Nanosensitizers Containing High-Z Elements For Enhanced X-Ray Induced Therapy Of Deep-seated Tumors

Compared with the commonly used radiotherapy strategies in clinical cancer treatment,the emerging X-ray induced photodynamic therapy(X-PDT)requires a lower radiation dose to stimulate the combined effect of photodynamic therapy and radiotherapy to kill cancer cells.Moreover,the X-PDT strategy overcomes the limitation of limited tissue penetration depth in traditional photodynamic therapy and can be used for non-invasive treatment of deep tumors,with high scientific significance and research value.With the development of more than ten years,the in vivo application of the X-PDT strategy has attracted increasing attention and has great potential for clinical transformation.However,due to complicated preparation,low irradiation utilization,unstable physicochemical properties,biological toxicity and other adverse factors,the in vivo application of nanosensitizers mediated X-PDT effect has been limited.In this thesis,we fabricated two kinds of "theranostic" X-PDT nanosensitizers containing high-Z elements and with good biocompatibility,and realized the enhanced X-PDT treatment for deep-seated tumors under the guidance of multi-mode imaging.The main research contents are summarized as follows(1)In Chapter based on the difficulty of traditional photodynamic therapy applied in clinical,we introduced an X-ray induced dynamic therapy,and detailed its historical development,research background,action principle and tumor cell killing mechanism.Then,we described in detail the three main stages of development of X-PDT strategy(in solution;at the cellular level;in vivo application).Finally,in view of the problems faced by the current research status of the X-PDT strategy in the diagnosis and treatment of deep-seated tumors,we determined the research topic of the fabrication of nanosensitizers with good biocompatibility,biological stability and tumor specific uptake for X-PDT for deep-seated tumors(2)In Chapter 2,we developed a size and X-ray-excited luminescence properties adjustable and uniformly dispersed silicate nanoscintillator.After covalent coupling with photosensitizer rose Bengal which has four high-Z iodine,the enhanced X-ray imaging and radiation/photodynamic therapy were achieved.After modifying the tumor-targeting molecules,the nanosensitizer has high specific tumor uptake,and can effectively inhibit the growth of deep-seated tumors under the action of low-dose X-ray irradiation(3)In Chapter 3,in order to further improve the absorption capacity and utilization efficiency of X-ray,we prepared the aggregation of fluorescence gold clusters conjugated with rose Bengal by coating with cationic polymer(allyl amine hydrochloride).Biomolecule are used as stabilizers to improve the biocompatibility of materials.The aggregation of fluorescence gold clusters had the property of aggregated induced enhanced luminescence under the excitation of low-dose X-ray.Through resonance energy transfer effect,the enhanced luminescence stimulated the photodynamic effect of the coupled photosensitizer.And,the nanosensitizers consist of a large number of high-Z iodine and gold atoms,showing enhanced radiotherapy for tumor cells.In vivo investigation indicated nanosensitizer could effectively escape from reticuloendothelial system and accumulated in tumors,achieving effective tumor ablation under low dose of irradiation(4)In Chapter 4,we briefly summarized some improvements needed in future in my research and the possibly future research directions of X-PDT strategy.