Metalloprotease-specific poly(ethylene glycol) methyl ether-peptide-doxorubicin conjugate for targeting anticancer drug delivery based on angiogenesis.
This article proposes a novel cancer-targeting drug-delivery system based on angiogenesis, in which the enzymatic activity of type IV collagenases is used to cleave the inactive drug conjugate, thereby activating drug fragments. In this study, the amount and distribution of metalloprotease (MMP)-2 and MMP-9 secreted from Lewis lung carcinoma (LCC) cells and the formation of blood vessels were evaluated by gelatin zymography, in situ film zymography and immunostaining. LLC cells secreted MMP-2 and MMP-9, thereby distributing large amounts of MMPs around a solid tumor. The newly developed blood vessels were also found in a solid LLC tumor. The anticancer drug conjugate (mPEG-GPLGV-DOX) was synthesized by conjugating doxorubicin with Gly-Pro-Leu-Gly-Val (GPLGV) peptide and poly(ethylene glycol) methyl ether (mPEG). GPLGV pentapeptide was used as a substrate for MMP-2 and MMP-9, where the cleavage of Gly-Val bond by MMP was expected. In addition, mPEG was grafted to peptide-doxorubicin conjugate to increase the circulation time in the body and to reduce the cytotoxicity of the anticancer drug. The mPEG-GPLGV-DOX conjugate formed a micelle structure in aqueous solution, with a critical micelle concentration (CMC) of about 0.25 mg/ml and a diameter of 73.1 +/- 12.7 nm at 1 mg/ml. In an in vivo experiment, mPEG-GPLGV-DOX showed 20% chemotherapeutic activity compared with free doxorubicin. Although a 50 mg/kg dose of mPEG-GPLGV-DOX showed similar therapeutic effects to a 10 mg/kg dose of doxorubicin, the life span of mice in the conjugate group was significantly increased. Therefore, an efficient anticancer drug-delivery system could be created by increasing therapeutic efficiency and decreasing drug-toxicity by optimizing the degradation rate of the peptide link by MMP and circulation time in the body.
Bae
M
M
Department of Materials Science and Engineering, Kwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Korea.
Cho
S
S
Song
J
J
Lee
G Y
GY
Kim
K
K
Yang
J
J
Cho
K
K
Kim
S Y
SY
Byun
Y
Y
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry*; D016503:Drug Delivery Systems; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D009842:Oligopeptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D008823:Micelles; D009842:Oligopeptides; D011355:Prodrugs; D011092:Polyethylene Glycols; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9