title: A dual-mediated liposomal drug delivery system targeting the brain: rational construction, integrity evaluation across the blood-brain barrier, and the transporting mechanism to glioma cells.
abstract: As the global population ages, cancer rates increase worldwide, and degenerative diseases of the central nervous system (CNS), brain tumors, and inflammation threaten human health more frequently. We designed a dual-mediated (receptor-mediated and adsorption-mediated) liposome, named transferrin-cell penetrating peptide-sterically stabilized liposome (TF-CPP-SSL), to improve therapy for gliomas through combining molecular recognition of transferrin receptors (TF-Rs) on the blood-brain barrier (BBB) and glioma cells with the internalization and lysosomal escaping ability of CPP. Based on the systematic investigation of structure-activity relations on the cellular level, we constructed TF-CPP-SSL rationally by conjugating TF and CPP moieties to the liposomes via PEG3.4Kand PEG2.0K, respectively, and found the optimum densities of TF and CPP were 1.8% and 4%, respectively. These liposomes had the highest targeting efficacy for brain microvascular endothelial cell and C6 cell uptake but avoided capture by normal cells. Fluorescence resonance energy transfer technology and coculture models of BBB and glioma C6 cells indicated that TF-CPP-SSL was transported across the BBB without drug leakage, liposome breakup, or cleavage of ligand. TF-CPP-SSL offered advantages for crossing the BBB and entering into glioma C6 cells. Real-time confocal viewing revealed that TF-CPP-SSL was entrapped in endosomes of glioma C6 cells and then escaped from lysosomes successfully to release the liposomal contents into the cytosol. Entrapped contents, such as doxorubicin, could then enter the nucleus to exert pharmacological effects.
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Xiao-Na
authors.initials: XN
authors.lastname: Liu
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Gui-Ling
authors.initials: GL
authors.lastname: Wang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hei
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Shuai
authors.initials: S
authors.lastname: Meng
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Ling-Fei
authors.initials: LF
authors.lastname: Yang
authors.affiliation: Medical and Healthy Analysis Center, Peking University, Beijing, People's Republic of China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism
chemical_list: D057846:Cell-Penetrating Peptides; D008081:Liposomes; D014168:Transferrin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: cell-penetrating peptide; dual ligand-modified liposomes; fluorescence resonance energy transfer; real-time confocal; transferrin; tumor targeting