Tumor Microenvironment-specific Activation Of Rare Earth Upconversion Nanomaterial For Tumor Synergistic Therapy

Recently,with the continuous development of nanotechnology,the intersection research between nanomaterials and biological fields has received wide attention.Rare earth upconversion luminescent nanomaterials are one of widely used groups of nanomaterials and have been extensively used for tumor therapy,because of their stable chemical properties,low toxicity,near-infrared excitation,and stable upconversion luminescence properties.Tumor microenvironment(TME)has the characteristics of high intertissue fluid pressure,abnormal blood vessels,lack of oxygen,low pH,high levels of glutathione and hydrogen peroxide compared with normal tissues.How to utilize TME is one of the strategies to achieve effective tumor therapy.In this paper,focusing on the efficient treatment of tumors,the following two TME-responsive nanocomposites were constructed for tumor therapy based on rare earth upconversion nanoparticles(UCNP),which are mainly as follows:(1)Liposome-modified UCNP nanocomposites for autophagy inhibitionregulated synergistic tumor photodynamic therapy(PDT).The nanocomposite UCNP@FL-MEL,which combines photodynamic therapy and autophagy inhibition for tumor therapy,was constructed on the basis of Er,Tm co-doped UCNP.Then,the photosensitizer FL,which is hypoxia-sensitive and has strong absorption in both UVvisible region,was combined with UCNP.The spectral energy matching between FL and UCNP could fully utilize UCNP’s luminescence spectrum and improve the utilization of light by photosensitizer.And the nitroreductase in hypoxia TME specifically activates FL and resonates energy transfer with UCNP to increase the production of reactive oxygen species(ROS),realizing the hypoxia TME activated PDT.After that,we further connected the melittin pre-peptide MEL to the materials.MEL can be processed by legumain to melittin in TME,which could inhibit the autophagic process of cancer cells and amplify the killing effect of PDT to cancer cells.Since both the photosensitizer and MEL can be specifically activated by TME,and the fluorescence imaging function of UCNP can provide localization for PDT,the treatment is more precise and effective,and the damage to normal tissues is also avoided.(2)Construction of degradable mesoporous silica-coated UCNP nanocomposites and application for chemotherapy and chemodynamic therapy(CDT).The nanocomposite UCNP@(S-S)SiO2(abbreviated as UCNP@MON)was synthesized by modified sol-gel method,and electrostatic adsorption of Fe2+ ions and loading of chemotherapeutic drug curcumin(CUR)were carried out to synthesize the nanocomposite UCNP@MON(Fe)-CUR.Because of the disulfide bond in SiO2 shell layer,the material could be resolved in TME with high level glutathione(GSH),which lead to the release of chemotherapeutic drug CUR loaded in the SiO2 shell layer.On the other hand,the upconversion fluorescence would recover along with the degradation of mesoporous SiO2,which can be used to monitor the release of CUR.Meanwhile,the electrostatically adsorbed Fe2+ can mediate the generation of Fenton reaction with a high level of H2O2 in the TME and produce toxic ·OH to realize CDT.The material UCNP@MON(Fe)-CUR achieves TME-activated synergy between chemotherapy and CDT,and perform better cancer cell killing than both alone.