title: Aptamer-functionalized peptide H3CR5C as a novel nanovehicle for codelivery of fasudil and miRNA-195 targeting hepatocellular carcinoma.
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 (Fasudil)ST21-H3R5-PEGmiR195 had strong silencing activity of ROCK2 and VEGF, as compared with (Fasudil)H3R5-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.
authors: Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine.
authors: Ying
authors: Y
authors: Liu
authors: Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine.
authors: Xin
authors: X
authors: Wu
authors: Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.
authors: Yuan
authors: Y
authors: Gao
authors: Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine.
authors: Jigang
authors: J
authors: Zhang
authors: Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine.
authors: Dandan
authors: D
authors: Zhang
authors: Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine.
authors: Shengying
authors: S
authors: Gu
authors: Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine.
authors: Guanhua
authors: G
authors: Zhu
authors: Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine.
authors: Gaolin
authors: G
authors: Liu
authors: Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine.
authors: Xiaoyu
authors: X
authors: Li
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000645:Ammonium Sulfate / Q000737:chemistry; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D052158:Aptamers, Peptide / Q000008:administration & dosage / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage*; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D052158:Aptamers, Peptide; D057846:Cell-Penetrating Peptides; C552722:MIRN195 microRNA, human; D035683:MicroRNAs; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; C015462:polyarginine; D011092:Polyethylene Glycols; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil; D000645:Ammonium Sulfate
keywords: aptamer; combined therapy; fasudil; hepatocellular carcinoma; miR195