The Effect Of Ionizing Radiation On The Interaction Of Nanoparticles With Cells And Its Application In Cancer Therapy

In the past decades,Cancer does harm to people's health.In order to overcome the threat of tumors,various treatments including surgical treatment,chemotherapy and radiotherapy,have been widely applied in clinic.To avoid the shortcomings such as unnecessary side-effects and thorough treatment caused by single treatment,it is necessary to combine two or more types of therapeutic methods together,further improving the therapeutic efficiency of cancer.In recent years,nanotechnology provides a novel platform for the development of biomedicine,further enhancing the clinlic translation of nanomaterials.Relying on the intrinsic advantages of nanoparticles in the field of radiotherapy of cancer,we try to understand the relationship between nanoparticles and radiotherapy,further developing radiation-based nanomedicine.In this doctoral dissertation,we first observed the changes of interaction between cells with nanoparticles under ionizing radiation.We then analyzed systematically this phenomenon.Based on the changes of those phenomena,we examined the application of clinical nano-drug for combination therapy.Finally,we synthesized a series of copper-based nanotheranostics nanoprobes for radiotherapy and combined therapy.The main findings are as follows:Chapter 1:We introduced the recent research progress of nanoparticles in the field of radiotherapy,and summarized several radiosensitizing strategies.Next,we introduced the use of nanomaterials in radiotherapy and combined therapy.Meanwhile,the interaction between nanoparticles and biological interfaces,which could be affected by ionizing radiation,is an important part in the field of nanomedicine.We also had a brief introduction in this aspect.Chapter 2:Study of the interaction between nanoparticles and cells caused by ionizing radiation and its mechanism.We prepared various nanoparticles including albumin nanoparticles,liposome nanospheres,gold nanoparticles,and silicon nanoparticles in this work.Different cancer cell lines were then selected to investigate the changed uptake and efflux of nanoparticles by tumor cells under ionizing radiation.Ionizing radiation?e.g.,X-ray?can significantly increase the cell uptake of many different types of nanoparticles,and meanwhile obviously reduce their efflux.Such a phenomenon may be attributed to the X-ray-induced cell cycle change and up-expression of Caveolin-1.This finding will beneficial to the use of nanoparticles for radiotherapy and combined therapy,and has great significance in basic medicine and clinical medicine.Chapter 3:Albumin-based nano-drugs exhibited significantly therapeutic efficiency of cancer under ionizing radiation.Ionizing radiation caused the up-expression of Caveolin-1 in the cancer cell.Meanwhile,the change of Caveolin-1content is directly related to the endocytosis of nanoparticles.Therefore,ionizing radiation significantly increased the in vitro cellular uptake of albumin-based nanocarriers.In vivo tumor models radiated by X-ray showed high accumulation and long retention of albumin nanoparticles.Then chemotherapeutic drug paclitaxel?PTX?,vascular inhibitor sunitinib?SUN?or radionuclide ¹³¹I was loaded onto the surface of albumin nanoparticles for combined therapy of tumors under X-ray radiation,achieving excellent therapeutic efficiency.In order to further increase tumor accumulation,the A15 peptide,which could target clotting of tumor after radiation,was selected to conjugate albumin nanoparticles for enhancing cancer therapeutic efficiency.Chapter 4:We synthesized copper sulfide nanoparticles using melanin as template for combined radio-chemotherapy of tumors.Considering the single of function of albumin,we synthesized a series of copper sulfide?CuS?based nanoprobes for cancer theranostics,further highlighting the multifunctional properties of nanoprobe.In this section,CuS nanoparticles were synthesized using melanin as template,and modified with PEG?CuS@Melanin-PEG?to improve the biocompatibility.Anticancer drug,DOX could be loaded onto the surface of CuS@Melanin-PEG nanoparticles via hydrophobic interaction.Cancer cells radiated by ionizing radiation exhibited high accumulation of CuS@Melanin-PEG and the loaded DOX by nanoparticles,while decreased the cell efflux of nanoparticles.In addition,CuS@Melanin-PEG nanoparticles could be used as radiosensitizers for raditherapy and contrast agents for photoacoustic imagingChapter 5:Iodine-doped copper sulfide nanoparticles for combined radio-photothermal therapy of tumors.Tumor metastasis leads to the treatment failure.However,owing to the lack of a clear outline of metastasis,external radiotherapy is limited for the treatment of metastatic tumors.Therefore,internal radionuclide therapy is the main method for treatment of tumor metastases.Photothermal therapy is a new type of cancer treatment,and has received great attention in recent years,owing to the safety and high efficiency.Therapeutic radionuclide ¹³¹I were doped into the copper sulfide nanocrystal lattice,yielding CuS/^[131I]I nanoparticles.PEG were used to modify CuS/[¹³¹I]I(CuS/[¹³¹I]I-PEG)nanoparticles to improve the biocompatibility.Owing to the effective photothermal conversion efficiency of copper sulfide and radiation properties of ¹³¹I,CuS/[¹³¹I]I-PEG could be used for CT/?imaging-guided radio-photothermal therapy for lymphoma metastasis.More importantly,we found that the cellular uptake of CuS/I-PEG nanoparticles were significantly increased when ¹³¹I was induced,further promoting the tumor photothermal therapy.The change of the interaction between cancer cells and nanoparticles under ionizing radiation is beneficial to combination of radiotherapy and photothermal therapy.In summary,our results revealed the mechanism of the interaction between nanoparticles and tumor cells under ionizing radiation.On the hand,tumor cells enhanced the uptake of various nanoparticles and the loaded drug,while decrease their efflux.On the other hand,both of cell cycle and the expression of Caveolin-1 of cancer cells have been changed after ionizing radiation.Taking advantage of this phenomenon,nanomedicine will be rapidly developed and provide a novel platform for cancer treatment.Our results will provide valuable information for the development of radiation nanomedicine,further promoting the clinical applications of nanomaterials.