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This study developed novel stimuli responsive injectable hydrogels composed of a biocompatible and anti-adhesive cartilage acellularized matrix (CAM) and a diselenide bridge-containing cross-linker by using norbornene (Nb)-tetrazine (Tz) click chemistry. The crosslinking reaction between CAM-Nb and the Tz-cross-linker evolved nitrogen gas and resulted in injectable hydrogels with highly porous structures. The synthesized hydrogels demonstrated high drug loading efficiencies, good swelling ratios, and better rheological properties. The doxorubicin (DOX)-loaded hydrogels released minimal amounts of DOX in simulated physiological medium, however, sustained release of DOX was detected in reducing conditions, revealing more than 90% DOX release after 96 h. Interestingly, the indocyanine green (ICG) incorporated hydrogels produced reactive oxygen species upon exposure to NIR light and exhibited burst release (> 50% DOX release) of DOX during the first 4 h, followed by a sustained release phase. The in vitro biocompatibility studies showed that the synthesized CAM-Nb and hydrogels are essentially non-toxic to human fibroblast cells and human colorectal adenocarcinoma cells. Furthermore, DOX-loaded and DOX+ICG-loaded hydrogels inhibited the metabolic activities of cancer cells after glutathione (GSH) or NIR exposure, and induced anti-tumor effects, which were similar to that of the DOX only. And we expand to in vivo studies. Results showed that NIR exposed ICG and DOX loaded hydrogels have thermal effect and suppressive tumor growing. Therefore, these cartilage extracellular matrix and click chemistry complex injectable hydrogels could be promising candidates for minimally invasive local delivery of cancer therapeutics.
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