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Novel glutathione (GSH)-dependent micelles based on carboxymethyl chitosan (CMCS) were developed for triggered intracellular release of doxorubicin (DOX). DOX-33′-Dithiobis (N-hydroxysuccinimidyl propionate)-CMCS (DOX-DSP-CMCS) prodrugs were synthesized. DOX was attached to the amino group on CMCS via disulfide bonds and drug-loaded micelles were formed by self-assembly. The micelles formed core–shell structure with CMCS and DOX as the shell and core, respectively, in aqueous media. The structure of the prodrugs was confirmed by IR and proton nuclear magnetic resonance (1H NMR) spectroscopy. The drug-loading capacity determined by UV spectrophotometry was 4.96% and the critical micelle concentration of polymer prodrugs determined by pyrene fluorescence was 0.089 mg/mL. Micelles were spherical and the mean size of the nanoparticles was 174 nm, with a narrow polydispersity index of 0.106. Moreover,in vitrodrug release experiments showed that the micelles were highly GSH-sensitive owing to the reductively degradable disulfide bonds. Cell counting kit (CCK-8) assays revealed that DOX-DSP-CMCS micelles exhibited effective cytotoxicity against HeLa cells. Moreover, confocal laser scanning microscopy (CLSM) demonstrated that DOX-DSP-CMCS micelles could efficiently deliver and release DOX in the cancer cells. In conclusion, the DOX-DSP-CMCS nanosystem is a promising drug delivery vehicle for cancer therapy. [ABSTRACT FROM AUTHOR]

The delivery of combination chemotherapy by nanoscale platforms has been demonstrated to enhance cancer treatment in the clinic. Cisplatin (CDDP)-crosslinked, glutathione-sensitive, tumor-targeting micelles based on carboxymethyl chitosan were designed for synergistic cisplatin-doxorubicin (DOX) combination chemotherapy. In our study, DOX was conjugated to carboxymethyl chitosan through a disulfide bond, which was structurally characterized by 1 H NMR. The micelles formed by self-assembly were spherical, with the mean diameter of 274 nm. The in vitro release studies revealed that the micelles were highly glutathione-sensitive. Cytotoxicity analysis demonstrated that the cisplatin-crosslinked micelles loaded with DOX exhibited enhanced therapeutic efficacy compared with the DOX-loaded nanoparticles, free DOX, and free CDDP. Cellular uptake and intracellular release revealed that the cisplatin-crosslinked micelles loaded with DOX could efficiently deliver and release DOX into the cancer cells. These results clearly indicate that tumor-targeting and glutathione-sensitive micelles provide means for combination drug delivery in cancer treatment. [ABSTRACT FROM AUTHOR]

Abstract: The liver targeting and controlled release nanoparticles based on carboxymethyl chitosan derivatives were prepared: firstly, novel thiolated lactosaminated carboxymethyl chitosan (LAC-CMC) was synthesized, its chemical structure was characterized by 1H NMR spectroscopy. Then, glycyrrhizic acid was chosen as model drug and encapsulated within thiolated LAC-CMC nanoparticles through ionic gelification. The crosslinked glycyrrhizic acid-loaded nanoparticles dissociated to release drug in the presence of glutathione (GSH) at a concentration comparable to the intracellular environment, featuring the potential ability of this system for intracellular delivery. Crosslinked nanoparticles modify the tissue distribution profile of the glycyrrhizic acid solution, the kidney excretion rate is reduced and the drug accumulation in the liver is increased. According to these results, the nanoparticles have the potential to be used as drug delivery system with hepatic targeting and controlled release properties. [Copyright &y& Elsevier]