D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS)-modified carboxymethyl chitosan-rhein (TCR) polymeric micelles (PMs) self-assembled by TCR conjugate were constructed for oral delivery of paclitaxel (PTX). PTX-loaded TCR PMs with a drug loading capacity of 47.52 ± 1.65 % significantly improved the intestinal absorption and oral bioavailability of PTX. TCR PMs loaded with PTX displayed time- and concentration-dependent cytotoxicity in Caco-2, MCF-7 and Taxol-resistant MCF-7 (MCF-7/Taxol) cells. In MCF-7/Taxol cells, PTX-loaded TCR PMs promoted apoptosis and changed cell cycle, and TCR conjugate exhibited a P-gp inhibition ability and caused ATP depletion. Moreover, confocal imaging of intestinal sections, Caco-2 cell uptake assay and in vivo bioimaging using environmental response fluorescence probe suggested that TCR PMs loaded with drugs can be absorbed as a whole through the intestinal epithelium after oral administration, enter systemic circulation, and then get to the tumor site. Remarkably, PTX-loaded TCR PMs displayed a significant antitumor effect in H22 tumor xenograft mice and the MCF-7 or MCF-7/Taxol xenograft zebrafish model, which was related to the inhibitory function of TCR conjugate for P-gp activity and P-gp and MDR1 expression. Functionalized TCR PMs are expected to improve the oral therapeutic efficacy of poorly water-soluble antitumor drugs and treat drug-resistant tumors.
Keywords: Carboxymethyl chitosan; Oral drug delivery; Paclitaxel; Polymeric micelles; Zebrafish xenograft model.
Copyright © 2022 Elsevier B.V. All rights reserved.