Reduction of polyethylenimine-coated iron oxide nanoparticles induced autophagy and cytotoxicity by lactosylation

Superparamagnetic iron oxide(SPIO)nanoparticles are excellent magnetic resonance contrast agents and surface engineering can expand their applications.When covered with amphiphilic alkyl-polyethyleneimine(PEI),the modified SPIO nanoparticles can be used as MRI visible gene/drug delivery carriers and cell tracking probes.However,the positively charged amines of PEI can also cause cytotoxicity and restricts their further applications.In this study,we used lactose to modify amphiphilic low molecular weight polyethylenimine(C_(12-)PEI_(2K))at different lactosylation degree.It was found that the N-alkyl-PEI-lactobionic acid wrapped SPIO nanocomposites show better cell viability without compromising their labelling efficacy as well as MR imaging capability in RAW 264.7 cells,comparing to the unsubstituted ones.Besides,we found the PEI induced cell autophagy can be reduced via lactose modification,indicating the increased cell viability might rely on down-regulating autophagy.Thus,our findings provide a new approach to overcome the toxicity of PEI wrapped SPIO nanocomposites by lactose modification.

Iron oxide nanoparticles promote vascular endothelial cells survival from oxidative stress by enhancement of autophagy

Dextran-coated superparamagnetic iron oxide nanoparticles(Dex-SPIONs)are excellent magnetic resonance imaging contrast agents for disease diagnosis and therapy.They can be delivered to target tissues mainly though vascular endothelium cells,which are major targets of oxidative stress.In cardiovascular cells,autophagy serves primarily on a pro-survival approach that protects the cells from oxidative stress even some autophagy inducers have been developed for adjuvant therapy of cardiovascular disorders.Our study demonstrated that the nanoparticles could be taken up by human umbilical vein endothelial cells(HUVECs)without causing obvious cytotoxicity but triggering autophagy.Furthermore,our results revealed that Dex-SPIONs could enhance HUVECs survival and reverse the reduction of nitric oxide secretion under the condition of H2O2 damage.However,these effects could be diminished by the autophagy inhibitor.In particular,we discovered that Dex-SPIONs evoked autophagy in HUVECs by reducing the phosphorylation of PRAS40,an upstream regulator of autophagy initiation.These results suggested that Dex-SPIONs functions as an autophagic-related antioxidant in HUVECs which may be utilized as an adjuvant therapy to cardiovascular disease associated with oxidative stress.