The development of stimuli-responsive polymeric micelles for targeted drug delivery has attracted much research interest in improving therapeutic outcomes. This study designs copolymers responsive to ultraviolet (UV) light and glutathione (GSH). A disulfide linkage is positioned between a hydrophilic poly(ethylene glycol) monomethyl ether (mPEG) and a hydrophobic o-nitrobenzyl methacrylate (ONBMA) to yield amphiphilic copolymers termed mPEG-SS-pONBMA. Three copolymers with different ONBMA lengths are synthesized and formulated into micelles. An increase in particle size and a decrease in critical micelle concentration go together with increasing ONBMA lengths. The ONB cleavage from mPEG-SS-pONBMA-formed micelles results in the transformation of hydrophobic cores into hydrophilic ones, accelerating drug release from the micelles. Obvious changes in morphology and molecular weight of micelles upon combinational treatments account for the dual-stimuli responsive property. Enhancement of a cell-killing effect is clearly observed in doxorubicin (DOX)-loaded micelles containing disulfide bonds compared with those containing dicarbon bonds upon UV light irradiation. Collectedly, the dual-stimuli-responsive mPEG-SS-pONBMA micelle is a better drug delivery carrier than the single-stimuli-responsive mPEG-CC-pONBMA micelle. After HT1080 cells were treated with the DOX-loaded micelles, the high expression levels of RIP-1 and MLKL indicate that the mechanism involved in cell death is mainly via the DOX-induced necroptosis pathway.
Major depressive disorder (MDD) is one of the most common psychiatric disorders, and frequently co‐occurs with multiple comorbidities, especially Type 2 diabetes mellitus. Selective serotonin reuptake inhibitors (SSRIs) are the most widely used class of antidepressants. This study aimed to investigate the effects of fluoxetine (Prozac®), a SSRIs, on metabolic abnormalities induced by chronic high‐fat diet (HDF). Male HDF‐induced insulin resistance mice were administrated with fluoxetine (10 mg/kg and 20 mg/kg) by intraperitoneal injection for four weeks. The behavioral tests showed that fluoxetine significantly reversed the depressive‐like behaviors induced by chronic HDF, including the reduced sucrose preference and increased immobility time in the forced swimming test and tail suspension test. Moreover, fluoxetine also reduced serum level of glucose and improved blood lipid profiles in HFD‐treated mice. Furthermore, fluoxetine improved impaired glucose tolerance and insulin sensitivity. Our results indicated that fluoxetine could ameliorate depressive‐like behaviors and metabolic abnormalities induced by chronic HFD, which suggested that the multiple effects of fluoxetine could be beneficial for patients with depression and/or metabolic syndrome.Support or Funding InformationThis work is supported by Ministry of Science and Technology, Taiwan (MOST 106‐2320‐B‐006‐058‐MY3)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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