Studies On Nanomedicines For Tumor Treatment Under External Irradiation

Using external radiation source or light source to irradiate the tumor site to kill the tumor cells is one of the effective ways to treat tumor nowadays.The principle is to transmit the energy from external irradiation source to the tumor site to perform specific ablation of tumor cells.Rational use of the special physicochemical properties of nanomedicines can further improve the effectiveness of external irradiation treatment.However,the non-tumor-specific distribution of nanomedicines and the energy diffusion of the irradiation source outside the tumor area can cause damage to normal tissues,thus weakening the overall therapeutic efficacy.Therefore,from the perspective of reducing normal tissue damage,it has become a hot research topic to investigate novel nanomedicine-assisted external irradiation tumor treatment methods and to study the treatment mechanism.Based on this,this thesis carries out the following works:1.Particle therapy and boron neutron capture therapy are two radiation treatment modalities that can concentrate most of the irradiation energy to the tumor site.Compared with X-ray radiation therapy,these two radiation treatment modalities cause less damage to normal tissues,and the combination with nanomedicines is expected to further improve their therapeutic effects.Based on this,we synthesized boron nanosheets via liquid phase exfoliation method.Cellular experiments showed that boron nanosheets have low cytotoxicity:the survival rate of the tested cells was maintained above 80%at a drug concentration of 250 mg/m L.Subsequently,we also used simulation model to evaluate their potential application in particle therapy and boron neutron capture therapy as radiosensitizers.The results show that boron nanosheets have the greatest therapeutic potential in boron neutron capture therapy.This study provides a new idea for the application of nanomedicines in novel radiation therapy.2.The boron nanosheets mentioned above do not have tumor targeting and in vivo long circulation capabilities,which may lead to non-tumor specific distribution and thus harm to normal tissues.In Chapter 3 we developed a platelet biomimetic single atomic enzyme（PMS）for mild-therapy photothermal therapy.PMS has good photothermal properties in near-infrared II window,high peroxidase-like activity and good tumor targeting ability.In vitro experiments showed that PMS could inhibit the expression of heat shock proteins by damaging mitochondria,thus ultimately enhancing the effect of mild-therapy photothermal therapy.In addition,in vivo experiments showed that PMS could effectively accumulate at tumor sites and significantly inhibit tumor growth when combined with mild-therapy photothermal therapy,and showed very low toxicity to normal tissues at the same time.3.In the previous chapter we increased the tumor targeting of nanodrugs by bionic design,which reduced the toxicity of normal tissues while ensuring treatment efficacy.However,biomimetic nanomedicines are administered intravenously,which makes them encounter many obstacles during the long cycle of intravenous delivery,thus affecting the percentage of nanomedicines that entry into the tumor.In Chapter 4 we designed a photothermal-stimulus-responsively injectable hydrogel system containing the chemotherapeutic drug camptothecin（CPT）and FeS₂ nanomedicine for the combination of photothermal therapy and enzyme-catalyzed therapy.The system improves the level of oxidative stress within the tumor and enables both FeS₂-mediated photothermal therapy and nanoenzyme-catalyzed therapy.In vitro experiments have shown that after laser irradiation,the hydrogel gradually softens due to the photothermal effect of FeS₂,which allows CPT and FeS₂to be released into the tumor microenvironment.Then the FeS₂ can catalyze H₂O₂ to hydroxy radical to achieve efficient tumor treatment with the combination with the photothermal therapy.In addition,FeS₂ can also deplete excess glutathione at the cellular level,further amplifying oxidative stress.The next work will further validate the correctness of the treatment protocols presented in this chapter through in vivo tumor treatment experiments.4.Our previous works indicated the therapeutic effect of nanomedicine-assisted external irradiation treatment is closely related to the three-dimensional（3D）distribution of nanomedicine.Therefore,it is necessary to develop suitable methods for detecting the 3D distribution of nanomedicine in vivo.In Chapter 5,we present a parallel registration 3D reconstruction algorithm for serials two-dimensional element images,and use it to observe the distribution of gold nanoparticles in tumors.The algorithm can combine the feature point spatial information and image gray information together to improve the registration accuracy,and the parallel registration pattern makes the registration speed faster.The good reconstruction results show that the present algorithm has great applications.Our proposed algorithm can help researchers to detect the distribution of nanomedicines,providing feasible tools for further investigating the mechanism of nanomedicine-assisted external irradiation therapy.This paper focuses on the damage to normal tissues in nanomedicine-assisted external irradiation tumor treatment.After investigation,three novel therapeutic approaches were explored to address this problem.Besides,a method to detect 3D distribution of nanomedicine in tumors was also proposed,which is expected to contribute to the further investigation of mechanisms of nanomedicines-assisted external irradiation treatment.The research in this paper provides new strategies and research ideas for novel nanomedicine-assisted external irradiation for tumor treatment.