Hepatoma-targeting and reactive oxygen species-responsive chitosan-based polymeric micelles for delivery of celastrol.

A glycyrrhetinic acid-modified carboxymethyl chitosan-thioketal-rhein (GCTR) conjugate was designed and synthesized for the in vivo delivery of celastrol (Cela). Cela was encapsulated into polymeric micelles (PMs) formed by GCTR conjugates self-assembly in water to form Cela/GCTR PMs with high drug loading capacity and small particle size. Cela/GCTR PMs had a sustained-release characteristic in the blood environment and a rapid-release feature in the tumor microenvironment. Cela/GCTR PMs had a significant proliferation inhibitory effect on HepG2 and BEL-7402 cells, but a negligible impact on L-02 cells at low concentrations. Cela/GCTR PMs possessed reactive oxygen species (ROS)-responsive properties in vitro and in cells, could improve the bioavailability of Cela, and exert remarkable hepatoma-targeting properties. Cela/GCTR PMs could also effectively inhibit tumor growth with no apparent damage to different organs. In summary, GCTR PMs with good ROS-responsive and hepatoma-targeting properties are expected to be possible delivery carriers for hydrophobic antineoplastic drugs for hepatocellular carcinoma therapy.

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.

Signal-on fluorescence assay for pyrophosphate ions based on DNA-stabilized silver nanoclusters.

Pyrophosphate anion (P2 O7 4- , PPi) is considered as a potential biomarker for arthritic diseases because high levels of PPi may result in calcium pyrophosphate dehydrate crystal deposition diseases. In this study, a simple fluorescence method for PPi was demonstrated by organic integration of the efficient fluorescence quenching ability of copper ions to DNA-scaffolded silver nanoclusters and the strong affinity of PPi towards copper ions. This simple fluorescence sensor showed a low detection limit (0.28 µM based on signal/noise = 3) towards the detection of PPi. Practical application of this method was also validated by detection of PPi in the synovial fluid.