title: Core-shell type lipid/rPAA-Chol polymer hybrid nanoparticles for in vivo siRNA delivery.
abstract: Our previous study had reported that cholesterol-grafted poly(amidoamine) (rPAA-Chol polymer) was able to self-assemble into cationic nanoparticles and act as a potential carrier for siRNA transfection. In this study, the core-shell type lipid/rPAA-Chol hybrid nanoparticles (PEG-LP/siRNA NPs and T7-LP/siRNA NPs) were developed for improving in vivo siRNA delivery by modifying the surface of rPAA-Chol/siRNA nanoplex core with a lipid shell, followed by post-insertion of polyethylene glycol phospholipid (DSPE-PEG) and/or peptide (HAIYPRH, named as T7) modified DSPE-PEG-T7. The integrative hybrid nanostructures of LP/siRNA NPs were evidenced by dynamic light scattering (DLS), confocal laser scanning microscope (CLSM), cryo-transmission electron microscope (Cryo-TEM) and surface plasmon resonance (SPR) assay. It was demonstrated that the T7 peptide modified LP/siRNA NPs (T7-LP/siRNA NPs) exhibited uniform and spherical structures with particle size of 99.39 ± 0.65 nm and surface potential of 42.53 ± 1.03 mV, and showed high cellular uptake efficiency and rapid endosomal/lysosomal escape ability in MCF-7 cells. Importantly, in vitro gene silencing experiment demonstrated that both of pegylated and targeted LP/siEGFR NPs exhibited significantly stronger downregulation of EGFR protein expression level in MCF-7 cells, compared to that of the physical mixture of siRNA lipoplexes and rPAA-Chol/siRNA nanoplexes. In vivo tumor therapy on nude mice bearing MCF-7 tumors further confirmed that the targeted T7-LP/siEGFR NPs exhibited the greatest inhibition on tumor growth via transferrin receptor-mediated targeting delivery, without any activation of immune responses and significant body weight loss following systemic administration. These findings indicated that the core-shell type T7-LP/siRNA nanoparticles would be promising siRNA delivery systems for in vivo tumor-targeted therapy.
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China.
authors: Ling-Yan
authors: LY
authors: Gao
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China.
authors: Xiao-Yan
authors: XY
authors: Liu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China.
authors: Cheng-Jun
authors: CJ
authors: Chen
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China. Electronic address: wang-jc@bjmu.edu.cn.
authors: Jian-Cheng
authors: JC
authors: Wang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China.
authors: Qiang
authors: Q
authors: Feng
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China.
authors: Min-Zhi
authors: MZ
authors: Yu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China.
authors: Xiao-Fei
authors: XF
authors: Ma
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China.
authors: Xi-Wei
authors: XW
authors: Pei
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China.
authors: Yu-Jie
authors: YJ
authors: Niu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China.
authors: Chong
authors: C
authors: Qiu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China.
authors: Wen-Hao
authors: WH
authors: Pang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical science, Peking University, Beijing 100191, China.
authors: Qiang
authors: Q
authors: Zhang
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000502:physiology; D020349:Surface Plasmon Resonance
chemical_list: D011108:Polymers; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols
keywords: Core-Shell hybrid nanoparticle; Receptor-mediated targeting; Tumor therapy; siRNA delivery