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Cationic polymers have been studied as promising nonviral gene delivery vectors. In contrast to the conventional polycations with long sequences of covalently bonded repeating units, we have developed a series of novel cationic polyrotaxanes consisting of multiple oligoethyleneimine-grafted β-cyclodextrin rings threaded on a poly(ethylene glycol)−poly(propylene glycol)−poly(ethylene glycol) triblock copolymer chain. In this study, these cationic polyrotaxanes with different oligoethyleneimine chain lengths were investigated for DNA binding ability, cytotoxicity, and gene transfection efficiency in cancer cells. Fluorescent titration assay results indicated that all the polyrotaxanes could completely condense plasmid DNA and form stable complexes at N/P ratio of 2, where the N/P ratio is the molar ration of amine groups in the cationic molecule to phosphate groups in the DNA. Particularly, tapping mode AFM imaging in aqueous environment was conducted to observe the morphology of the polyrotaxane/DNA complexes and their formation processes in real time. In both SK-OV-3 and PC3 cancer cells, these polyrotaxanes showed low cytotoxicity and high transfection efficiency which is comparable to or significantly higher than that of high molecular weight branched polyethylenimine (25 kDa), one of the most effective gene-delivery polymers studied to date. In addition, the synthesized polyrotaxanes displayed sustained gene delivery capability in PC3 cells in the presence or absence of serum. Therefore, these cationic polyrotaxanes with strong DNA binding ability, low cytotoxicity, and high and sustained gene delivery capability have a high potential as novel nonviral gene carriers in clinical cancer gene therapy. [ABSTRACT FROM AUTHOR]

Under evolutionary pressure from chemotherapy, cancer cells develop resistance characteristics such as a low redox state, which eventually leads to treatment failures. An attractive option for combatting resistance is producing a high concentration of produced free radicals in situ. Here, we report the production and use of dispersible hollow carbon nanospheres (HCSs) as a novel platform for delivering the drug doxorubicine (DOX) and generating additional cellular reactive oxygen species using near-infrared laser irradiation. These irradiated HCSs catalyzed sufficiently persistent free radicals to produce a large number of heat shock factor-1 protein homotrimers, thereby suppressing the activation and function of resistance-related genes. Laser irradiation also promoted the release of DOX from lysosomal DOX@HCSs into the cytoplasm so that it could enter cell nuclei. As a result, DOX@HCSs reduced the resistance of human breast cancer cells (MCF-7/ADR) to DOX through the synergy among photothermal effects, increased generation of free radicals, and chemotherapy with the aid of laser irradiation. HCSs can provide a unique and versatile platform for combatting chemotherapy-resistant cancer cells. These findings provide new clinical strategies and insights for the treatment of resistant cancers. [ABSTRACT FROM AUTHOR]

c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of p-p stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development. [ABSTRACT FROM AUTHOR]