Design, Synthesis And Biological Application Of Radiosensitizer Based On Titanium Dioxide

Cancer,also called as malignant tumor,is a disease caused by the abnormal cells with abnormal differentiation and proliferation,infiltration and metastasis under some endogenous or exogenous carcinogenic factors.In recent years,the incidence of cancer has increased year by year.Cancer has become the first killer for human beings.It is difficult for human to cure cancer effectively in the field of medicine.Radiotherapy?RT?is one of the main methods for the treatment of cancer in clinic,which uses high-energy electromagnetic radiation?such as X-ray,electron beam,etc.?to irradiate tumor tissues and destroy DNA in tumor cells directly or produce reactive oxygen species to kill tumor cells indirectly,thus to achieve tumor therapy.There are many problems in the process of radiotherapy,such as the long period of radiotherapy,the high dose of high-energy radiation,and the inevitable damage to normal cells.This will not only bring pain to the patients and lower living quality,but also affect the effectiveness of the treatment.So the patient's tolerance to the treatment will be reduced,and some patients have to stop the treatment in halfway.Therefore,how to improve the effect of cancer radiotherapy on the basis of reducing the dose of high-energy radiation has been a hot topic in biomedicine.In recent years,the rapid development of the radiosensitization effect of nanomaterials and its application in cancer radiotherapy provide new methods and ideas for solving the problems existing in cancer radiotherapy.Titanium dioxide is an important inorganic functional material that has been widely used in solar cells,photocatalysis,sensors and other fields.It can also absorb the radiation energy and transfer the energy to the surrounding oxygen or water molecules to produce reactive oxygen species such as O₂^·-,·OH.These reactive oxygen species can kill tumor cells for cancer treatment.Although radiosensitization for cancer therapy can reduce the side effects of conventional radiotherapy to some extent,the effect of cancer treatment is still unsatisfactory.Therefore,it is of great significance to develop a strategy of radiotherapy to achieve accurate targeting and better therapeutic effect.Based on titanium dioxide,gold nanoparticles,camptothecin,triphenylphosphine,TAT penetrating peptide and RGD cyclic peptide,we designed and synthesized nanocomposites that could achieve cellular targeting and regulate cell division cycle,and achieve the effective treatment of cancer finally.It mainly includes the following sections:1.A mitochondrial targeted radiosensitizer was designed and synthesized,which can induce mitochondrial domino effect.The radiosensitizer is composed of titanium dioxide as the main material,which binds gold nanoparticles to titanium dioxide by gold-ammonia bond.The mitochondrial targeting group of triphenylphosphine was connected on the surface of titanium dioxide by amide bond to form a nanosatellite structure of TiO₂-Au-TPP.The nanosensitizer could specifically enter the mitochondria of cancer cells and produce a large amount of reactive oxygen species under the radiation of X-ray.By breaking the balance of reactive oxygen species in mitochondria,causing mitochondrial dysfunction,inducing domino reactive oxygen species explosion and leading to apoptosis of tumor cells,the introduction of this nanosensitizer can reduce the dose of high-energy radiation and the frequency of irradiation.This targeted strategy of radiosensitization not only provides new ideas for radiotherapy of malignant tumors,but also has a good prospect in clinical treatment.2.Titanium dioxide nanoparticles with mesoporous structure were successfully prepared and further modified with two kinds of peptides?TAT and RGDs?on the surface,which allows it to enter tumor tissues and selectively enter the nuclei of tumor cells during blood circulation.At the same time,titanium dioxide has mesoporous structure,and the hydrophobic drug 7-ethyl-10-hydroxycamptothecin?SN-38?could be loaded into mesoporous titanium dioxide.Mesoporous titanium dioxide as a radiosensitizer could absorb the radiation energy and transfer the energy to the surrounding molecules of oxygen or water to produce cytotoxic reactive oxygen species.As a cell cycle blocker,SN-38 can regulate the cell cycle of tumor cells and put them in the radiosensitive G1 and G2/M phases as well as increase the radiosensitivity of tumor cells to radiation.This nanocomposites can be combined with radiotherapy and chemotherapy,and is expected to kill cancer cells with better therapeutic effects.This integrated nanocomposite can significantly reduce the dose of radiation,reduce the damage to normal tissues and organs caused by excessive dose,and have great potential for enhancing the effect of radiotherapy and improving the radiation resistance of tumor.It is a promising radiosensitizer for individualized cancer radiotherapy.