Cs_xWO3 Nanoparticles For Multifunctional Imaging And Phototherapy Of Tumor

Being the second leading cause of death in the world,cancer has already threatened the lives and health of human beings seriously.However,the tranditional treatments like surgical treatment and chemotherap y,often suffer the disadvantages of large surgical area and side effects etc.Photothermal therapy?PTT?and photodynamic therapy?PDT?rely on photothermal effect of photoactive substances and photo-induced reactive oxygen species,to induce tumor cell apoptosis or ablate cancer tissues,respectively.Compared to tranditional treatments,PTT and PDT exhibit favorable characteristics such as low side effects,short time and repeatable therapy,thus providing an effective approach for cancer therapy.However,PDT effect decreases over time due to the depletion of tissue oxygen,while the PTT effect gradually increases upon irradiation,thus combining PDT and PTT would produce a synergistic effect.Moreover,how to realize the precision diagnosis and therapy of cancer is a crucial problem.One effective way is developing cancer theranostic platform by introducing imaging during multi-modal therapy process,which can realize real-time monitoring during the treatment,improve the accuracy of cancer treatment and decrease the side effects.To date,most theranostic systems have been constructed by integrating multiple components with different functions?imaging or therapy?in a complex system.However,simple combination of different materials often results in a series of shortcomings such as mutual interference between ingredients,easy collapse of the complex systems in vivo and complicated operation.To overcome above problems,in this thesis,Cs_xWO₃ nanoparticles have been synthesized and functionalized with bioactive component according to their interaction with cells and tumor tissues.The functionalized Cs_xWO₃ nanoparticles exhibited high photodynamic effect,photothermal conversion efficiency and high atomic number,thus can be used as multifunctional theranosic agent,for multifunctional imaging and photothermal/photodynamic synergistic therapy.The specific research contents are as follows:Cs_xWO₃ nanoparticles were prepared by solval thermal approach.The influence of synthetic conditions on the nanostructure and optical properties of Cs_xWO₃particles were investigated firstly,including the composition of solvent,the reaction temperature,the type of reaction medium,the molar ratio of cesium to tungsten and the way of water introduction.The optimum synthetic conditions of Cs_xWO₃nanoparticles were determined by UV-vis-NIR absorption spectra,transmission electron microscope and X-ray diffraction.Finally,the optimized Cs_xWO₃nanoparticles with suitable size,strong near infrared absorption and significant PTT and PDT effects were obtained,which provided the basis for the construction of the multi-functional theranostic systems in the following chapters.To solve the problem of poor dispersion stability of bare Cs_xWO₃ under physiological and simulated physiological conditions,the positively charged poly?allylamine hydrochloride?and negtively chargedpoly?sodium 4-styrenesulfonate?were alternately modified on the surface of Cs_xWO₃ nanoparticles by an electrostatic interaction mediated layer-by-layer method.As a result,the polyelectrolyte modified Cs_xWO₃ nanoparticles?M-Cs_xWO₃?were successfully prepared.Both of in vivo and in vitro tests manifested great potential of Cs_xWO₃ NPs for cancer photoacoustic and CT imaging.Meanwhile,the M-Cs_xWO₃ NPs are qualified for photothermal and photodynamic synergistic therapy in both"first biological window"and"second biological window",respectively.Given the above,this part of content achieved the combination of cancer diagnosis and treatment in single M-Cs_xWO₃,which realized tumor dual-mode imaging,dual-spectral response and dual-phototherapeutic modalities.To overcome the deterioration of photodynamic efficacy caused by tumor hypoxic environment,the Cs_xWO₃ nanoparticles were encapsulated with perfluoro-15-crown-5-ether?PFC?,which is a nontoxic dissolved-oxygen carrier,to achieve the improved the PDT effect.Comparative trials between therapeutic effects of PFC encapsulated Cs_xWO₃ nanoparticles?Cs_xWO₃@PFC?on chemically induced hypoxic pancreatic cancer cells?PANC-1-H?and normoxic pancreatic cancer cells?Bx PC-3/PANC-1?has been proved that the Cs_xWO₃@PFC possessed improved PDT effect due to the oxygen on-demand supplement.This part of the study evidenced positive results for the treatment of pancreatic cancer?PANC-1-H?,which is typically as hypoxic and drug resistant properties.In addition,Cs_xWO₃@PFC also has the expected photoacoustic and CT imaging capabilities.To improve active targeting abilities of Cs_xWO₃ nanoparticles toward the tumors,the CRGDK peptide was modified on the surface of Cs_xWO₃ to obtain targeted Cs_xWO₃@CRGDK nano-theranostic agent,which could actively target to MDA-MB-231 cancer cells.In addition,a NIR light source with continuous wavelength of 800-1300 nm was used for photothermal/photodynamic therapy for the first time,aiming to overcome the adaptability of tumor tissue during phototherapy to a single wavelength laser.These results showed that the therapeutic effect of NIR mediated group was much better than that of single wavelength of 880 nm or 1064 nm under the same power density.The photothermal/photodynamic synergistic therapy on triple-negative breast cancer was realized by NIR,as well as realizing triple-surveillance of fluorescence imaging,photoacoustic imaging and CT imaging.