Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2487965 | Journal of Pharmaceutical Sciences | 2006 | 10 Pages |
Abstract
Folate receptor (FR) has been proposed as a promising target for tumor drug targeting. The aim of this study was to increase the chemoâsensitivity of FRâpositive cells to doxorubicin by folateâdirected enzyme prodrug therapy (FDEPT). Folate conjugated penicillinâG amidase was prepared and its ability to hydrolyze Nâ(phenylacetyl) doxorubicin was measured by HPLC. Fluorescence and confocal image analysis revealed that FolateâPGA can be specifically delivered into FRâpositive HeLa and SKOV3 tumor cells. In vitro cytotoxity assays, IC50 was reduced with Nâ(phenylacetyl) doxorubicin versus doxorubicin for HeLa (3.1âfold reduction; pâ<â0.001) and SKOV3 (3.3âfold reduction; pâ<â0.001) when FolateâPGA was specifically bound to the cells. Complete activation was confirmed in HeLa and SKOV3 cells pretreated with free folic acid (1 mM), where the combination of Nâ(phenylacetyl) doxorubicin with FolateâPGA did not show any significant cell toxicity to the IC50 of doxorubicin. Pharmacokinetic clearance and biodistribution studies in vivo showed that 125IâFolateâPGA was cleared from blood within 24 h and had significantly higher tumor uptake compared to 125IâPGA (pâ<â0.05). These results demonstrate that the FDEPT approach may be a potential promising strategy to improve chemotherapyâresistant cancers therapeutic ratio and warranted future studies.
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Authors
Q.i. Zhang, Guangya Xiang, Youjiu Zhang, Keya Yang, W.o. Fan, Jialiang Lin, Fanbo Zeng, Jizhou Wu,