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: 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
• Journal: Biomaterials (Biomaterials) Vol. 35 Issue 6 Pg. 2066-78 (Feb 2014) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 24315577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Polymers
• RNA, Small Interfering
• Polyethylene Glycols

Topics

• Animals
• Cell Survival (genetics, physiology)
• Flow Cytometry
• Humans
• MCF-7 Cells
• Mice
• Microscopy, Confocal
• Nanoparticles (chemistry)
• Polyethylene Glycols (chemistry)
• Polymers (chemistry)
• RNA, Small Interfering (chemistry, physiology)
• Surface Plasmon Resonance