title: Dual Functional LipoMET Mediates Envelope-type Nanoparticles to Combinational Oncogene Silencing and Tumor Growth Inhibition.
abstract: The success of small interfering RNA (siRNA)-mediated gene silencing for cancer therapy is still limited because of its instability and poor intracellular internalization. Traditional cationic carriers cannot adequately meet the need for clinical application of siRNA. We herein report a dual-functional liposome containing a cholesterol derivative of metformin, i.e., LipoMET, which takes advantage of the fusogenic activity as well as intrinsic tumor apoptosis inducing ability of biguanide moiety to achieve a combinational anti-oncogenic effect. In this study, the vascular endothelial growth factor (VEGF)-specific siRNAs were first electrostatically condensed into a ternary nanocomplex composed of polycation and hyaluronate, which was subsequently enveloped by LipoMET through membrane fusion. In comparison with common cationic control group, the resulting envelope-type nanoparticles (PH@LipoMET nanoparticles [NPs]) showed the ability of rapid cellular internalization and effective endosomal escape of siRNA during intracellular trafficking studies. Systemic administration of the targeted LipoMETs was capable of inducing apoptosis and tumor growth inhibition in the NCI-H460 xenograft model. When carrying VEGF-specific siRNAs, PH@LipoMET NPs remarkably downregulated the expression of VEGF and led to even more tumor suppression in vivo. Thus, LipoMET originated envelope-type nanoparticles may serve as a potential dual-functional siRNA delivery system to improve therapeutic effect of oncogene silencing.
authors.affiliation: Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Shi
authors.affiliation: Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Miao
authors.affiliation: Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Satterlee
authors.affiliation: Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Haynes
authors.affiliation: Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Luo
authors.affiliation: Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Musetti
authors.affiliation: Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: leafh@unc.edu.
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008687:Metformin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D034741:RNA, Small Interfering; D017480:Receptors, sigma; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D006820:Hyaluronic Acid; D008687:Metformin; D002784:Cholesterol
keywords: cancer therapy; envelope-type nanoparticle; fusogenic liposome; metformin; siRNA delivery