Detection And Treatment Of Early Breast Cancer And Lymph Node Metastasis By Nano-molecular Imaging-probe

Background:Breast cancer has become the world leading cause of female malignant disease,its continuous high mortality has seriously affected the physical and mental health of women.Therefore,the diagnosis and treatment of breast cancer,especially the earlier breast cancer and occult lymph node metastasis,is particularly important.There are several imaging methods used to diagnose the breast cancer,such as ultrasound imaging,Mo-target mammography,CT and magnetic resonance imaging,which have their own advantages and disadvantages in terms of sensitivity and resolution.For the treatment of breast cancer,surgery,chemotherapy and radiotherapy are the main approaches.Surgery faces the risks of over-treatment and wound infection,even for minimally invasive surgery.Chemotherapy usually causes serious side effects for patients,and low-dose radiotherapy could cause tolerance of cancer cells to radiation.With the development of imaging technology and nano-technology,nanoprobe-based molecular imaging can be used to assess the microenvironment,cell metabolism and blood vessel etc in tumor site,to provide guidance for the treatment and prognosis of the tumor.In addition,some molecular imaging probes also act as agents for treatment of cancer by photothermal conversion,carrying drugs and sensitizing X-rays.Development of nanotheranostic agents with multi-modal imaging and multiple therapy capabilities is highly important for early diagnosis and early treatment of breast cancer.Objective:With the assistance of nanoprobes,complementary multi-modal molecular imaging has been used to study early breast cancer and lymph node metastasis,and provide insights for the precise diagnosis and treatment of breast cancer.Method:In the first part of thesis,a novel nanotheranostic agent was developed for multi-modal imaging and therapy of early breast cancer.First,ultra-small WO_3-x nanoprobe with strong localized surface plasmon resonance?LSRP?in the near-infrared region was prepared by a one-pot reaction method,and their LSRP was enhanced under weak acidic and hypoxia conditions.The resultant ultrasmall biocompatible WO_3-x nano-probe was employed as a contrast agent for photoacoustic imaging,and as a transducer for photothermal therapy.Owing to the high atomic number of W and strong X-ray attenuation coefficient,ultrasmall WO_3-x nano-probe was also as contrast agent for CT imaging,and as a radiosensitizer for radiotherapyr.In the second part of thesis,lymph node metastasis of breast cancer was studied by the multi-modal molecular imaging.The lymph node metastasis model was established by injection of 4T1 tumor cells into the foot pad of the mouse.Limited by the specificity of lymph node location and volume,fluorescence imaging and SPECT/CT imaging with high sensitivity and specificity were selected to investigate lymph node metastasis.First,water-soluble and biocompatible NaGdF₄:Yb,Er@NaGdF₄ nano-probe was prepared by high temperature thermal decomposition method,followed by the ligand exchange,andthen used to diagnose different period of Lymph node metastasis through the specific up-conversion fluorescence.Result:The experimental results show that ultrasmall biocompatible WO_3-x nanodots not only have excellent attenuation and sensitization to X-rays for CT imaging and radiaotherapy of breast cancer,but also exhibit high photothermal conversion efficiency for its photoacoustic imaging and photothermal therapy.Combination of photothermal therapy and radiation therapy is the most effective method for killing tumor and preventing it recurrence.The NaGdF₄:Yb,Er@NaGd F₄ nano-probe was successfully used to diagnose the early,mid-term and late breast lymph node metastasis by up-conversion fluorescence imaging,and clearly distinguish the nomal and abnormal lymph nodes in vivo.Further studies showed that NaGdF₄:Yb,Er@NaGdF₄ nano-probe was distributed in the metastatic lymph nodes margin site,clearly distinguishing the boundary of tumor.Conclusion:With the assistance of ultrasmall novel nanotheranostic WO_3-x nanodots,breast cancer can be detected at an early stage through multimodal imaging,and treated by combined photothermal therapy and radiotherapy.The results could provide guidance for clinical treatment of breast cancer.The successful diagnosis of breast cancer lymph node metastasis at different times can clearly distinguish the boundary of metastases,which guides the surgery for accurate resection and avoids excessive cutting lymph nodes.