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

Folate receptor alpha (FRα) 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 β‐CyD (Fol‐c(1)‐β‐CyD) was developed as an FRα‐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‐c(1)‐β‐CyD (PTX/Fol‐c(1)‐β‐CyD) in EOC‐derived cell lines. We found that PTX/Fol‐c(1)‐β‐CyD killed not only FRα‐expressing cells but also FRα‐negative cells. In the FRα‐negative A2780 cells, knockdown of proton‐coupled folate transporter (PCFT) significantly decreased the cytotoxicity of PTX/Fol‐c(1)‐β‐CyD, whereas knockdown of FRα did not. By contrast, knockdown of either FRα or proton‐coupled folate transporter (PCFT) decreased the cytotoxicity of PTX/Fol‐c(1)‐β‐CyD in FRα‐expressing SK‐OV‐3 cells. Furthermore, the cytotoxicity of PTX/Fol‐c(1)‐β‐CyD in A2780 cells was increased at acidic pH, and this increase was suppressed by PCFT inhibitor. In mice intraperitoneally inoculated with FRα‐expressing or PCFT‐expressing EOC cells, intraperitoneal administration of PTX/Fol‐c(1)‐β‐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‐c(1)‐β‐CyD targets not only FRα but also PCFT, and can efficiently deliver anticancer drugs to EOC cells in the peritoneal cavity.