Development And Optimization Of Several Sonosensitizers And Their Application In Synergistic Therapy Of Tumor

Ultrasound-triggered sonodynamic therapy(SDT),as a promising non-invasive therapy,has received more and more attention in recent years.Among them,sonosensitizers can be activated by low-intensity ultrasound to produce toxic reactive oxygen species(ROS)for treating tumors.SDT offers many advantages over phototherapy,such as greater tissue penetration,non-phototoxicity,and less side effects to the body.However,previous studies have also proved its limitations,such as low quantum yield of inorganic nanosensitizers,low oxygen(O2)content and high level of glutathione(GSH)in tumor microenvironment.Thanks to the simple engineering nature of nanotechnology,many multifunctional nanoplatforms are being applied in this emerging field to address these inherent barriers and enable continuous innovation.In addition,the combination of SDT with other treatments also showed superior efficacy in improving anti-tumor activity compared to treatment alone.In this paper,we designed and developed several systems based on the above mentioned limitations to maximize the actual therapeutic effect of SDT,aiming to promote the transformation of SDT into clinical application.(1)Titanium dioxide(TiO2),as a typical inorganic nanosensitizer,has been widely reported.However,due to the quick recombination of electron-hole pairs after excitation,the quantum yield of ROS is greatly limited,resulting in a poor SDT effect.To solve this problem,we simultaneously integrated precious metal Pt nanoparticles and oxygen defect layer onto the surface of TiO2 to reduce the recombination of electron-hole pairs,thus improving the ROS generation efficiency.In addition,the prepared TiO2 has a large cavity,which can be used as a storage to load doxorubicin(DOX)for chemotherapy.DOX itself is a kind of high performance organic small molecule sonosensitizer,it can also be used for ultrasound-triggered ROS production.The modified Pt nanoparticles can also act as nano-enzyme to catalyze the decomposition of endogenous high levels of hydrogen peroxide(H2O2)to generate O2 to alleviate tumor hypoxia,reduce the resistance to chemotherapy,and provide sufficient oxygen source for SDT-induced ROS production.In conclusion,the nanosystem has been systematically demonstrated to have a high chemo-sonodynamic synergistic therapeutic effect in vitro and in vivo experiments.(2)We prepared a defect-rich titanium based MOF(D-MOF(Ti))for enhancing the efficacy of sonodynamic cancer therapy.Compared with TiO2 sonosensitizer,D-MOF(Ti)has a narrower bandgap and could achieve more electron-hole separation under ultrasonic irradiation to produce more ROS.At the same time,D-MOF(Ti)also exhibited a high level of Fenton-like activity due to the presence of Ti3+ions,which enabled it to perform Chemodynamic therapy(CDT).In particular,ultrasound,as an exciting source of SDT,could also enhance the Fenton-like response,achieving a significant synergistic effect of tumor therapy.More importantly,D-MOF(Ti)can be metabolized out of the body after completing the therapeutic function,reducing the long-term toxic and side effects on the body.In conclusion,we have identified a novel biosafety Ti-familial of sonosensitizers that show great potential for synergistic sonodynamic and chemodynamic cancer therapy.(3)VS4 nanocrystals with relatively narrow bandgap were proposed as a highly effective sonosensitizer.It can easily separate electron-hole pairs under the action of ultrasound and achieve a high ROS generation efficiency.Especially,we further optimized its sonosensitization performance through rational design of Pt nanoparticles and endogenous high level GSH.Pt,as a co-catalyst,is beneficial to capture electrons,while GSH,as a natural hole-scavenger,is easy to capture holes.Compared with the original VS4 sonosensitizer,GSH-Pt-VS4 nanocomposite can greatly prolong the life of the sonosensitized separated charge,thus further improving the ROS generation activity.In addition,the nanoplatform can overcome tumor hypoxia,improve the production of ROS triggered by SDT,catalyze endogenous H2O2 for CDT,and amplify the oxidative stress in tumors by consuming GSH,thus realizing the excessive production of ROS.All of these combined effects resulted in a significantly synergistic tumor suppression outcome.