Hepatic Carcinoma Selective Nucleic Acid Nanovector Assembled by Endogenous Molecules Based on Modular Strategy

摘要

We rationally formulated a nucleic acid nano-following steps nucleic acids are initially packed by a vector platform utilizing endogenous molecules in the 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 (R-16) 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 R-16 and 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.