Preparation And Preliminary Research On Ultrasonic Controlled Release Drug Delivery System Based On Mesoporous Titanium Dioxide

At present,chemotherapy is still one of the indispensable tools for the treatment of malignant tumor.But this therapeutic method is poor targeting,poor drug selective and serious side effect so it has great restrictions in clinical applications.Therefore,it is an effective solution to construct the appropriated drug delievery systems?DDSs?to load the chemotherapeutic agent to improve the selectivity and targeting of the drug to the tumor tissue and reduce the toxicity to the normal tissues.In this study,the mesoporous titanium dioxide nanoparticles?MTN?which is characterized by high biosafety,ultrasonically sensibility and high drug loading was used as the carrier and the insoluble antitumor drug Docetaxel?DTX?was loaded into the pores of MTN to achieve the intelligent controlled release characteristics of drugs.Finally,1-Tetradecanol?TD,phase transition temperature: 38–39°C?was wrapped to the surface of the drug-loaded MTN to avoid the premature release of DTX.The use of ultrasonic heat caused by the property of TD phase transition can construct a drug delivery system with characteristics of ultrasound controlled drug release.The main features of the drug delivery system are:First,high-resolution ultrasound responsive drug release: this drug delivery system was heated under the radiation of focused ultrasound,then temperature rising.When the temperature rose to 38-39?,gatekeeper?TD?was changed from solid to liquid and break away from the surface of the MTN,the channel of MTN opening and the DTX released efficiently.In the absence of US,the TD on the surface of the drug delivery system remains solid-state and blocks the DTX in the channel without being released.This feature can significantly improve the efficiency of treatment and avoid the side effects of chemotherapy drugs.Second,the multi-mechanism cocktail therapy to the treatment of tumors: onthe one hand,the drug delivery system was responsive to release DTX under the radiation of US for chemotherapy;on the other hand,under the radiation of focused ultrasound,MTN produce a lot of reactive oxygen species?ROS,such as singlet oxygen?¹O₂?and so on?which can be used for tumor-specific sonodynamic therapy?SDT?to kill tumor cell.In addition,the heat generated by ultrasound also has a certain lethality to tumor cells which is called as hyperthermia therapy.Multi-mechanism co-treatment of tumors will significantly improve the treatment efficiency.Third,due to enhanced permeability and retention effect?EPR effect?of tumor,and the appropriate nano-scale of MTN/DTX@TD?about 220 nm?,the DDS can break through the biological barrier in vivo and target to tumor tissue.In this study,this ultrasound-sensitive drug delivery system significantly improved the therapeutic efficiency of DTX?targeted drug delivery,multiple mechanisms of treatments?,and reduced the side effects of DTX?ultrasound-controlled drug release?.This study mainly carried out the following three aspects:1.Preparation and characterization of ultrasound-sensitive nano-drug delivery system.The MTN with uniform particle size was synthesized by sol-gel route.Then the surface of MTN connected with Hyaluronic acid?HA?and DTX was loaded into the pores of MTN via the crystallization method.After surface of MTN was wrapped with TD,a good water-soluble nano-drug system was constructed.Finally,a series of characterization methods?Dynamic Laser Light Scattering?DLS?,Fourier Transform Infrared Spectroscopy?FT-IR?,Transmission Electron Microscopy?TEM?,Scanning Electron Microscopy?SEM?,Physical Adsorption Instrument?were systematically used for characterizing the constructed DDS.2.The behavior of ultrasound-sensitive nano-drug delivery system in vitro.The stability of the drug delivery system was investigated on the three common biological systems in vitro.Ultrasound fever behavior and ¹O₂ production of MTN-NH2-HA under the irradiation of ultrasound were also investigated.Therelease behavior of the drug delivery system in vitro was investigated in different temperature?37?,40?,45??of the releasing environment.It's also investigated whether there is a US role or not of the release behavior.The results showed that MTN/DTX@TD is stable in these three common biological systems.Focused ultrasound has a good heating effect and MTN-NH2-HA can produce more ¹O₂ under the irradiation of ultrasound,which can be used for SDT.The cumulative release rate increased with the risng temperature of releasing environment?37?,40?,45??which indicated that MTN/DTX@TD had high temperature sensitivity.In the other hand,the drug releasing rate and extent of the US group was significantly higher than that of the non-ultrasound group,indicating that the drug delivery system was ultrasonically sensitive.3.The behavior of ultrasound-sensitive nano-drug delivery system in vivo.The distribution behavior,antitumor activity in vivo,pathological features and blood routine experiment of MTN/DTX@TD were investigated.The results showed that MTN/DTX@TD had a certain targeting to tumor tissue,and the inhibitory effect on tumor tissue was greatly improved under the effect of US?the rate of tumor inhibition was 92.6%?,and the toxicity to normal tissue was greatly reduced,especially for liver and blood toxicity.In this study,an ultrasound-sensitive drug delivery system with high temporal resolution was prepared by MTN and TD.The system significantly improved the therapeutic efficiency of the tumor through the combination of multiple mechanisms and effectively reduced the toxicity of drugs by efficient ultrasound controlled release.It provided a new way of thinking for malignant tumor multi-mechanism treatment and intelligent controlled drug release.