title: Hepatic Carcinoma Selective Nucleic Acid Nanovector Assembled by Endogenous Molecules Based on Modular Strategy.
abstract: We rationally formulated a nucleic acid nanovector platform utilizing endogenous molecules in the following steps: nucleic acids are initially packed by a multifunctional peptide and a cationic liposome to form positively charged ternary complexes through electrostatic interaction; then the ternary complexes were coated with hyaluronic acid (HA) to form negatively charged quaternary nanocomplexes (Q-complexes). Among the components of Q-complexes, the multifunctional peptide was composed of a poly-16-arginine (R16) and a hepatic tumor-targeted cell penetrating peptide (KRPTMRFRYTWNPMK); the cationic lipid component included DOTAP and fusogenic lipid DOPE; the HA component shielded the cationic ternary complexes and actively targeted the CD44 overexpressed on the surface of tumor cells. Q-complexes have showed a relatively high stability in the medium, and HA component partially separated from the nanocomplexes after the Q-complexes bound to the cancer cells. The Q-complexes showed significantly enhanced nucleic acid delivery activity than the corresponding quaternary complexes containing R16and nonvisible cytotoxicity in SCMM-7721 cells. In vivo, a selected Q-complex HLP1R specifically targeted and entered tumor cells without affecting normal tissues. Furthermore, HLP1R wrapped survivin siRNA efficiently and silenced the targeting gene in the liver orthotropic transplantation tumor models and showed nontoxic in vivo. This study reveals that Q-complexes are reasonable and feasible gene therapeutic carriers.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Luchen
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Peng
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.affiliation: School of Medicine, Shanghai Jiao Tong University , 280 Chongqing South Road, Shanghai 200127, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Pu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Zixiu
authors.identifier: 0000-0002-3865-1779
authors.initials: Z
authors.lastname: Du
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D008081:Liposomes / Q000737:chemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D053761:Nanocomposites / Q000737:chemistry; D009696:Nucleic Acids / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D009696:Nucleic Acids; D010455:Peptides; D000077022:Survivin; D006820:Hyaluronic Acid; D008156:Luciferases
keywords: cationic lipid component; hepatic carcinoma selective delivery system; hyaluronic acid; modular design; multifunctional peptide