期刊
MOLECULAR PHARMACEUTICS
卷 9, 期 1, 页码 168-175出版社
AMER CHEMICAL SOC
DOI: 10.1021/mp200434n
关键词
monomethylauristatin E (MMAE); prodrug; integrin; legumain; prodrug activation
资金
- US National Cancer Institute [CA120289, CA127535]
- US Department of Defense [W81XWH-09-1-0690, W81XWH-07-1-0389]
Novel monomethylauristatin E (MMAE) prodrug 8 was designed and prepared that bound cell surface glycoprotein integrin alpha v beta 3, and was activated using legumain protease as a catalyst. Upon activation, prodrug 8 strongly induced the death of MDA-MB-435 cells that express integrin alpha v beta 3 on cell surface. Efficacies of prodrug 8 were also determined in vivo using animal models of 4T1 murine breast cancer, D121 Lewis lung carcinoma, and MDA-MB-435 human breast cancer. The results demonstrated that prodrug 8 decreased tumor growth and metastasis effectively. In comparison to the parent cytotoxin, MMAE, and prodrug 3, prodrug 8 was less toxic to mouse white blood cells. The latter caused no loss in weight gain of mice at a dose 3 mg/kg, which is over 30 times in excess to MMAE (0.1 mg/kg). We hypothesize that overexpression and colocalization of integrin alpha v beta 3 and legumain protease on tumor cells, tumor vasculature, and/or tumor microenvironments can be exploited to enhance the efficacy and selectivity of potent cytotoxins, such as MMAE, which is otherwise too toxic to use for therapy.
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