TY - JOUR
T1 - Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid
AU - Hatakeyama, Hiroto
AU - Akita, Hidetaka
AU - Kogure, Kentaro
AU - Harashima, Hideyoshi
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2007/10
Y1 - 2007/10
N2 - 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.
AB - 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.
KW - Cancer gene therapy
KW - Cleavable PEG system
KW - Matrix metalloproteinase
KW - Multifunctional envelope-type nano device (MEND)
KW - Systemic gene delivery
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U2 - 10.1248/yakushi.127.1549
DO - 10.1248/yakushi.127.1549
M3 - Review article
C2 - 17917417
AN - SCOPUS:34848844320
SN - 0031-6903
VL - 127
SP - 1549
EP - 1556
JO - Yakugaku Zasshi
JF - Yakugaku Zasshi
IS - 10
ER -