Tumor-targeted paclitaxel delivery and enhanced penetration using TAT-decorated liposomes comprising redox-responsive poly(ethylene glycol).
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.
['Fu|Han|H|', 'Shi|Kairong|K|', 'Hu|Guanlian|G|', 'Yang|Yuting|Y|', 'Kuang|Qifang|Q|', 'Lu|Libao|L|', 'Zhang|Li|L|', 'Chen|Wenfei|W|', 'Dong|Mingling|M|', 'Chen|Yantao|Y|', 'He|Qin|Q|']
D000818:Animals D000972:Antineoplastic Agents, Phytogenic D045744:Cell Line, Tumor D002463:Cell Membrane Permeability D049109:Cell Proliferation D057846:Cell-Penetrating Peptides D002626:Chemistry, Pharmaceutical D004305:Dose-Response Relationship, Drug D005978:Glutathione D008055:Lipids D008081:Liposomes D008297:Male D008546:Melanoma, Experimental D008810:Mice, Inbred C57BL D036103:Nanotechnology D010084:Oxidation-Reduction D017239:Paclitaxel D011092:Polyethylene Glycols D013678:Technology, Pharmaceutical D054322:tat Gene Products, Human Immunodeficiency Virus
paclitaxel liposomes TAT cleavable PEG cancer exogenous glutathione nanotechnology pegylation safety evaluation targeted drug delivery