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

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.

Evaluation of intestinal permeation enhancement with carboxymethyl chitosan-rhein polymeric micelles for oral delivery of paclitaxel.

Polymeric micelles (PMs) are currently under investigation as potential nanocarriers for oral administration of paclitaxel (PTX). Previously, we developed amphiphilic carboxymethyl chitosan-rhein (CR) conjugate for oral delivery of PTX. PTX-loaded CR PMs exhibited a homogeneous and small size (<200 nm) with a drug loading capacity (DL) of 35.46 ±â€¯1.07%. However, The absorption parameters of PTX using CR PMs have not been studied before. Here, we evaluated the intestinal permeation of CR PMs by in situ intestinal absorption experiments. PTX-loaded CR PMs enhanced the absorption of PTX in the intestine without causing significant intestinal villi injury. Compared to the P-glycoprotein (P-gp) inhibition of verapamil, the transport mechanism of CR PMs across intestinal epithelial cells may bypass P-gp efflux. Caco-2 cell uptake assays also confirmed that CR PMs can be taken up into the enterocyte as whole and independent of P-gp. Local biodistribution evaluation showed that fluorescence-labeled CR PMs were absorbed into the intestinal villi. In vivo bioimaging of tumor-bearing mice verified a significant portion of CR PMs were intactly absorbed through the intestine, then distributed and accumulated at the tumor site. For their significant intestinal permeation enhancement, CR PMs might be considered as promising oral delivery carriers for PTX and other water-insoluble drugs.

Preparation and evaluation of carboxymethyl chitosan-rhein polymeric micelles with synergistic antitumor effect for oral delivery of paclitaxel.

An amphiphilic carboxymethyl chitosan-rhein (CR) conjugate was prepared, characterized, and evaluated as a potential carrier material for oral delivery of paclitaxel (PTX). CR conjugate self-assembled in aqueous environment into CR polymeric micelles (CR PMs). The drug loading capacity and entrapment efficiency of PTX-loaded CR PMs were 35.24 ± 1.58% and 86.99 ± 12.26%, respectively. Pharmacokinetic results indicate that PTX-loaded CR PMs could significantly enhance the oral bioavailability of PTX. Confocal imaging of intestinal sections verified many of CR PMs were absorbed as whole through the intestinal membrane. The cytotoxicity assays in Caco-2 cells and in vivo antitumor efficacy showed that PTX-loaded CR PMs had a stronger antitumor efficacy. A synergistic antitumor effect between CR conjugate and PTX was proven in MCF-7 cells and antitumor efficacy studies. The investigation of CR conjugate developed in this study showed that CR PMs are promising for oral delivery of water-insoluble antitumor drugs.