title: Dual-modified liposomes with a two-photon-sensitive cell penetrating peptide and NGR ligand for siRNA targeting delivery.
abstract: Tumor-oriented nanocarrier drug delivery approaches with photosensitivity have drawn considerable attention over the years. However, due to its low penetrability and ability to harm tissues, the use of UV light for triggered nanocarrier release in in vivo applications has been limited. Compared with UV light, near-infrared (NIR) light deeply penetrates tissues and is less damaging to cells. In this study, we devised and tested a strategy for functional siRNA delivery to cells by loading siRNA into cationic liposomes bearing a photolabile-caged cell-penetrating peptide (pcCPP) and asparagine-glycine-arginine peptide (NGR) molecules attached to the liposome surface (pcCPP/NGR-LP). Here, the positive charges of the lysine residues on the CPP were temporarily caged by the photosensitive group (PG), neutralizing its charges and thereby forming a pcCPP. This event subsequently led to conditional NIR light-dependent cell-penetrating functionality. After administration, the pcCPP/NRG-LP was inactivated in the circulatory system as it could not penetrate the tumor cell membrane. The NGR moiety selectively bound to CD13-positive tumors, which facilitated the active accumulation of pcCPP/NGR-LP in tumor tissues. Then, upon illumination using NIR light at the tumor site, the PG was uncaged, the interaction of the CPP with the cell membrane was restored and the activated dual-modified liposomes exhibited enhanced tumor cellular uptake and selectivity due to the synergistic effect of CPP-mediated cellular entry and NGR-mediated endocytosis. Subsequent research demonstrated that the pcCPP/NGR-LP showed good physicochemical properties, effective cellular uptake, endosomal escape and significant gene silencing in HT-1080 cells in vitro. Additionally, after systemic administration in mice, pcCPP/NGR-LP accumulated in the tumor, augmented c-myc silencing and delayed tumor progression. In conclusion, the combined application of these pcCPP and NGR modifications may provide a reasonable approach for the selectively targeted delivery of siRNA.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
authors.forename: YanFang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China; Wuhan General Hospital of Guangzhou Military Command, Wuhan 430070, China.
authors.forename: XiangYang
authors.initials: X
authors.lastname: Xie
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
authors.forename: ZhiYuan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
authors.forename: FangLin
authors.initials: F
authors.lastname: Yu
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
authors.forename: ZhiPing
authors.initials: Z
authors.lastname: Li
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China. Electronic address: amms2013@126.com.
authors.forename: XingGuo
authors.initials: X
authors.lastname: Mei
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008024:Ligands; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D017785:Photons; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D057846:Cell-Penetrating Peptides; D008024:Ligands; D008081:Liposomes; D009842:Oligopeptides; D034741:RNA, Small Interfering
keywords: Cell-penetrating peptides; NGR-targeted; Near-infrared (NIR) two-photon photolysis; Small interfering RNA