Original ArticleA new opportunity for nanomedicines: Micellar cytochrome P450 inhibitors to improve drug efficacy in a cancer therapy model

Nanomedicines are mainly used as drug delivery systems; here we evaluate a new application - to inhibit a drug's metabolism thereby enhancing its effective dose. Micelles containing the natural furanocoumarin 6′,7′-dihydroxybergamottin (DHB), a known CYP450 inhibitor, were developed to transiently block hepatic CYP450-mediated drug metabolism and increase the bioavailability of the oncology drug docetaxel. Administered in mice 24 h prior to the drug, DHB-micelles enhanced antitumor efficacy in the tumor xenograft models HT-29 and MDA-MB-231, when compared to the drug alone. These DHB-micelles have similar composition to marketed docetaxel-micelles for human use. Despite not being optimized in terms of targeting hepatocytes, they do represent the first injectable example of nanosized metabolism-blocking agents and open the way for further work on such nanomedicines in man.

To prevent the issue of extensive and variable drug metabolism between individuals, we evaluate a new concept: preparing the body to receive the drug. A nanomedicine inhibiting first-pass metabolism of the drug docetaxel in the liver is injected in tumor xenografted mice prior to the drug to enhance its efficacy.150