Piezoelectric Semiconductor Nanomaterials For Tumor Sonodynamic Therapy

Sonodynamic therapy（SDT）is a less invasive cancer treatment strategy in which sonosensitizers are activated under ultrasound（US）irradiation,and then undergo electron transfer with nearby oxygen-containing composites to produce highly cytotoxic reactive oxygen species（ROS）to kill tumor cells.However,the inefficient separation and rapid recombination of electrons and holes in traditional inorganic sonosensitizers result in low ROS yields,which in turn affects the efficacy of SDT.In recent years,piezoelectric semiconductor nanomaterials,which have both piezoelectric and semiconductor properties,are gradually attracting interest as a new type of inorganic sonosensitizers.When exposed to US irradiation,the coupling of piezoelectric and semiconductor properties,known as piezotronic effect,can modulate the migration behavior of charge carriers,achieve efficient separation of electrons and holes,prevent their rapid recombination,and potentially lead to band bending,thereby improving the ROS generation ability of these piezoelectric semiconductors.Moreover,the weak acidity,hypoxia,high concentration of hydrogen peroxide（H₂O₂）and glutathione（GSH）as typical features of tumor microenvironment（TME）provide favorable conditions for the formation,development,and metastasis of tumors,while the hypoxic microenvironment significantly reducing the ROS generation of,leading to unsatisfactory SDT efficacy.Based on the theoretical foundation of piezotronics,this thesis proposes several approaches to construct novel and efficient barium titanate（Ba Ti O₃）-based piezoelectric semiconductor sonosensitizers by combining piezoelectric effects,semiconductor properties,and TME characteristics.The main contents and innovations are summarized as follows:（1）Based on the characteristics of hypoxia,high concentration of H₂O₂ and GSH in TME,manganese dioxide（Mn O₂）coated Ba Ti O₃ nanoparticles（BTO@M NPs）with TME regulation capacity were successfully prepared.As a multifunctional piezoelectric sonosensitizer,BTO@M NPs can not only improve ROS generation,but also regulate TME from various aspects to achieve efficient SDT.In short,the construction of BTO@M heterostructure promotes the separation of US-triggered electrons and holes,while the built-in electric field generated by piezotronic effect further promotes the migration of electrons and holes in opposite directions,thereby improving the generation efficiency of ROS.In terms of TME regulation,Mn O₂ with catalase-like activity can decompose endogenous H₂O₂ into O₂,effectively alleviate the hypoxia of tumor,and further enhance the O₂ dependent SDT.In addition,Mn O₂ can also reduce the antioxidant capacity of cells by consuming GSH,achieving enhanced tumor growth inhibition（66.2%）through enzymatic activities.（2）Aiming at solving the rapid recombination of electrons and holes in Ba Ti O₃,copper oxide-Ba Ti O₃ nanoparticles(Cu_2-xO-BTO NPs)were prepared and used as piezoelectric semiconductor sonosensitizers for enhanced SDT.On the one hand,the electrons and holes in the Cu_2-xO-BTO heterojunction are separated by US irradiation,and with the influence of built-in electric field,the electrons and holes migrate in opposite direction and accumulate continuously on the surface,ultimately leading to the band bending to a position more favorable to ROS generation.In addition,Cu_2-xO-BTO has a high Fenton-like activity,which can respond to the acidic environment at the tumor site to convert endogenous H₂O₂ into hydroxyl radicals（·OH）for tumor chemodynamic therapy（CDT）.Both in vitro and in vivo results showed that the combination of SDT and CDT significantly promoted intracellular ROS production and mitochondrial damage,and showed high cytotoxicity and tumor growth inhibition（76.0%）in 4T1 breast cancer bearing mice.（3）Considering that single-mode SDT has limited ability for eradicating tumors,strontium（Sr）-doped Ba Ti O₃ nanoparticles（BST NPs）were prepared by a one-pot solvothermal method,and then the surface of BST NPs was modified with L-arginine（LA）to obtain a piezoelectric nanomaterial（BST@LA）for SDT combined with nitric oxide（NO）gas therapy.Compared to Ba Ti O₃,BST NPs have a narrower band gap,indicating that they are more susceptible to US excitation,facilitating the separation of electrons and holes.In addition,BST NPs have lower electrochemical impedance,indicating that Sr doping can promote the migration of electrons and holes.As a result,BST exhibits more pronounced ROS generation capacity under US irradiation,amplifying the oxidative damage of tumor cells.On the other hand,as a donor of NO molecules,LA can be converted into NO gas under the stimulation of US and ROS,realizing the controllable delivery of NO at the tumor site for gas therapy.In vitro and in vivo experiments have demonstrated that BST@LA has high cytotoxicity and tumor inhibition effect on 4T1 breast cancer bearing mouse model（89.5%）.In summary,based on piezotronic effect and piezoelectric semiconductors,we have prepared novel piezoelectric nanomaterials through strategies of ion doping and heterojunction construction,and achieved enhanced tumor SDT.In addition,the prepared piezoelectric semiconductor sonosensitizers exhibit negligible cytotoxicity to normal cells,and have good blood compatibility and biosafety.Therefore,this doctoral thesis expands solutions for the design of piezoelectric semiconductor sonosensitizers,provides ideas for the integration of SDT and other therapies in piezoelectric semiconductor sonosensitizer,and offers more possible approaches for future clinical cancer treatment.