Core-Shell type lipid/rPAA-Chol polymer hybrid nanoparticles for in聽vivo siRNA delivery

详细信息    查看全文

• 作者：Ling-Yan Gao ; Xiao-Yan Liu ; Cheng-Jun Chen ; Jian-Cheng Wang ; Qiang Feng ; Min-Zhi Yu ; Xiao-Fei Ma ; Xi-Wei Pei ; Yu-Jie Niu ; Chong Qiu ; Wen-Hao Pang ; Qiang Zhang
• 关键词：Core-Shell hybrid nanoparticle ; siRNA delivery ; Receptor-mediated targeting ; Tumor therapy
• 刊名：Biomaterials
• 出版年：February, 2014
• 年：2014
• 卷：35
• 期：6
• 页码：2066-2078
• 全文大小：5552 K

文摘

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聽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聽卤聽0.65聽nm and surface potential of 42.53聽卤聽1.03聽mV, and showed high cellular uptake efficiency and rapid endosomal/lysosomal escape ability in MCF-7 cells. Importantly, in聽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聽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聽vivo tumor-targeted therapy.