Folate-appended cyclodextrin carrier targets ovarian cancer cells expressing the proton-coupled folate transporter.

ABSTRACT: Folate receptor alpha (FR?) is overexpressed in >80% of epithelial ovarian cancer (EOC). Accordingly, folate is attracting attention as a targeting ligand for EOC. For EOC patients, paclitaxel (PTX) is generally used as a first-line chemotherapeutic agent in combination with platinum-based drugs. Cyclodextrin (CyD) is a potential new formulation vehicle for PTX that could replace Cremophor-EL, a traditional formulation vehicle that causes significant side effects, including neutropenia. Several years ago, folate-appended ?-CyD (Fol-c1 -?-CyD) was developed as an FR?-targeting drug carrier, but its efficacy as a treatment for EOC remains to be determined. In this study, we assessed the antitumor activity of PTX in Fol-c1 -?-CyD (PTX/Fol-c1 -?-CyD) in EOC-derived cell lines. We found that PTX/Fol-c1 -?-CyD killed not only FR?-expressing cells but also FR?-negative cells. In the FR?-negative A2780 cells, knockdown of proton-coupled folate transporter (PCFT) significantly decreased the cytotoxicity of PTX/Fol-c1 -?-CyD, whereas knockdown of FR? did not. By contrast, knockdown of either FR? or proton-coupled folate transporter (PCFT) decreased the cytotoxicity of PTX/Fol-c1 -?-CyD in FR?-expressing SK-OV-3 cells. Furthermore, the cytotoxicity of PTX/Fol-c1 -?-CyD in A2780 cells was increased at acidic pH, and this increase was suppressed by PCFT inhibitor. In mice intraperitoneally inoculated with FR?-expressing or PCFT-expressing EOC cells, intraperitoneal administration of PTX/Fol-c1 -?-CyD significantly suppressed the growth of both types of EOC cells relative to PTX alone, without inducing a significant change in the neutrophil/white blood cell ratio. Our data suggest that Fol-c1 -?-CyD targets not only FR? but also PCFT, and can efficiently deliver anticancer drugs to EOC cells in the peritoneal cavity.

SUBMITTER: Saito S 

PROVIDER: S-EPMC7226238 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature