Construction Of Target Upconversion Nanophotosensitizer And Its Bio-application

Cancer is one of the major diseases threatening human health.According to statistics, only in our country the deaths caused by cancerare more than1.8million every year. Why is cancer the top one killeramong all the diseases threatening human health? The most importantreason is that it is difficult to diagnose cancer precisely in early stagesunder the current medical level. The patients in the clinical medicine areusually diagnosed in terminal stages, and the cancer cells even have awidespread shift in the body then. Thus the best treatment phase has beenmissed, and the treatment becomes very difficult. In recent years, people have devoted themselves to the research of early diagnosis and treatmentof tumor. Beside of the traditional surgery, radiotherapy andchemotherapy, other anti-tumor therapy approaches are emerging, such asthe gene therapy, the photodynamic therapy, etc. People are studying newmethods in the treatment of cancer using nanomaterial along with thedevelopment of the nanotechnology. Compared with traditional cancertreatments, the nanotechnology for tumor diagnosis and treatment hasmany advantages. It is more precise, and can reduce the pain of patients,which means it prolongs the patient’s survival time, and improves thepatient’s quality of life at the same time. Therefore it is a hotspot ofcurrent research. People developed a series of materials for diagnosis andtreatment of cancer by combining chemical, biological, andnanotechnology, for example: semiconductor quantum dots, polymer,mesoporous silica nanoparticles, up-conversion luminescencenanoparticles and so on. These nanomaterials have the abilities to targettumor and transport mark functions to achieve early diagnosis andtreatment of the cancer, which brings new hope.In recent years, the combination of nanotechnology and molecular biology has developed into a new field: nano biotechnology.Upconversion nanoparticles doped by rare earth elements have become akind of nanometer materials used as new fluorescent probes and opticalpower treatment due to its various advantages. Upconversionnanoparticles (UCNPs) doped by rare earth elements is a kind ofmaterials which can transform the long wavelength radiation to the shortwavelength radiation, compared with the traditional down conversionmaterials such as organic dyes or semiconductor quantum dots.Upconversion nanoparticles were excited by the near-infrared light,therefore it presents a series of unique advantages in biomedicalapplications: less damage to the biological tissue, deeper tissuepenetration, high sensitivity imaging, stable luminescence properties, andhard to be bleached by light, etc. In addition, the upconversionnanoparticles themselves are easy to be prepared by chemicalmodification, and they are low in toxicity. So it has attracted a great dealof interest in the biomedical field. At present a series of researchs andexplorations have been done in the synthesis and preparation, surfacemodification, photodynamic therapy, multimodal imaging of theup-conversion nanoparticles, and the imaging guided treatment of cancer. There are still many problems in these studies, such as the low efficiencyof upconversion nanoparticles, the poor stability of the surface biologicalfunctionalization, targeting ability of tumor, the low efficiency of singletoxygen generation in photodynamic therapy and so on. In this paper, wehave prepared NaYF4: Yb3+, Er3+UCNPs in hexagonal phase byoptimizing synthetic conditions and designing core-shell structure withdifferent doping ratio, and the nanoparticles have good performance inuniform size distribution, crystallization and luminous efficiency; wehave realized the surface modification of nanoparticles by the aminopolymer obtaining the nanoparticles with an excellent water solubilityand biocompatibility. On this basis, on purpose of raising the yield ofsinglet oxygen, reducing the irradiation light power density and avoidingthe heat effect of the980nm laser, we also realized the assembly of thephotosensitizer and the nanoparticles through covalent coupling andphysical adsorption, building a kind of light-emitting compositenanoparticles which have the function of diagnosis and treatment at thesame time. It greatly increases the yield of singlet oxygen of UCNPs andreduces the light power density of the irradiation. At last weaccomplished targeted marker on tumor cells in vitro and the photodynamic therapy of a tumor-beared mice animal model. This papermainly discusses several questions on how to improve the production ofsinglet oxygen of UCNPs, reduce the radiation dose and enhance thesecurity at the near-infrared light power treatment. The main results of thestudy are summarized as follows:(1) The preparation of efficient UCNPs with good biocompatibility:we have prepared the NaYF4: Yb3+, Er3+UCNPs which have goodperformance in uniform size distribution, crystallization by thermaldecomposition and the hydro(solvo)thermal method. By changing theconcentration of the doped rare earth and the core-shell structure of theUCNPs, we have regulated the luminous intensity at the wavelength of540nm and650nm. We realized the phase transfer from hydrophobic tohydrophilic solution by using Poly(allylamine)(PAAM) as the ligand ofthe UCNPs. The nanoparticles have very good water solubility andbiocompatibility, which lay a solid foundation for the multifunction ofbiological and the application in the future.(2) The physical adsorption method realizes assembly of theupconversion nano photosensitizer platform which is used as thephotodynamic therapy: basing on the synthesis of amino modified polymer nanoparticles, we have loaded two kinds of photosensitizers onthe surface of the nanoparticles by one-step. By regulating the loadingcapacity of the photosensitizer, we maximized the yield of singlet oxygenfrom the nanocomposite of the up-conversion photosensitizer. We alsoproved the feasibility of the targeted imaging and the photodynamictherapy in vitro at the same time.(3) The preparation of the upconversion nano photosensitizer withhigh biological safety, high efficiency and good performance in targetingcancer cell: based on red light-enhanced NaYF4: Yb3+, Er3+UCNPs withthe surface modification of PAAM, photosensitizer zinc phthalocyanine(ZnPc), targeted molecular folic acid (FA) and polyethylene glycol (PEG)were modified to the surface of UCNPs by the covalent method, and webuilt a composite platform which had the function of targeting imagingand photodynamic therapy, greatly improving the drug loading capacityof the photosensitizer, the efficiency of the energy transition from UCNPsto photosensitizer, and the yield of the singlet oxygen. We also studied theability of the targeting to the cells at different levels of the expression offolate receptor, and the photodynamic therapy of the C57tumor-bearedmice animal model (4)The preparation of composite targeting materials which arecovalent double photosensitizers on the efficient upconversionnanopaticles: the double photosensitizers with different absorptionwavelength are covalent on the surface of the core-shell structure NaYF4:Yb, Er up-conversion nanoparticles at the same time, and it made full useof the energy of the upconversion emission band, further improving theproduction of the singlet oxygen of the photosensitizer compositematerials. And it shows its targeting in vitro cell, proving its safety andefficacy in the treatment of the mice animal model.