用于对胰腺肿瘤给药的蠕虫型磁性纳米复合材料

胰腺癌的死亡率极高。胰腺肿瘤组织中存在高度纤维化的基质屏障，严重阻滞高分子/纳米药物载体从血管向肿瘤细胞迁移。本项目拟制备能在外加磁场驱动下穿越胰腺基质屏障的智能磁性纳米蠕虫作为抗癌药物载体。首先利用N-羧基环内酸酐（NCA）单体开环聚合，合成一系列侧链含有乙烯基、乙炔基、叔丁酯基的聚乙二醇 -聚氨基酸-聚乙二醇 ABA三嵌段共聚物。利用羰基铁与炔烃官能团的交联作用，对聚氨基酸嵌段进行分子内交联得到直径10nm的单链颗粒。对单链颗粒加热即能够以颗粒部位为模板，原位生成纳米铁。聚合物侧链留置的叔丁酯基可水解为羧基，与乙烯基和乙炔基一起，分别作为与药物分子、荧光标记和靶向配体相结合的功能基团，实现单链颗粒的药物装载。将磁性单链颗粒通过自组装形成纳米蠕虫并部分交联，研究其在外加磁场驱动下的运动规律。最后构建体外肿瘤模型和动物模型，考察载药蠕虫对胰腺基质屏障的穿透能力和对肿瘤细胞的抑制效果。

Pancreatic Ductal Adenocarcinoma (PDAC) is also known as pancreatic cancer. Its 5-year survival rate is lower than 10%. There exists a dense fibrotic stroma within the pancreatic cancer tissue, which severely blocks the transportation of therapeutic nano-drug carriers from blood vessels to the cancer cells. The aim of this proposal is to design a magnetic nanomotor that can swim across the pancreatic stroma barrier, and to be used as the anti-cancer drug carrier. First, PEG-b-Polypeptide-b-PEG ABA triblock copolymers were synthesized via polymerization of N-carboxyanhydrides (NCA) monomers containing vinyl, ethynyl, and tert-butoxyl side groups. Intramolecular crosslinking of the triblock copolymer single chain was conducted via coordination reaction between iron pentacarbonyl (Fe(CO)5) and the ethynyl side groups. The single-chain particle can be further used as a template to generate metallic iron by heating. The remaining ethynyl, vinyl and carboxyl groups can bind with drugs, fluorescent molecules and tumor-targeting peptides to form nanoparticle prodrug. These drug-loaded nanoparticles will then self-assemble into magnetic worms via dipolar interactions. Magnetic fields will be applied to explore their movement patterns. The ability of these magnetic worms to penetrate the pancreatic stroma barrier will be studied within 3D spheroid models and animal models. Their anti-tumor activity will also be evaluated in vitro and in vivo.