Preparation Of Nanocomposite Based On Pt Nanoparticles And Metal-Organic Frameworks And Their Antitumor Research

Photodynamic therapy（PDT）is a new type of antitumor therapy,which reactive oxygen species（ROS）with cytotoxicity are generated via photochemical reaction mediated by photosensitizers（PSs）and oxygen（O₂）to kill tumor cells.At present,most PSs have the common disadvantages of low solubility and low tumor targeting,which hinder the further development and application of PDT for deep tumor.Hypoxia is the main physiological characteristic of tumor microenvironment,which can not only promote the malignant progression of tumor,but also cause rapid invasion and metastasis of tumor.In addition,hypoxia hinders the ROS generation of oxygen-dependent PDT,affecting the antitumor effect of PDT.To solve the above problems,this work constructed a novel nanosystem（HMPC）by integrating small size Pt nanoparticles（PtNPs）and near-infrared photosensitizer CyI into metal organic frameworks（MOFs）.Hyaluronic acid（HA）was further coated to make HMPC actively target to tumor cells through the interaction between HA and the overexpressed CD44 receptor on tumor cell membrane.Iron-base MOFs not only serve as the carrier of PSs,but also catalyze hydrogen peroxide（H₂O₂）through Fenton reaction to produce hydroxyl radical（·OH）,causing intracellular glutathione（GSH）depletion,reducing activity of glutathione peroxidase（GPX4）and excessive accumulation of lipid peroxide（LPO）,finally leading to ferroptosis.Pt NPs alleviate tumor hypoxia by catalyzing H₂O₂ to generate O₂,and provides O₂ required for PDT.Under the irradiation of 808 nm laser,CyI generates heat,and with the assistance of Pt NPs,more singlet oxygen（¹O₂）is generated,exerting enhance PDT and photothermal therapy（PTT）.Iron-based MOF was prepared by solvothermal method.Small size Pt NPs were prepared by ethanol reduction method.The morphology and elemental composition of HMPC were characterized by transmission electron microscope and energy dispersion spectrometer.3,3’,5,5’-tetramethylbenzidine（TMB）and singlet oxygen sensor green（SOSG）were used to detect the formation of ·OH and ¹O₂,respectively.The catalase-like activity of HMPC was determined by H₂O₂ fluorescence probe and dissolved oxygen meter.The tumor hypoxia was investigated by image-i T^TM green hypoxia reagent and hypoxia-inducible factor 1α（HIF-1α）immunofluorescence staining.C11-BODIPY581/591 fluorescent probe and GPX4 immunofluorescence staining were used to investigate LPO accumulation and GPX4 activity,respectively.Near infrared thermal imager and thermocouple thermometer were used to evaluate the photothermal effect.Confocal microscopy,flow cytometry and IVIS? spectrum in vivo imaging system were used to evaluate the targeting ability.The results show that the prepared HMPC are monodisperse nanospheres with small size Pt NPs distributed on the surface.With the particle size of less than 200 nm,HMPC achieved effective accumulation at the tumor site through enhanced permeability and retention（EPR）effect.In addition,HMPC showed a negative potential under physiological conditions and had good stability.In vitro functional evaluation experiments showed that HMPC had good catalase-like activity and catalyzed H₂O₂ into O₂ required by PDT.Under near infrared laser irradiation,HMPC showed good photothermal effect and enhanced PDT effect.In vitro cell experiments showed that more HMPC was uptaked by tumor cells through HA-mediated active targeting.In addition,·OH was generated by HMPC through Fenton reaction,which reduces intracellular GSH content,inhibits GPX4 activity,enhances intracellular LPO accumulation,effectively induces ferropotosis,and successfully inhibits the proliferation of tumor cells.To investigate the safety of HMPC in vivo and its antitumor effect on CT26 tumor-bearing mice.The results showed that HMPC had good safety in vivo.Under near infrared laser irradiation,HMPC showed enhanced PDT and PTT effect.In addition,the results showed that HMPC can effectively inhibit tumor by inducing apoptosis,inhibiting proliferation and inducing iron death.In conclusion,the prepared HMPC in this work effectively alleviates tumor hypoxia and inhibits growth and proliferation of tumor through the combined strategy of PTT/PDT/ferroptosis,which has good antitumor effect and provides a new scheme for hypoxic tumors.