Reactive Oxygen Species (ROS)-Degradable Polymeric Nanoplatform for Hypoxia-Targeted Gene Delivery: Unpacking DNA and Reducing Toxicity.

Smart polymers as ideal gene carriers have drawn increasing attentions due to the effective DNA release once triggered by intrinsic stimuli, as well as reduced cytotoxicity. Herein, a stimulus-responsive, positively charged and water-soluble polymer (OEI-TK x) was facilely engineered by cross-linking low molecular weight oligoethylenimine (OEI) via thioketal (TK) linkages that would cleave selectively in reactive oxygen species (ROS)-rich environments induced by hypoxia. Agarose gel electrophoresis assay demonstrated that the threshold N/P ratios for complete retardation of negatively charged DNA migration were above 5 for OEI-TK x. The reduction in DNA-condensing capability and the changes in particle size, size distribution and particle morphology all illustrated that OEI-TK x possessed excellent ROS responsiveness. OEI-TK x/DNA polyplexes showed lower toxicity and higher gene transfection efficiency compared with PEI/DNA polyplexes. The optimum formulation, OEI-TK x/DNA polyplexes (N/P = 40), showed a little better performance than PEI/DNA polyplexes in cellular uptake profile. Furthermore, OEI-TK x/DNA polyplexes could escape from endosomes to the cytosol as efficiently as PEI/DNA polyplexes. Confocal images confirmed that OEI-TK x/DNA polyplexes could more effectively release DNA than PEI/DNA polyplexes, mainly owing to the valid cleavage of thioketal linkages induced by characteristic rich-ROS in Hela cells. These results suggested that OEI-TK x could represent an on-demand stimulus-responsive gene delivery platform.

Synthesis and characterization of timolol maleate-loaded quaternized chitosan-based thermosensitive hydrogel: A transparent topical ocular delivery system for the treatment of glaucoma.

The chitosan-based thermosensitive hydrogel is one of the attractive in situ forming drug delivery systems that are suggested for ophthalmic applications. However, the use of this thermogel has been limited by non-transparency, relatively low solubility and prolonged gelation time. In this study, a convenient approach has been reported to develop transparent thermosensitive hydrogel with suitable cytocompatibility and gelation properties for glaucoma treatment. After obtaining the optimum quaternization conditions, the developed in-situ gelling formulation of quaternized chitosan was achieved by mixing sodium hydrogen carbonate with ß-glycerophosphate as a gelling agent. The formulation was a solution below or at room temperature and turned to a transparent hydrogel around ocular surface temperature within several minutes. The results of thermal and rheological evaluations demonstrated that adding sodium hydrogen carbonate has a synergic effect in enhancing the thermosensitivity of the hydrogel. Also, the prepared hydrogels based on quaternized chitosan presented obvious porous architectures, good swelling, and degradability. Hemolysis and cytotoxicity evaluations suggested that the developed hydrogels indicated good biocompatibility as a drug carrier. Finally, the in vitro release profile of timolol maleate as an anti-glaucoma model drug showed the initial burst release in the early hours and a steady linear release of drug from the hydrogel over 1 week. The obtained results confirmed that the developed hydrogel can be considered as an efficient drug delivery candidate for glaucoma therapy.

Therapeutic efficacy of thermosensitive Pluronic hydrogel for codelivery of resveratrol microspheres and cisplatin in the treatment of liver cancer ascites.

Ascites constitutes the most frequent decompensating event in patients with advanced liver cancer and is associated with poor quality of life and high mortality. Intraperitoneal chemotherapy appears to be a reliable treatment strategy for advanced liver cancer ascites. However, the rapid metabolism of drugs and ascites dilution limits the efficacy of chemotherapeutics. Therefore, the present study aimed to develop a novel thermosensitive hydrogel drug system for targeted therapy of advanced hepatocellular carcinoma (HCC) ascites through intraperitoneal administration. The system was prepared by blending resveratrol (RES) microspheres and cisplatin (DDP) into thermosensitive Pluronic F127 hydrogel. The in vitro anti-tumor activity against H22 cells indicated that the prepared drug system could initiate apoptosis and induce cell cycle arrest at the G1 phase. The mice model of ascites with advanced HCC was established to validate the therapeutic potential of the F127 hydrogel drug system in vivo. The results revealed that intraperitoneal administration of F127 hydrogel drug could significantly inhibit the number of ascites, the proliferation of tumor cells, micro-angiogenesis, and prolong the survival of mice, thus, augmenting the efficacy of intraperitoneal chemotherapy. Moreover, immunohistochemical staining revealed that the F127 hydrogel drug system was safe and presented low toxicity to major vital organs. Collectively, this study highlights the clinical application potential of the F127 hydrogel drug delivery system.