Evaluation and antitumor mechanism of functionalized chitosan-based polymeric micelles for oral delivery of paclitaxel

• Published in: International journal of pharmaceutics 2022-09, Vol.625, p.122138-122138, Article 122138
• Main Authors: Wang, Xiaoying, Zheng, Yaling, Qiu, Liangzhen, Ouyang, Huizhi, Xu, Xueya, Xu, Wen, Zhang, Yuqin, Xu, Wei
• Format: Article
• Language: English
• Subjects: Carboxymethyl chitosan; Oral drug delivery; Paclitaxel; Polymeric micelles; Zebrafish xenograft model
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2022.122138

[Display omitted] •The chitosan-based polymeric micelles were constructed for oral drug delivery.•The micelles displayed a high drug loading capacity and P-gp inhibition function.•Zebrafish models were used to reveal the antitumor efficacy and mechanism of the micelles.•The chitosan-based conjugate can inhibit P-gp activity and P-gp and MDR1 expression. 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.