Original articles
Xiyue Zhao, Xiaoyu Liu, Pengcheng Zhang, Yiran Liu, Wei Ran, Ying Cai, Junyang Wang, Yihui Zhai, Guanru Wang, Yaping Ding, Yaping Li. Injectable peptide hydrogel as intraperitoneal triptolide depot for the treatment of orthotopic hepatocellular carcinoma[J]. Acta Pharmaceutica Sinica B, 2019, 9(5): 1050-1060

Injectable peptide hydrogel as intraperitoneal triptolide depot for the treatment of orthotopic hepatocellular carcinoma
Xiyue Zhaoa,b, Xiaoyu Liub, Pengcheng Zhangb,c,e, Yiran Liub,f, Wei Ranb,e, Ying Caib,e, Junyang Wangb,g, Yihui Zhaib,e, Guanru Wangb, Yaping Dinga, Yaping Lib,d,e
a Department of Chemistry, Shanghai University, Shanghai 200444, China;
b State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
c Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China;
d School of Pharmacy, Yantai University, Yantai 264005, China;
e University of Chinese Academy of Sciences, Beijing 100049, China;
f Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China;
g Jilin University, Changchun 130012, China
Abstract:
Chemotherapy is among the limited choices approved for the treatment of hepatocellular carcinoma (HCC) at intermediate and advanced stages. Preferential and prolonged drug exposure in diseased sites is required to maximize the therapeutic index of the drug. Here, we report an injectable supramolecular peptide hydrogel as an intraperitoneal depot for localized and sustained release of triptolide for the treatment of orthotopic HCC. We chose peptide amphiphile C16-GNNQQNYKD-OH-based nanofibers as gelators and carriers for triptolide. Sustained triptolide release from the hydrogel was achieved over 14 days in vitro, with higher accumulation in and cytotoxicity against human HCC Bel-7402 in comparison with L-02 fetal hepatocytes. After intraperitoneal injection, the hydrogel showed prolonged retention over 13 days and preferential accumulation in the liver, realizing HCC growth inhibition by 99.7±0.1% and animal median survival extension from 19 to 43 days, without causing noticeable pathological changes in the major organs. These results demonstrate that injectable peptide hydrogel can be a potential carrier for localized chemotherapy of HCC.
Key words:    Self-assembly    Hydrogel    Peptide amphiphile    Triptolide    Hepatocellular carcinoma   
Received: 2019-04-17     Revised: 2019-05-10
DOI: 10.1016/j.apsb.2019.06.001
Funds: We thank the National Natural Science Foundation of China (Nos. 81690265, 31870995, 81671808 and 81630052),Youth Innovation Promotion Association of the Chinese Academy of Sciences (2017335, China), and SA-SIBS Scholarship Program for financial support (China). We are grateful to National Centre for Protein Science Shanghai (Electron Microscopy system) for instrument support and technical assistance during data collection.
Corresponding author: Pengcheng Zhang, Yaping Li     Email:pzhang@simm.ac.cn;ypli@simm.ac.cn
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Xiyue Zhao
Xiaoyu Liu
Pengcheng Zhang
Yiran Liu
Wei Ran
Ying Cai
Junyang Wang
Yihui Zhai
Guanru Wang
Yaping Ding
Yaping Li

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