title: Tumor-targeted paclitaxel delivery and enhanced penetration using TAT-decorated liposomes comprising redox-responsive poly(ethylene glycol).
abstract: To combine the advantage of poly(ethylene gylcol) (PEG) for longer circulation and cell-penetrating peptides (CPPs) for efficient cellular uptake, paclitaxel (PTX)-loaded liposomes functionalized with TAT, the most frequently used CPP, and cleavable PEG via a redox-responsive disulfide linker (PTX-C-TAT-LP) were successfully developed here. Under physiological conditions, TAT was shielded by PEG layer and liposomes exhibited a long blood circulation. At tumor site, PEG could be detached in the presence of exogenous reducing agent [glutathione (GSH)] and TAT was exposed to facilitate cell internalization. In the presence of GSH, the liposomal vesicle C-TAT-LP showed increased cellular uptake and improved three-dimensional tumor spheroids penetration in vitro compared with analogous stable shielded liposomes. C-TAT-LP achieved enhanced tumor distribution and demonstrated superior delivery efficiency in vivo. PTX-C-TAT-LP with GSH strongly inhibited the proliferation of murine melanoma B16F1 tumor cells in vitro and in vivo with the tumor inhibition rate being 69.4% on B16F1-bearing mice. In addition, the serum aspartate transaminase level, alanine transaminase level, and creatine kinase level were almost completely within normal range in the PTX-C-TAT-LP with GSH group, revealing PTX-C-TAT-LP with GSH had no obvious drug-related adverse events for liver and heart. Taken together, C-TAT-LP is a promising tumor-targeting drug carrier.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
authors.forename: Han
authors.initials: H
authors.lastname: Fu
authors.forename: Kairong
authors.initials: K
authors.lastname: Shi
authors.forename: Guanlian
authors.initials: G
authors.lastname: Hu
authors.forename: Yuting
authors.initials: Y
authors.lastname: Yang
authors.forename: Qifang
authors.initials: Q
authors.lastname: Kuang
authors.forename: Libao
authors.initials: L
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Wenfei
authors.initials: W
authors.lastname: Chen
authors.forename: Mingling
authors.initials: M
authors.lastname: Dong
authors.forename: Yantao
authors.initials: Y
authors.lastname: Chen
authors.forename: Qin
authors.initials: Q
authors.lastname: He
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D036103:Nanotechnology; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D057846:Cell-Penetrating Peptides; D008055:Lipids; D008081:Liposomes; D054322:tat Gene Products, Human Immunodeficiency Virus; D011092:Polyethylene Glycols; D005978:Glutathione; D017239:Paclitaxel
keywords: TAT; cancer; cleavable PEG; exogenous glutathione; liposomes; nanotechnology; paclitaxel; pegylation; safety evaluation; targeted drug delivery