[Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid].
For successful cancer gene therapy via intravenous administration, it is essential to optimize the stability of carriers in the systemic circulation and the cellular association after the accumulation of the carrier in tumor tissue. However, a dilemma exists regarding the use of poly(ethylene glycol) (PEG), which is useful for conferring stability in the systemic circulation, but is undesirable for the cellular uptake and subsequent processes. We report the development of a PEG-peptide-lipid ternary conjugate (PPD). In this strategy, PEG is removed from the carriers via cleavage by a matrix metalloproteinase (MMP), which is specifically expressed in tumor tissues. An in vitro study revealed that the PPD-modified gene carrier (multifunctional envelope-type nano device, MEND) exhibited pDNA expression activity that was dependent on the MMP expression level in the host cells. In vivo studies further revealed that the PPD was potent in stabilizing MEND in the systemic circulation and facilitating tumor accumulation. Moreover, the intravenous administration of PPD or PEG/PPD dually modified MEND resulted in the stimulation of pDNA expression in tumor tissue, as compared with a conventional PEG-modified MEND. Thus MEND modified with PPD is a promising device with the potential to make in vivo cancer gene therapy achievable.
Hatakeyama
Hiroto
H
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Sapporo 060-0812, Japan. hiroto@pharm.hokudai.ac.jp
Akita
Hidetaka
H
Kogure
Kentaro
K
Harashima
Hideyoshi
H
D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008055:Lipids; D020782:Matrix Metalloproteinases; D053758:Nanoparticles; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000628:therapy*; D010455:Peptides; D011092:Polyethylene Glycols / Q000378:metabolism
D008055:Lipids; D010455:Peptides; D011092:Polyethylene Glycols; D020782:Matrix Metalloproteinases