Novel Functional Nanomaterials For Sonodynamic Cancer Therapy

Sonodynamic therapy(SDT)is a novel treatment method that utilizes low-intensity ultrasound(US)to stimulate sonosensitizers to generate cytotoxic reactive oxygen species(ROS),resulting in cell apoptosis.US can penetrate deep tissues and focus on the tumor sites to precisely activate the sonosensitizer,thereby killing tumor cells without damaging surrounding normal tissues.Compared with traditional light-triggered therapy,SDT has the advantages of remarkable therapeutic effect,deep tissue penetration,good patient compliance,and fewer side effects.In recent years,with the rapid development of nanomaterials and biotechnology,a large number of new sonosensitizers have been developed and applied for SDT to achieve better tumor treatment effect.However,the efficiency of SDT is mainly limited by the sonosensitizers,tumor microenvironment,biosafety,and so on.In order to improve the sonosensitization efficiency,researchers have developed multiple strategies strategies to enhance SDT.For example,safe and efficient novel sonosensitizers are designed for improvement of structural properties,which significantly enhances the quantum yield of ROS under US irradiation;the tumor microenvironment was modulated to destroy the intratumoral redox homeostasis for amplified ROS level;other treatments are combined with SDT,such as light-triggered therapy and chemotherapy,to maximize the therapeutic effect.Therefore,a series of novel nanoplatforms have been constructed for enhanced SDT,however,some problems still exist including low sonosensitization efficiency and toxicity of sonosensitizers.Therefore,the development of high-efficiency and low-toxic sonosensitizers is a hot and difficult point in the field of SDT.Based on this,this master’s thesis mainly aims at the developing bioscompatible sonosensitizer to improve the efficiency of SDT.The main research contents include:First of all,the development trend of SDT is briefly reviewed,and the basic mechanism of SDT is introduced,including the classification,the advantages and disadvantages of inorganic and organic sonosensitizers,and their respective development.Strategies to enhance SDT are summarized,including optimizing the performance structure of sonosensitizers,modulating the tumor microenvironment,and combining precise treatment modalities.Finally,the topic selection and project basis of this thesis is introduced.The first research subject is iron phthalocyanine(FePc)-based nanodots for chemodynamic-sonodynamic combined tumor therapy.In this work,ultrasmall iron phthalocyanine nanodots(FePc-NDs)by high-temperature oil-phase thermal decomposition were prepared,and their physicochemical properties were determined by characterization methods.The FePc-NDs showed uniform size distribution and good physiological stability after PEG modification,as well as excellent sonodynamic effect and 1O2 generation efficiency under US irradiation.It is speculated that the catalytic activity was improved due to the enhancement of N-H bonds after heat-treatment.Attributed to catalysis of Fe ions in the precursor,FePc-NDs prepared at high temperature exhibited efficient ·OH generation in H2O2 environment,thereby enhancing the efficacy of SDT.The results of systematic cell and animal experiments further verified that the combined chemokinetic and sonodynamic therapy under US irradiation can significantly inhibit the growth of tumor cells.In addition,the synthesized ultrasmall FePc-NDs(2.26 nm)were more easily metabolized in vivo after tail vein injection,and no obvious toxicity was found.Therefore,the structure-optimized FePc-NDs after high temperature treatment have excellent chemical catalysis and sonosensitization,and show great potential in exploring novel tumor treatments.The following subject is sonosensitizer-encapsulated GelMA microspheres for deep tumor SDT.In this work,sonosensitizer-encapsulated hydrogel microspheres were fabricated for the interventional embolization of hepatic tumors with SDT.Firstly,the photocurable cross-linkable gelatin methacrylate(GelMA)and the reported series of metal oxide sonosensitizers were synthesized.Embolic hydrogel microspheres of different sizes(50～100 μm)were prepared by adjusting the parameters of microfluidic chip technology.The sonosensitizers encapsulated in hydrogel microspheres have excellent ROS generation ability.In vitro experiments showed that the hydrogel microspheres can significantly inhibit the growth of animal liver cancer cells under US irradiation.This work showed that sonosensitizer-encapsulated hydrogel microspheres have great potential in in vivo interventional embolization of tumors,and provided a certain reference for precise and deep SDT of liver cancer.In conclusion,in this master’s thesis,two platforms were designed and constructed,including iron phthalocyanine-based nanodots and sonosensitizer-encapsulated GelMA microspheres,to improve the efficiency and safety of SDT.Firstly,by improving the structural properties of the sonosensitizer and combined with chemical catalysis,the enhanced sonodynamic efficiency was obtained.At the same time,thanks to the easily metabolized ultrasmall nanostructures of FePc-NDs,the sonodynamic therapeutic effect with high efficiency and low toxicity was achieved.Attributed to the deep penetration of US,we further constructed sonosensitizers-encapsulated hydrogel microspheres,hoping to achieve interventional embolization therapy of deep tumor.