Research On Nanodrugs Based On Regulation Of Oxidative Stress To Improve Antitumor Effect

BackgroundMalignant tumor is the primary disease threatening human life and health,and chemotherapy is an important part of its comprehensive treatment.However,traditional small molecule chemotherapy drugs have disadvantages such as strong toxic and side effects,poor targeting,and easy drug resistance.Nanodrug delivery systems have the advantages of controllable drug release,prolonging blood circulation time,enhancing biocompatibility and tumor targeting,and are the research hotspots of tumor chemotherapy and combination with other treatment methods.Radiation therapy is one of the treatment methods for inoperable locally advanced tumors.Cytotoxic oxygen free radicals can be produced by cell hydroionization,which can kill cancer cells without depth limitation.However,due to the damage of surrounding normal tissues,it is difficult to increase the dose according to needs.At the same time,radiation resistance caused by hypoxic tumor microenvironment(TME)also limits the efficacy of radiotherapy.It is expected to construct efficient and stable new radiotherapy sensitizers using nano-drug loading system,and improve the efficacy of radiotherapy.Sonodynamic therapy(SDT)has shown great therapeutic potential and application prospects in deep tumor ablation,but its efficacy is still limited by the tumor hypoxic microenvironment.The development of sonodynamic therapy sensitizers to improve the tumor hypoxic microenvironment based on nano-drug loading system also has good clinical application potential.ObjectiveConstruct FePd-modified carbon nanotubes(FePd@CNTs)to develop radiosensitizers with high penetration and tumor enrichment capabilities.Using tumor cell membrane,manganese dioxide(MnO2)nanoparticles and curcumin(Cur)to construct biomimetic nanocatalysts to develop sonodynamic therapy sensitizers with tumor recognition ability and improvement of tumor hypoxic microenvironment.Methods1.Synthesize and construct FePd-loaded carbon nanotubes(FePd@CNTs)by a one-step reduction method,and characterize the morphology and properties of FePd@CNTs by transmission electron microscopy,XDR,and zeta potential;2.To explore the cytotoxicity,radiosensitization effect and cellular uptake efficiency of FePd@CNTs through in vitro cell experiments;3.To explore the systemic toxicity,radiosensitization effect,in vivo circulation and tumor accumulation ability of FePd@CNTs using the mouse subcutaneous tumor-bearing model;4.MnO2 hollow nanoparticles were synthesized and equipped with Cur by mechanical mixing method,and tumor cell membrane was used as the outer envelope to construct a new biomimetic catalyst(CMC).Transmission electron microscopy,dynamic light scattering and Zeta potential were used to analyze the morphology,properties and stability of CMC.The protein composition of CMC was detected by protein electrophoresis.5.Detect the in vitro ROS catalytic generation ability and tumor microenvironment response ability of CMC;6.To explore the pharmacokinetics,tissue distribution,sensitization effect and biosafety of CMC on sonodynamic therapy using a mouse subcutaneous tumor-bearing model.Results1.The morphology of FePd is uniform and can be successfully modified on the surface of carbon nanotubes to form FePd@CNTs;CCK-8 results showed that FePd@CNTs could reduce the cytotoxicity of FePd.FePd@CNTs Combined with radiotherapy can produce strong cytotoxicity in vitro and mediate high levels of cell DNA fragmentation and ROS generation.The clone formation experiment showed that FePd@CNTs had a good radiosensitization effect.Carbon nanotubes increased the cellular uptake efficiency of FePd.2.In the mouse model of breast cancer,FePd@CNTs has good safety in vivo and improves the therapeutic effect of radiotherapy,and FePd@CNTs combined with radiotherapy significantly increases the level of ROS in tumors;Carbon nanotubes increased the circulation time of FePd in vivo and the accumulation in tumor.3.MnO2 nanoparticles have uniform morphology,which can effectively carry Cur and be wrapped by cell membrane;CMC can effectively retain the protein components of tumor cell membrane,has good stability,has a good ability to catalyze ROS generation in vitro,and can respond to the weak acidic tumor microenvironment and release efficiently.CMC has good phagocytosis and escape characteristics,and synergies with SDT can produce a large number of ROS.4.In the mouse model of liver cancer,CMC has good in vivo circulation and tumor accumulation ability,can significantly enhance the anti-tumor effect of SDT,and has good in vivo safety.ConclusionIn this study,FePd modified carbon nanotube radiosensitization nanomedicine and sonodynamic therapy sensitization biomimetic nanocatalites based on tumor cell membrane,manganese dioxide and curcumin were designed.Both nanodrugs have enhanced in vivo circulation ability and tumor accumulation ability,and can be used in combination with radiation therapy or sonodynamic therapy respectively,and can significantly increase the level of ROS in the tumor and improve the tumor inhibition effect;meanwhile,they have good biological safety,and demonstrates efficient sensitization effect and good clinical translation potential.