Peptide-doxorubicin conjugates specifically degraded by matrix metalloproteinases expressed from tumor

초록

Specific peptide-doxorubicin conjugates were developed for targeting matrix metalloproteinases (MMPs) expressed from tumors. The pepticle-doxorubicin conjugates were designed to be cleaved by MMP-2 and MMP-9 in order that doxorubicin or the active form that acts as an anticancer agent was released free from the peptide fragment at the tumor site. Three types of peptide-doxorubicin conjugates were synthesized using the peptides: GPLG (Gly-Pro-Leu-Gly), GPLGV (Gly-Pro-Leu-Gly-Val), and GPLGPAG (Gly-Pro-Leu-Gly-Pro-Ala-Gly). The synthesized pepticle-doxorubicin conjugates were characterized for their degradation behavior and bioactivity in vitro, and their antitumoral activity was assessed using the Lewis lung carcinoma (LLC) model, which expresses MMP-2 and MMP-9. After incubation with active MMP-2 for 24h, GPLG-doxorubicin was barely degraded, whereas GPLGV-doxorubicin and GPLGPAG-doxorubicin were considerably degraded by active MMP-2. Consequently, all pepticle-doxorubicin conjugates had significantly low cytotoxicity compared to doxorubicin, but tumor growth suppression was exhibited only by GPLGV-doxorubicin and GPLGPAG-doxorubicin. The tumor growth suppression by the two conjugates was higher compared to control, although it did not exceed the suppression level shown by doxorubicin. The low toxicity exhibited by pepticle-doxorubicin conjugates resulted in only slight body weight loss in mice, whereas doxorubicin greatly reduced body weight and induced severe side effects. Therefore, we propose MMPs-specific peptide-doxorubicin conjugates in targeting anti-cancer drug delivery that could reduce systemic toxicities.

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