Polyethylenimine–Bisphosphonate–Cyclodextrin Ternary Conjugates: Supramolecular Systems for the Delivery of Antineoplastic Drugs

Bisphosphonates (BPs) are bone-binding molecules that provide targeting capabilities to bone cancer cells when conjugated with drug-carrying polymers. This work reports the design, synthesis, and biological evaluation of polyethyleneimine–BP–cyclodextrin (PEI-BP-CD) ternary conjugates with supramolecular capabilities for the loading of antineoplastic drugs. A straightforward, modular, and versatile strategy based on the click aza-Michael addition reaction of vinyl sulfones (VSs) allows the grafting of BPs targeting ligands and βCD carrier appendages to the PEI polymeric scaffold. The in vitro evaluation (cytotoxicity, cellular uptake, internalization routes, and subcellular distribution) for the ternary conjugates and their doxorubicin inclusion complexes in different bone-related cancer cell lines (MC3T3-E1 osteoblasts, MG-63 sarcoma cells, and MDA-MB-231 breast cancer cells) confirmed specificity, mitochondrial targeting, and overall capability to mediate a targeted drug transport to those cells. The in vivo evaluation using xenografts of MG-63 and MDA-MB-231 cells on mice also confirmed the targeting of the conjugates.双膦酸盐（bisphosphonates，BPs）是一类可与骨组织特异性结合的分子，当其与载药聚合物结合后，可赋予其靶向骨癌细胞的能力。本研究报道了聚乙烯亚胺-双膦酸盐-环糊精（polyethyleneimine–BP–cyclodextrin，PEI-BP-CD）三元结合物的设计、合成与生物学评价，该结合物具备超分子负载抗肿瘤药物的性能。本研究采用基于乙烯基砜（vinyl sulfones，VSs）的点击化学氮杂迈克尔加成反应的简便、模块化且通用的策略，可将双膦酸盐靶向配体与β-环糊精（βCD）载体臂接枝至聚乙烯亚胺聚合物骨架之上。针对该三元结合物及其多柔比星（doxorubicin）包合复合物，研究团队在多种骨相关癌细胞系（MC3T3-E1成骨细胞、MG-63肉瘤细胞与MDA-MB-231乳腺癌细胞）中开展了体外评价，涵盖细胞毒性、细胞摄取、内吞途径与亚细胞分布等内容，结果证实该结合物具备靶向特异性、线粒体靶向能力，以及介导靶向药物转运至上述细胞的综合性能。在小鼠体内开展的MG-63与MDA-MB-231细胞异种移植瘤（xenografts）实验也进一步验证了该结合物的靶向性能。