Preparation And Anti-Tumor Performance Of Ruthenium Nanoenzyme Drug Delivery System For Improving Tumor Hypoxia

Cancer is the second leading cause of human death worldwide in 2020,according to the latest World Health Organization（WHO）statistics.Nanomedicines have developed rapidly in the field of anti-tumor,and have obvious effects in inhibiting the growth and metastasis of cancer cells.Cutting off the nutrient supply can effectively inhibit the growth of tumor cells.However,the effect of starvation treatment is not ideal due to the lack of oxygen at the tumor site.Nanozyme as a new type of catalyst has attracted attention in tumor treatment.In this study,whether ruthenium nanoparticles have enzyme activity was explored for cancer starvation therapy.Ruthenium was loaded into tumor cell membrane hybrid liposomes and polydopamine nano drug carrier systems,respectively.Two nano drug delivery systems were constructed.The possible mechanisms and effects of different nano drugs on tumor killing in vitro and in vivo were studied according to the factors of hypoxia,micro acidity,overexpression of H₂O₂ and high interstitial pressure in tumor microenvironment.The specific main research contents are as follows:（1）Tumor targeting liposome nanoparticles（Ru@ATO@Lip/MNPs）were synthesized by hybridization of cell membrane coated ruthenium nanoparticles（RuNPs）and atorvaquone（ATO）.The homologous targeting of the cell membrane makes the drug easy to be ingested by tumor cells after the nanomedicine reaches the tumor site by high enhanced permeability and retention（EPR）effect.The acidic environment of the tumor stimulates RuNPs to catalyze H₂O₂ to produce·OH,and stimulates Ru’s glucose-like oxidase performance,which catalyzes the reaction of glucose with O₂ to produce gluconic acid and H₂O₂,providing sufficient reaction substrates for the Fenton-like reaction to continuously produce·OH.As an oxygen consumption inhibitor,ATO realsed by liposomal rupture improves the hypoxia of the tumor microenvironment,further aggravates Ru-induced starvation and Fenton-like reaction,and achieves a sustained synergistic anti-tumor effect.（2）Ruthenium nanoparticles（RuNPs）and calcium peroxide（CaO₂）were combined on polydopamine spheres（PDA/Ca O₂/Ru,PCR）,and hyaluronic acid（HA）with tumor specific targeting properties were coaded to form nanomedicine（PDA/CaO₂/Ru@HA,PCRH）.After PCRH circulates to the tumor site via the EPR effect,HA on the surface of the drug could specifically target the cancer cells and then be ingested by the cancer cells.The tumor site was irradiated by near infrared（NIR）laser,resulted in the disintegration of polydopamine nanoparticles,released RuNPs and CaO₂ on them,and heated up the tumor.CaO₂ reacted with the water in the interstitial fluid of the tumor site to produce H₂O₂ and O₂ under the conditions of heat and tumor micro-acidity,which reduced the volume of the interstitial fluid of the tumor and the interstitial hydraulic pressure.It is beneficial for the blood and the drugs carried by PCRH to the tumor,increased the accumulation of drugs in the tumor,improved hypoxia,and also provided H₂O₂.Ru NPs catalyze H₂O₂ to produce·OH in acidic environment（chemodynamic therapy,CDT）.Ru NPs can also catalyze the reaction of glucose with O₂ to produce glucoic acid and H₂O₂,which provides sufficient reaction substrates for chemodynamic therapy,and then produce·OH continuously to achieve effective killings of tumors.