title: Structural contributions of blocked or grafted poly(2-dimethylaminoethyl methacrylate) on PEGylated polycaprolactone nanoparticles in siRNA delivery.
abstract: The multiformity in polymer structure and conformation design provides a great potential in improving the gene silencing efficiency of siRNA by polymer vectors. In order to provide information on the polymer design for siRNA delivery, the structural contributions of blocked or grafted poly(2-dimethylaminoethyl methacrylate) on PEGylated polycaprolactone nanoparticles (NPs) in siRNA delivery were studied. Herein, two kinds of self-assembly nanoparticles (NPs) formed by amphiphilic cationic polymers, methoxy poly(ethylene glycol)-block-polycaprolactone-block-poly(2-dimethylaminoethyl methacrylate) (mPEG-PCL-b-PDMAEMA, PECbD) and methoxy poly(ethylene glycol)-block-(polycaprolactone-graft-poly(2-dimethylaminoethyl methacrylate)) (mPEG-PCL-g-PDMAEMA, PECgD), were used to deliver siRNA for in vitro and in vivo studies. The physiochemical properties including size and zeta potential of PECbD NPs/siRNA and PECgD NPs/siRNA complexes were characterized. In vitro cytotoxicity, cellular uptake and siRNA knockdown efficiency were evaluated in HeLa-Luc cells. The endosome escape and intracellular distribution of PECbD NPs/siRNA and PECgD NPs/siRNA in HeLa-Luc cells were also observed. In vivo polymer mediated siRNA delivery and the complexes distribution in isolated organs were studied using mice and tumor-bearing mice. At the same total degree of polymerization (DP) of DMAEMA, PECgD NPs/siRNA complexes possessed higher zeta potentials than PECbD NPs/siRNA complexes (at the same N/P ratio), which may be the reason that PECgD NPs/siRNA complexes can deliver more siRNA into the cytoplasm and lead to higher in vitro luciferase and lamin A/C silencing efficiency than PECbD NPs/siRNA complexes. The in vivo imaging measurement and histochemical analysis also confirmed that siRNA could be delivered to lungs, livers, pancreas and HeLa-Luc tumors more efficiently by PECgD NPs than PECbD NPs. Meanwhile, the PDMAEMA chains of PECgD could be shortened which provides benefits for clearing. Therefore, PECgD NPs have great potential to be used as efficient non-viral carriers for in vivo siRNA delivery.
authors: Department of Polymer Science and Technology, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
authors: Daoshu
authors: D
authors: Lin
authors: Yuanyu
authors: Y
authors: Huang
authors: Qian
authors: Q
authors: Jiang
authors: Wendi
authors: W
authors: Zhang
authors: Xinye
authors: X
authors: Yue
authors: Shutao
authors: S
authors: Guo
authors: Ping
authors: P
authors: Xiao
authors: Quan
authors: Q
authors: Du
authors: Jinfeng
authors: J
authors: Xing
authors: Liandong
authors: L
authors: Deng
authors: Zicai
authors: Z
authors: Liang
authors: Anjie
authors: A
authors: Dong
mesh_terms: D000818:Animals; D001483:Base Sequence; D004587:Electrophoresis, Agar Gel; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008689:Methacrylates / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D053758:Nanoparticles; D009757:Nylons / Q000737:chemistry*; D011091:Polyesters / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D008689:Methacrylates; D009757:Nylons; D011091:Polyesters; D034741:RNA, Small Interfering; C407037:poly(2-(dimethylamino)ethyl methacrylate); C016240:polycaprolactone