Construction Of The Magnetic Nanoparticles Drug Delivery System Mediated By Folate Receptor And Its Applicaton In Cancer Diagnosis And Treatment

From a worldwide perspective,tumor is a great threat to hunman health,how to treat tumor diseases effectively and improve the living quality of patients is an urgent problem to be soved in the field of tumor research.Early diagnosis and treatment of tumor disease are the most important factors for curing tumor diseases.The traditional diagnosis and treatment methods of tumor are two independent processes severally.Tt is difficult to give an diagnosis in the early stage of the disease that have to use imaging technique for assistment.Magnetic resonance imaging(MRI)is a safe and painless procedure for diagnosis with a wide using in clinical treatment.The contrast agent is an important part for MRI and used for nearly 50%patients who taken MRI scanning.However the traditional contrast agents for MRI have many serious drawbacks,such as poor tissue targeting,large side effects and short time in vivo,which limit their further clinical application.Traditional cancer treatment methods include surgery,radiation therapy,chemotherapy and so on.Chemotherapy is a major treatment modality in clinical treatment.Conventional chemotherapy mainly depended on systemic administration of antineoplastic drugs,leading to nonspecific drug molecular biodistribution throughout the body and nondifferential killing of cancer cells and also healthy tissues.All the fatal obstacles limit their further clinical application for cancer curing.In recent years,the concept of theranostics is proposed,it is designed to combine diagnosis and treatment for improving the effect and reducing the side effects of drugs,the changes of tissue lesions and the therapeutic effects can be monitored so that the treatment plan can be adjusted timely,which avoid the inadequate or excessive treatment of the cancer diseases.Nanomaterials can be used as drug carriers because of their special physical and chemical properties,easy surface modification and functional design.The purpose of this dissertation is to construct a platform for the integration of tumor diagnosis and treatment based on nano materials.It is not complicated for nanomaterial surface modification and functionalization,such as loading drugs and contrast agents.The physiological environment of tumor tissues is acid,which is different to human normal tissue with a nearly pH of 7.4.The surface of tumor cells can express some tumor markers such as folate receptor.The combination between folate and folate receptor can lead nanomedicine to recognize tumor cells specifically and release chemotherapeutic drugs to killing tumor cells.Because of superparamagnetic characteristics and good biocompatibility,the magnetic ferric oxide are choosed as multifunctional biomedical nanocarriers for tumor theranostics in this dissertation.The detailed contents are as follws:1.Review of tumor research literature,magnetic ferric oxide nanoparticles as MR imaging contrast agent have been used for disease diagnosis and treatment with long period.The ferric and gadolinium elements are the ideal materials as T1 and T2 MR imaging contrast agents.In the second chapter,we have modified the ferric oxide nanoparticles Fe3O4 and doped with gadolinium to compound GFON by solvothermal reaction.GFON nanoparticles showed good longtitudinal and tranverse relaxivities in magnetic examination,which can be used as T1 and T2 MR imaging contrast agent simultaneously.Folic acid(FA)and antitumor drug doxorubicin(DOX)were conjugated to the nanocarrier GFON by chemical grafting.For in vitro experiment,the release amount of DOX drug molecules from the new nanoparticles was tested and displayed a typical pH-depent release characteristic.Cell viability assay demonstrated this nanoparticles could effectively kill HeLa and SCC3 cells but nearly have no side effects to PDLS cells.The nanoparticles also can specificly identify and accumulate into tumor cells.2.The complexity of the environment in vivo is a limiting factor for many nanomedicine used for cancer therapy.In order to verify the imaging and therapeutic effect of the multifunctional nanoparticles FA-GFON-DOX in vivo,we established subcutaneous tumor xenograft models through injecting tumor cells(HeLa cells or SCC3 cells)suspension to immunodeficient nude mice.For in vivo experiments with tumor bearing mice,the new multifunctional nanoparticles showed a significant tumor inhibitory effect and enchanced MR imaging signal intensity of subcutaneous tumor tissue,displaying high treatment efficacy for cancer disease.3.Oral squamous carcinoma(OSCC)is one of the most common malignancies,its incidence rate is sixth in human common malignant tumors.Chemotherapy is one of the main treatments of OSCC,yet the use of conventional chemotherapeutic drugs are limited by the associated toxic side such as the no-targeted biodistribution in vivo.In the fourth chapter,we introduced a new type of multifunctional nanoprobe for the effective diagnosis and treatment of oral squamous cell carcinoma.Porous shell structure gadolinium doped ferric oxide nanoparticles(CSGFN)were synthesized and used for nanocarriers.Previous studies have shown that cisplatin(CDDP)was one of the most extensively effective chemotherapy drugs used in oral squamous carcinoma and folate receptor was highly expressed in squamous carcinoma cells.Shell-core structure is an attractive drug delivery system.Due to its high specific surface area,anticancer drugs could be easily loaded into the nanoplatform.CDDP could be easily loaded into the nanocarriers CSGFN to obtain SCGFN-CDDP,and CSGFN-CDDP displayed pH-responsive drug release behavior.FA was also conjugated to CSGFN-CDDP by chemical grafting simply to acquire the multifunctional nanoparticles FA-CSGFN-CDDP.Cell viability assay in vitro demonstrated the nanoparticles could kill SCC3 cells from human oral squamous cell carcinoma effectively.In order to verify the imaging and therapeutic effect of the multifunctional nanoparticles in vivo,we established tumor xenograft models through injecting SCC3 cells suspension to immunodeficient nude mice.Systemic delivery of the nanoprobe in vivo had no obvious toxicity for vital organs,displayed excellent T1-T2 dual-mode MR contrast enhancement and anticancer activity.Thus,FA-CSGFN-CDDP could be a potential nanotheranostic for targeted MRI and cancer chemotherapy.The nanomedicine developed to multi-functional with theranostics and the use of nanocarriers.It can be predicted that the magnetic nanoparticles drug delivery system mediated by folate receptor have great application potential for the diagnosis and treatment for tumors.