Loading docetaxel in β-cyclodextrin-based micelles for enhanced oral chemotherapy through inhibition of P-glycoprotein mediated efflux transport

Abstract

Oral administration of BCS Class IV drugs still faces great challenges owing to their poor dissolubility in the gastro-intestinal (GI) tract and low permeation capacity across the GI membrane. Here, we constructed a β-cyclodextrin-based polymeric micelle (PELC) to effectively deliver docetaxel (DTX), a typical BCS Class IV drug, by oral administration. Cellular uptake and bidirectional transport studies of PELC/DTX on MDCK-MDR1 cells revealed significantly enhanced absorption of DTX through inhibition of P-glycoprotein mediated efflux. In vivo pharmacokinetic studies showed that the relative oral bioavailability of PELC/DTX was 4.6-fold higher than free DTX. Correspondingly, orally administered PELC/DTX achieved superior anti-cancer efficacy against mouse sarcoma 180 tumor in vivo than free DTX with decreased subacute toxicity. Furthermore, we confirmed the vital effect of β-cyclodextrin on various functions of PELC throughout this study. These findings indicate that PELC copolymer displays great potential for the effective oral delivery of DTX.