Biotin-mediated drug delivery: does the biotin transporter mediate uptake of biotin conjugates?

Sodium-dependent multivitamin transporter (SMVT) is a biotin transporter over-expressed in various types of cancer cells and is commonly studied for targeted drug delivery using biotin conjugates. However, such conjugates lack the carboxyl group needed for recognition by SMVT. Previously, we proposed that SMVT is unlikely the transporter of biotin conjugates. To experimentally assess this hypothesis, we examined intracellular enrichment and activation of the biotin-conjugated version of a well-established CO prodrug pair in cell culture. Although prodrug enrichment in SMVT-over-expressing cells was observed, this enrichment was not affected by excess biotin, indicating the lack of competition for SMVT. Additionally, two biotin analogs lacking the carboxyl group exhibited either augmentative or inhibitory effects depending on specific structural features. These findings support the notion that SMVT is not the transporter of biotin conjugates and underscore the need for further mechanistic studies of the transport mechanism(s) of biotin conjugates.