Enhanced transfection of tumor cells in vivo using "Smart" pH-sensitive TAT-modified pegylated liposomes.
Liposomes have been prepared loaded with DNA (plasmid encoding for the green fluorescent protein, GFP) and additionally modified with TATp and PEG, with PEG being attached to the liposome surface via both pH-sensitive hydrazone and non-pH-sensitive bonds. The pGFP-loaded liposomal preparations have been administered intratumorarly in tumor-bearing mice and the efficacy of tumor cell transfection was followed after 72 h. The administration of pGFP-TATp-liposomes with non-pH-sensitive PEG coating has resulted in only minimal transfection of tumor cells because of steric hindrances for the liposome-to-cell interaction created by the PEG coat, which shielded the surface-attached TATp. At the same time, the administration of pGFP-TATp-liposomes with the low pH-detachable PEG resulted in at least three times more efficient transfection since the removal of PEG under the action of the decreased intratumoral pH leads to the exposure of the liposome-attached TATp residues, enhanced penetration of the liposomes inside tumor cells and more effective intracellular delivery of the pGFP. This result can be considered as an important step in the development of tumor-specific stimuli-sensitive drug and gene delivery systems.
Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
Amit A
AA
Kale
Vladimir P
VP
Torchilin
D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D015696:Gene Products, tat / Q000737:chemistry; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000008:administration & dosage; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D049408:Luminescent Agents / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D010539:Permeability; D010957:Plasmids / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000737:chemistry; D014162:Transfection / Q000379:methods*
D015696:Gene Products, tat; D008081:Liposomes; D049408:Luminescent Agents; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D004247:DNA