In situ autophagy regulation in synergy with phototherapy for breast cancer treatment

Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT.This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy.To achieve this goal,we first synthesized TRANSFERRIN(Tf)biomimetic mineralized nano-tellurium(Tf-Te)as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly.The autophagy inhibitor hydroxychloroquine(HCQ)and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ.After entering breast cancer cells through the“self-guidance system”,Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation,to efficiently induce PTT/PDT effect.Meanwhile,the disulfide bond broke down in response to GSH,and the nanoparticles disintegrated to release Fe2+and HCQ at fixed points.They simultaneously induce lysosomal alkalinization and increased osmotic pressure,effectively inhibit autophagy,and synergistically enhance the therapeutic effect of phototherapy.In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6%on 4T1 tumor-bearing mice.This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.

The“two-pronged”nanosystem to precisely improve lipid metabolism and inflammatory microenvironment for atherosclerotic plaque stabilization

The rupture of atherosclerosis(AS)vulnerable plaque is the major cause of fatal arterial thrombosis related diseases.The lipid dysbolism and pro-inflammatory microenvironment are considered two main driving factors for plaque rupture.Herein,a“two-pronged”nanosystem LCS-Se/Res was designed to efficiently stabilize AS plaques,by precisely regulating lipid metabolism and inflammatory microenvironment.LCS-Se/Res was constructed with the core of resveratrol(Res)loaded selenium(Se)nanoparticles(NPs),and the shell(LCS)of targeting peptide(LSIPPKA)modified chitosan(CS).This system was stable in blood circulation.When it arrived at the plaque site,LCS-Se/Res could actively recognize the highly expressed lectin-like oxidized low-density lipoprotein receptor 1(LOX-1)receptor and accumulate there.Thereafter,Res was released from LCS-Se nanocarriers in situ by responding to acidic plaque microenvironment.On the one hand,Res increased autophagy flux in damaged endothelial cells by activating cAMP-PKA-AMPK-SIRT1 signaling pathway to promote lipid degradation.Interestingly,LCS-Se also promoted cholesterol efflux to improve lipid metabolism.On the other hand,fixed-point separated Res and LCS-Se synergistically improved plaque inflammatory microenvironment by reversing macrophage phenotype(M1 to M2)and alleviating plaque oxidative stress.Pharmacodynamics result proved that the plaque vulnerability index(VI)decreased from 1.39±0.282 to 0.108±0.02 after LCS-Se/Res treatment.In short,this study provided a new therapeutic strategy for the atherosclerosis through the two-pronged approach.