because of the low targeting efficiency and inability to access the pre-metastatic lesion. Mounting evidences identify neutrophils as the main driver of metastasis, in which the activated neutrophils can specifically recognize CTC in the bloodstream and target pre-metastatic lesion during the inflammatory recruitment. Following biomimetic principle, here we designed a biodegradable neutrophil-mimicking vehicle (neutrophil-like-particles, NLP) by functionalizing the nanoparticle surface with inflammatory neutrophils cell membrane proteins, and co-load oleic acid conjugated epigallocatechin-3-gallateand docetaxel in the polymeric core for circulating tumor cells and pre-metastatic niche-targeting therapy. This biomimetic drug delivery system holds great potential in efficiently targeting and eliminating CTC and its pre-metastatic niche by three unique mechanisms: Firstly, by using the patients' own leukocyte membrane, the camouflaged NLP is endowed with minimum immunogenicity and long-circulating property. Secondly, translocation of intact adhesive proteins embedded in membrane synergistically enables efficient CTC and niche targeting. Thirdly, co-loading of the two compounds together could synergistically block multiple stages during metastatic progression. The CTC and pre-metastatic lesion targeting property will be studied in flowing blood in vitro and the metastatic inhibitory effect will also be evaluated in vivo. We believe this biomimetic drug delivery system will provide a novel and elegant strategy for cancer metastasis prevention and therapy.

肿瘤转移是治疗面临的巨大挑战，血循环中具有高侵袭力和运动能力的循环肿瘤细胞（CTC）起关键作用。以杀伤CTC为目的的研究仍存在靶向效率低及不能同时靶向前转移病灶问题。炎症环境激活的中性粒细胞具有天然靶向CTC及前转移病灶的能力。由此，本项目基于仿生学理念率先提出构建一种激活的中性粒细胞膜包覆的生物可降解粒子（NLP）：以聚酯材料制备纳米粒作为内核共包载多西他赛与油酸化的表没食子儿茶素没食子酸酯，表面包被中性粒细胞膜作为衣壳，其特点为：自体中性粒细胞膜的伪装具有免疫豁免和长循环特性；完整保留天然比例的膜粘附分子能协同高效靶向CTC及前转移病灶；两种药物的共包载能针对CTC的异质性及转移前微环境，在肿瘤转移各阶段发挥多靶点协同作用。建立体外模型研究NLP对流动的CTC及前转移病灶的靶向特性，结合体内实验探讨NLP对转移的抑制机制。该针对肿瘤转移的综合治疗策略国内外未见报道，具有较高创新意义。

转移是导致肿瘤患者高死亡率的主要原因，也是治疗面临的最大挑战。很多患者在早期就已经发生了微转移，但临床缺乏有效的针对转移的治疗药物。因此有必要通过研究转移形成的机制，探寻新的思路抑制肿瘤转移。血循环中具有高侵袭力和运动能力的循环肿瘤细胞（CTC）以及可使CTC定植的肿瘤转移前微环境起关键作用，但现在有治疗手段仍存在靶向效率低及不能同时靶向CTC和前转移病灶。炎症环境激活的中性粒细胞具有天然靶向CTC及前转移病灶的能力。由此，本项目基于仿生学理念率先提出构建一种激活的中性粒细胞膜包覆的生物可降解粒子（NLP）：以聚酯材料制备纳米粒作为内核共包载蛋白酶体抑制剂卡非佐米，表面包被中性粒细胞膜作为衣壳，其特点为：自体中性粒细胞膜的伪装具有免疫豁免和长循环特性；完整保留天然比例的膜粘附分子能协同高效靶向CTC及前转移病灶；包载的药物能针对CTC的异质性及转移前微环境，在肿瘤转移各阶段发挥多靶点协同作用。建立体外模型研究NLP对流动的CTC及前转移病灶的靶向特性，结合体内实验探讨NLP对转移的抑制机制。该针对肿瘤转移的综合治疗策略国内外未见报道，具有较高创新意义。.在此基础上项目申请人以通讯作者发表研究论文11篇，其中8篇影响因子高于10，大多发表于本专业权威期刊如ACS Nano, Nature Communications，Nano letters, Small, Biomaterials等。NIH纳米医学的权威陈小元教授在Chemical Reviews中评述:本研究构建的仿生技术可以延伸到利用患者自身的中性粒细胞构建药物递送系统，有望扩展到临床转化，实现“个性化治疗”；英国肿瘤研究协会在Nature Reviews Clinical Oncology中发表“POSITION PAPER”，认为可将此靶点可用于抗肿瘤转移药物开发的靶点。.本研究申请中国发明专利9项，授权3项。培养博士研究生3名，培养硕士研究生7名；其中1名博士研究生获复旦大学学术之星特等奖和光华自立奖，2名研究生获得上海市优秀毕业生。作为主要完成人获教育部自然科学二等奖、上海市科技进步一等奖各一项。