The Preparation Of Multifunctional Photonic Nanoplatform And Its Application In The Treatment Of Lung Cancer

Lung cancer is one of the most common and fatal malignant tumors.Worldwide,there is increasing of the incidence and mortality of lung cancer.The burden of lung cancer to the public is becoming more and more serious,and the control of lung cancer has become a worldwide concern.At present,the treatment of lung cancer is still mainly using surgery,radiotherapy and chemotherapy.Despite the continuous development of minimally invasive surgery,stereotactic radiotherapy,targeted therapy,and immunotherapy,the survival rate is still low in the majority of lung cancer patients,and the prognosis is poor.With the development of medical technology,despite the emergence of targeted therapy,gene therapy and so on,but with the continuous treatment,there are also secondary resistance at the same time,a group of initial treatment and have primary resistance.Therefore,it is necessary for us to continue our efforts to study the mechanism of tumor development,recurrence,metastasis and drug resistance.The multidisciplinary and standardized integrated treatment has become an inevitable trend in the treatment of lung cancer.With the continuous development of nanoscience and nanotechnology,nanomaterials are applied in cancer diagnosis and treatment,deriving some new methods and new technologies.Not only nanotechnology make the diagnosis and treatment of tumor more accurate,but also can largely reduce the toxic and side effect,even reduce the pain of patients,which can not only prolong the survival time of patients,but also can improve the prognosis of patients.However,the current researches mainly focuses on the design and preparation of nanomaterials,the research in biology is less,so the understanding of uptake,distribution of nanomaterials in the cell,toxicity and mechanism of action,provideing the relevant information to understand deeply the imperative of nanodrug.In this thesis,we investigated 1)cell uptake,the distribution of NPs in cell and subcellular organelles,as well as the related toxicity,2)The mechanism of efficient PDT at subcellular level,3)the preparetion of theranostic naoplatform and its application in the treatment of lung by the new method of photothermal therapy(PTT).Specific content can be summarized as follows:(1)Intensive investigations have been devoted to lanthanide-doped upconversion nanoparticles(UCNPs),which have shown great potential in applications such as biomedical imaging and therapy.Recently,various polymer-coated UCNPs,as novel bioprobes or nanocarriers,have been developed and their cellular uptake behavior and cytotoxicity have been widely studied.However,the interactions between the UCNPs and subcellular organelles are poorly understand,which restrict their applications in biomedicine.Herein,we engineered UCNPs with different surface charges(positive,negative,and neutral)and studied the dependence between cytotoxicity,internalization,and subcellular localization in normal and cancer cell lines.It was observed that UCNPs with positive or neutral charges entered most of the studied cell lines,whereas UCNPs with negative charges internalize mostly inside the cancer cell lines.Moreover,upon entering into the cells,these UCNPs are localized in different cell compartments,e.g.the cytoplasm,mitochondria or lysosomes,depending on their surface charges and incubation time with the cells.It is revealed that the cytotoxicity of the differently charged UCNPs towards the studied cell lines significantly depends on localization in the mitochondria rather than in the lysosomes or cytoplasm.The corresponding changes in the mitochondria structure were visualized showing the likelihood of cell death.These results have enriched our knowledge on the cytotoxicity of UCNPs in organelle and sheds light on the design of organelle-targeted UCNPs in tumor imaging and therapy.(2)Studies on cancer PDT guided by UCNPs-PS subcellular imaging.In this chapter,UCNP-based photosensitizer(UCNPs-PS)was synthetized and studied in vivo and in vitro.The main research results are as follows:UCNPs-PS constructed can be internalized into subcellular fraction of cancer cells.It is revealed that the UCNPs-PSS is first untaken in A549,secondly internalize into lysosome,then into mitochondria through the escape from lysosome.The best time of incubation of UCNPs-PSS into the mitochondria in A549 cell is 24 h.It was proved that the mechanism of A549 cell apoptosis mediated by UCNPS-PS results from the mitochondrial apoptotic pathway.(3)Study on construction of photothermal therapy(PTT)nanoplatform(IONPs)and its application for therapy of lung cancer guided by fluorescence bioimaging.In this chapter,the novel PTT nanoplatform(IONPs)was constructed.The results obtained were as follows:The PTT of IONPs nanoplatform prepared can be guided by dual mode imaging of fluorescence and MRI.Under the illumination of 808 nm,the irradiation dose of IONPs can be reduced down to 0.25W/cm~2 as low as,which is a rather low irradiation power density in present reports.The designed IONPs have charge reversal function in weak acid microenvironment,which shows a“intelligentialize”targeting to cancer cells,the precise PTT was achieved.