Injectable peptide hydrogel as intraperitoneal triptolide depot for the treatment of orthotopic hepatocellular carcinoma

Xiyue Zhao; Xiaoyu Liu; Pengcheng Zhang; Yiran Liu; Wei Ran; Ying Cai; Junyang Wang; Yihui Zhai; Guanru Wang; Yaping Ding; Yaping Li

doi:10.1016/j.apsb.2019.06.001

Injectable peptide hydrogel as intraperitoneal triptolide depot for the treatment of orthotopic hepatocellular carcinoma

Acta Pharm Sin B. 2019 Sep;9(5):1050-1060. doi: 10.1016/j.apsb.2019.06.001. Epub 2019 Jun 14.

Authors

Xiyue Zhao^{1

2}, Xiaoyu Liu², Pengcheng Zhang^{2

3

4}, Yiran Liu^{2

5}, Wei Ran^{2

4}, Ying Cai^{2

4}, Junyang Wang^{2

6}, Yihui Zhai^{2

4}, Guanru Wang², Yaping Ding¹, Yaping Li^{2

7

4}

Affiliations

¹ Department of Chemistry, Shanghai University, Shanghai 200444, China.
² State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China.
⁴ University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China.
⁶ Jilin University, Changchun 130012, China.
⁷ School of Pharmacy, Yantai University, Yantai 264005, 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.

Keywords: ANOVA, analysis of variance; AST, aspartate transaminase; ATL, alanine transaminase; AUC0–13, areas under the curve; AURKA, aurora A kinase; Akt, protein kinase B; BUN, blood urea nitrogen; Bel-7402/Luc, luciferase transfected human HCC cell line Bel-7402; C16-N, C16-GNNQQNYKD-OH; C16-N/DiI, DiI-labeled C16-N; C16-N/DiR, DiR-labeled C16-N hydrogel; C16-N/T, triptolide-loaded peptide amphiphile-based hydrogel; CAS, Chinese Academy of Sciences; CD, circular dichroism; CKS2, cyclin kinase subunit-2; CRE, creatinine; DL, drug loading; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]; DSPE-PEG/DiI, DiI-labeled DSPE-PEG; DSPE-PEG/DiR, DiR-labeled DSPE-PEG micelle; DSPE-PEG/T, drug-loaded DSPE-PEG micelles; EE, encapsulation efficiency; FBS, fetal bovine serum; FI range, fluorescence intensity range; FI, fluorescence intensity; GEMOX, gemcitabine and oxaliplatin; H&E, hematoxylin and eosin; HFIP, 1,1,1,3,3,3-hexafluoro-2-propanol; HPLC, high-performance liquid chromatography; Hepatocellular carcinoma; Hydrogel; LC–MS, liquid chromatography–mass spectrometry; OB glue, EPIGLUs; Peptide amphiphile; RFI, relative fluorescence intensity; Self-assembly; TACE, transarterial chemoembolization; TEM, transmission electron microscopy; TIR, tumor inhibition rate; Tmax, time to reach highest fluorescence intensity; Triptolide; d-Luciferin, (S)-4,5-dihydro-2-(6-hydroxy-2-benzothiazolyl)-4-thiazolecarboxylic acid potassium.