Guo Qingxiang, Liu Yifan, Wang Zhongyan, Zhang Jiamin, Mu Ganen, Wang Wei, Liu Jianfeng
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
College of Materials Science and Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China.
Acta Biomater. 2021 Mar 1;122:343-353. doi: 10.1016/j.actbio.2020.12.052. Epub 2021 Jan 11.
Poor nuclear delivery and accumulation are the main reasons for the reduced drug efficacy of many anticancer drugs that target DNA or enzymes in the nucleus, and it is a major obstacle to successful cancer therapy. To address this problem, developing practical drug delivery systems for nuclear delivery is urgently needed. Here we develop a supramolecular hydrogel by conjugating the anticancer agent 10-hydroxycamptothecine (HCPT) and macrocyclic polyamine cyclen to a self-assembling peptide. The cyclen fragment possesses nuclear localization and ATP hydrolysis properties, which can provide a synergistic therapeutic effect for cancer treatment. The HCPT-FFFK-cyclen nanofibers showed improved nuclear accumulation and inhibition capacity in cancer cells including drug-resistant cancer cells in vitro. The nanofibers also exhibited favorable ATP consuming ability in vitro. Moreover, the obtained nanomedicine showed enhanced anticancer efficiency and favorable biocompatibility in vivo when administered to mice via tail vein injection. This constructed self-delivery drug system significantly improved the delivery efficiency of the small molecule agents into the nucleus and showed favorable ATP consuming ability, offering new strategies for developing nanomedicines for cancer combination therapy.
核递送和积累不佳是许多靶向细胞核中DNA或酶的抗癌药物疗效降低的主要原因，也是成功进行癌症治疗的主要障碍。为了解决这个问题，迫切需要开发用于核递送的实用药物递送系统。在此，我们通过将抗癌剂10-羟基喜树碱（HCPT）和大环多胺环糊精与自组装肽缀合来开发一种超分子水凝胶。环糊精片段具有核定位和ATP水解特性，可为癌症治疗提供协同治疗效果。HCPT-FFFK-环糊精纳米纤维在体外对包括耐药癌细胞在内的癌细胞显示出改善的核积累和抑制能力。纳米纤维在体外也表现出良好的ATP消耗能力。此外，通过尾静脉注射给予小鼠时，所获得的纳米药物在体内显示出增强的抗癌效率和良好的生物相容性。这种构建的自递送药物系统显著提高了小分子药物进入细胞核的递送效率，并显示出良好的ATP消耗能力，为开发用于癌症联合治疗的纳米药物提供了新策略。
