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Elaboration on the distribution of hydrophobic segments in the chains of amphiphilic cationic polymers for siRNA delivery.

著者 Wang C , Du L , Zhou J , Meng L , Cheng Q , Wang C , Wang X , Zhao D , Huang Y , Zheng S , Cao H , Zhang J , Deng L , Liang Z , Dong A
ACS Appl Mater Interfaces.2017 Sep 01 ; ():.
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Hydrophobization of cationic polymers, as an efficient strategy, had widely been developed in construction of cationic polymeric micelles to improve the delivery efficiency of nucleic acids. However, the distribution of hydrophobic segments in the polymer chains is rarely considered. Here, we elaborated three types of hydrophobized PEG-blocked cationic polymers with different distribution of the hydrophobic segments in the polymer chains, respectively, PEG-PAM-PDP (E-A-D), PEG-PDP-PAM (E-D-A), and PEG-P(AM/DP) (E-(A/D)), which were prepared by reversible addition-fragmentation chain transfer polymerization (RAFT) of methoxy polyethylene glycol (PEG), cationic monomer aminoethyl methacrylate (AM) and pH-sensitive hydrophobic monomer 2-diisopropylaminoethyl methacrylate (DP). In aqueous solution, all of the three copolymers, E-A-D, E-D-A and E-(A/D), were able to spontaneously form nano-sized micelles (100~150nm) (ME-A-D, ME-D-A and ME-(A/D)), and well incorporated siRNA into complex micelles (CMs). The effect of distributions of the hydrophobic segments on siRNA delivery had been evaluated in vitro and in vivo. Compared with ME-D-A and ME-(A/D), ME-A-D showed best siRNA bonding capacity to form stable ME-A-D/siRNA CMs less than 100 nm, mediated best gene silence efficiency and tumor cell growth inhibition in vitro, and showed better liver gene silencing effect in vivo. In the case of ME-(A/D) with a random distribution of cationic and hydrophobic segment, higher gene silence efficiency than Lipo2000 but less than ME-A-D and ME-D-A was got. As the mole ratio of positive and negative charges increasing, ME-D-A/siRNA and ME-A-D/siRNA presented similar performances in size, zeta potential, cell uptake and gene silence, but ME-(A/D)/siRNA showed reversed performances. In addition, ME-A-D as the best carrier was evaluated to deliver siRNA into tumor tissue in the xenograft murine model, and showed good anticancer capacity. Obviously, the distribution of the hydrophobic segments in the amphiphilic cationic polymer chains should be seriously considered in the design of siRNA vectors.
PMID: 28862422 [PubMed - as supplied by publisher]
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