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Aptamer-functionalized peptide H3CR5C as a novel nanovehicle for codelivery of fasudil and miRNA-195 targeting hepatocellular carcinoma

Authors Liu Y, Wu X, Gao Y, Zhang J, Zhang D, Gu S, Zhu G, Liu G, Li X

Received 10 March 2016

Accepted for publication 23 May 2016

Published 12 August 2016 Volume 2016:11 Pages 3891—3905

DOI https://doi.org/10.2147/IJN.S108128

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Lei Yang


Ying Liu,1,* Xin Wu,1,* Yuan Gao,2,* Jigang Zhang,1 Dandan Zhang,1 Shengying Gu,1 Guanhua Zhu,1 Gaolin Liu,1 Xiaoyu Li1

1Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 2Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China

*These authors contributed equally to this work


Abstract: Liver cancer is the fifth most commonly diagnosed malignancy, of which hepatocellular carcinoma (HCC) represents the dominating histological subtype. Antiangiogenic therapy aimed at vascular endothelial growth factor (VEGF) has shown promising but deficient clinical prospects on account of vasculogenic mimicry, a highly patterned vascular channel distinguished from the endothelium-dependent blood vessel, which may function as blood supply networks occurring in aggressive tumors including HCC. In this study, we used a new cationic peptide, disulfide cross-linked stearylated polyarginine peptide modified with histidine (H3R5), as a reducible vector, cell penetrating peptide-modified aptamer (ST21) with specific binding to HCC cells to conjugate to peptide H3R5 as the targeting probe, miRNA-195 (miR195)as a powerful gene drug to inhibit VEGF, and fasudil to suppress vasculogenic mimicry by blocking ROCK2, all of which were simultaneously encapsulated in the same nanoparticles. Fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient and miR195 was condensed through electrostatic interaction. ST21-H3R5-polyethylene glycol (PEG) exhibited excellent loading capacities for both fasudil and miR195 with adjustable dosing ratios. Western blot analysis showed that FasudilST21-H3R5-PEGmiR195 had strong silencing activity of ROCK2 and VEGF, as compared with FasudilH3R5-PEGmiR195. In vitro and in vivo experiments confirmed that ST21-modified nanoparticles showed significantly higher cellular uptake and therapeutic efficacy in tumor cells or tumor tissues than the unmodified counterparts. These findings suggest that aptamer-conjugated peptide holds great promise for delivering chemical drugs and gene drugs simultaneously to overcome HCC.

Keywords: aptamer, fasudil, miR195, combined therapy, hepatocellular carcinoma

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