| Cancer is an important killer threatening human life worldwide.Although modern medical technology is already well developed,it is still difficult to cure malignant tumors.With the deepening of research,it has been found that traditional chemical therapy and radiation therapy have obvious side effects and low therapeutic efficiency.At the same time,some new treatment methods have entered people's research fields,such as photodynamic therapy?PDT?and photothermal therapy.?PTT?,photoacoustic therapy,etc.Compared with traditional treatment methods,PDT has good therapeutic effect and selectivity,small toxic and side effects,which is a cold-light chemical reaction,and can be repeatedly treated in the same affected area.It has been applied to the clinical treatment of some diseases.However,despite the popularity of PDT,there are still many problems in the face of in vivo tumor treatment,such as the hydrophobicity of photosensitizers,the targeting of tumor therapy in vivo,the monitoring of treatment progress,insufficient oxygen,insufficient depth of excitation light,and so on.In order to solve these problems,this thesis designs a variety of nanocarriers based on the purpose of enhanced photodynamic therapy,and explores the improvement of photosensitizer hydrophobicity,in vivo targeted therapy,fluorescence ratio monitoring,multi-mode therapy,etc.The therapeutic effects of each composite nanomaterial were studied at the cell level and in animal models.The details are as follows:?1?A multi-functional composite nano-system based on amphiphilic silane-coated magnetic navigation enhanced PDT was designed and synthesized to solve the problem of photosensitizer hydrophobicity and targeting in PDT.In this work,Fe3O4@Ce6/C6@silane was successfully prepared by hydrophobic-hydrophobic interaction using hydrophobic fluorescers and therapeutic agents into the nanospheres using amphiphilic silanes.During the treatment,nanocarriers can usually reach the tumor site through"high permeability and retention effect?EPR?of solid tumors,but this method is inefficient and non-specific;and magnetic navigation can use magnetic fields in vitro.Control is performed to induce aggregation of the vector at the tumor site,thereby enhancing PDT.The composite nanomaterial Fe3O4@Ce6/C6@silane can be used for photodynamic therapy of magnetic resonance imaging?MR?and fluorescence dual-mode imaging and magnetic targeting enhancement.At the same time,considering that excessive irradiation during treatment can cause harm to normal tissues,we adopted a fluorescence ratio strategy to monitor the consumption of photosensitizers and stop irradiation.The coumarin 6?C6?and the chlorin e6?Ce6?co-loaded into the composite carrier have the same excitation wavelength,and we can monitor the PDT process in real time by changing the fluorescence ratio of Ce6/C6.Afterwards,the cytotoxicity and PDT effect of Ce6/C6@silane and Fe3O4@Ce6/C6@silane composites were explored in MCF-7 cells,and MR and fluorescence doubles were further realized in the tumor-bearing mouse model.Finally,the magnetic targeting enhanced PDT of the multifunctional composite Fe3O4@Ce6/C6@silane achieved significant tumor inhibition in tumor-bearing mice.?2?Based on the research of multi-mode temperature feedback therapy combined with PDT and PTT,a composite nano-system based on lanthanide doped upconversion nanomaterials?UCNPs?was designed and synthesized.The nano-platform can realize real-time temperature feedback.Photothermal therapy?PTT?can also be combined with PDT for multimodal therapy.PTT is a non-invasive and highly effective method of tumor treatment,but the heat generated by over-treatment will be transmitted to the normal tissues around the affected area,causing serious damage.Therefore,real-time monitoring of temperature to achieve accurate PTT is to improve the treatment accuracy and promote PTT further.The necessary means of application.The UCNPs were synthesized by a modified solvothermal method,followed by loading the photosensitizer Ce6 while coating mesoporous silica?mSiO2?,and finally connecting the photothermal therapeutic agent CuS to the outside of the core-shell structure.Under the laser irradiation of 980 nm,the CuS on the surface of the composite nanoparticle UCNPs-Ce6@mSiO2-CuS began to conduct PTT,and the ratio of Er3+green fluorescence emission intensity in the UCNPs?I525/I545?can feedback the temperature of the PTT treatment site in real time.At the same time,the photosensitizer Ce6 in mSiO2 was excited by the red fluorescence of Er3+,and PDT was initiated for synergistic treatment.It is worth noting that in the overall synergistic treatment and temperature monitoring process,we only use the excitation light of980nm,which greatly simplifies the operation and speeds up the testing and treatment process.In this work,we carefully studied the temperature feedback performance of the composite,especially the temperature monitoring effect when it was incubated with the cells.Finally,the differences in therapeutic effects between different composite nanomaterials UCNPs-Ce6@mSiO2-CuS,UCNPs@mSiO2-CuS and UCNPs-Ce6@mSiO2 were explored at the cellular level and in animal models.?3?Designed to synthesize a composite nanomaterial BSA-Ce6-C6-TPZ combined with PDT and hypoxia activation therapy,mainly to solve the problem of PDT oxygen deficiency and the hydrophobicity of photosensitizer.This design strategy is mainly to solve two major problems that limit the efficiency of PDT,namely the problem of the delivery of hydrophobic photosensitizers in the body and the limitation of PDT by insufficient oxygen.We first increased the solubility and biocompatibility by loading a hydrophobic photosensitizer with a nanocarrier,and then using a hypoxic activating drug?Tirazamin,TPZ?to improve the PDT limitation of oxygen deficiency to obtain enhanced therapeutic results.Among them,the bovine serum albumin?BSA?selected as the carrier in this work has very good biocompatibility,biodegradability and non-immunogenicity,and can be self-assembled into a morphology after the addition of the cross-linking agent glutaraldehyde.Uniform nanospheres are one of the most promising nanocarriers.By emission spectroscopy,we confirmed that C6was successfully loaded and that PDT treatment progress was monitored by cell experiments demonstrating changes in the fluorescence intensity ratio of Ce6/C6.Under red light,PDT is first activated,consuming oxygen,causing a localized hypoxic environment,and then activating TPZ for further treatment.At the same time,we characterized the material in detail and performed cytotoxicity evaluation and combination therapy in human breast cancer cells?MCF-7?and mouse melanoma cells?B16?.Finally,in the B16 tumor-bearing mouse model,by comparing the therapeutic effects of different composite nanomaterials BSA-Ce6-C6-TPZ,BSA-Ce6-C6 and BSA-C6-TPZ,it was confirmed that the combination therapy has the effect of enhancing tumor suppression. |
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