Design And Anti-Tumor Performance Of Nearinfrared Light Responsed Upconverting Theronostic System

The novel optical therapies like photodynamic therapy（PDT）,photothermal therapy（PTT）have the advantages of minimally invasive,low toxicity and no drug resistance.However,characteristics of low photostability,high scattering light attrition and tumor hypoxia about phototherapy agents limit the application of PDT and PTT.Exploring the strategy of combination between optical therapy approaches and traditional therapy,simultaneously,applying upconversion luminescence rare-earth materials to drug carrier,can not only compensate for shortcomings of the various treatments,but also obtain the high performance synergistic antitumor effect.In turn,the construction of near-infrared-light light-controlled system achieving luminescence localization and targeted delivery of nanomedicine and near infrared light light-controlling excitations,implementing monospecifically targeted therapy and integration of diagnosis and treatment is an important pathway to solve the difficulty of traditional therapy.Based on this,designing of new optical diagnosis and treatment system toachieve multimodal medical angiography guidance synergistic chemo-photothermal-photodynamic therapy.The main findings of the study are as follows:Firstly,utilizing high-temperature solvents to prepare Na Gd F₄:Yb,Tm and Na Gd F₄:Yb,Tm@Na Gd F₄:Yb nanomaterials with a core-shell structure that responds to 980nm of near-infrared light.Cationic surfactant is used as template to prepare mesoporoussilica-coated UCNPs@m Si O₂ nanocomposite.Successfully loading efficient photosensitizers Zn O at the channels of mesoporous silica by thiol–metal coordination effect to obtain nanocomposite carriers.Fe Cl₃·6H₂O is used as oxidant for oxidative polymerization on the surface of UZNPs nanocomposites to obtaine nanoplatforms with excellent photothermal performance and favorable biosafety profile thus prepared.Under 980 nm NIR light excitation,UV-vis-NIR spectra generated by upconversion nanoparticles matches with the spectral response range of efficient photosensitizers Zn O,afterwards,when Zn O nanoparticles are irradiated by photons energy larger than the band gap energy,they will produce electron hole pairs.The hole has strong oxidizability,oxidizes the surrounding water molecules or oxygen molecules to form free radicals to obtain efficient tumor ablation.Moreover,its photothermal conversion efficiency could reach to 33.5%,under the excitation of 980 nm near-infrared light with power of 0.5 W cm^-2 with PDT synergistic effects could be effective at inhibiting tumor growth.Simultaneously,interstitial defect of the semiconductor Zn O QDs induced blue luminescence and NIR excitated blue/violet emission from upconverting nanoparticles to realize upconversion fluorescence imaging of nanocomposites at cell-living hierarchy,T₁ weighted magnetic resonance imaging with Gd as the contrast agent to structure multi-mode imaging guidance photodynamic and the combination of PDT and PTT mediated by a variety of medical imaging technologies shows excellent anti-tumor efficiency,and realizes the integration of diagnosis and treatment.In order to avoid the problems of premature leakage of photosensitizer and low loading rate of photosensitizer,the core-shel-shell structuredα-Na Yb F₄:Tm@Ca F₂:Nd@Zn O heterostructured nanoparticles were first constructed in an epitaxial growth manner with upconversion nanoparticles as core and semiconductor Zn O as shell,the reasonable Yb³⁺/Tm³⁺/Nd³⁺tri-doping can regulate NIR wavelength excitation at 808 nm with low photodamage and high penetration depth.The shell of Ca F₂ as the endogenous substances could avoid rare earth ions leakage to ensure that treatment agent has the excellent bio-safety.The obtained smaller particle sizes nanaoparticles with suitable size diameter and high upconversion emission intensities have the advantage of diffusion in the strong gap pressure and tight cell accumulation structure inside the tumor.The acid responsive characteristics of the obtained nanomaterials lead to the disintegration of PAA,and a large amount of DOX is originally released in the tumor site,which reduces the side effects of chemotherapy.α-Na Yb F₄:Tm@Ca F₂:Nd@Zn O-PAA-DOX diagnosis and treatment agent achieves NIR light-responsive CT imaging in vitro and in vivo,UCL/MRI imaging multimodality guidance integrated diagnosis and therapy platforms with PDT,PTT and chemotherapy.The problems of high oxygen dependence and low efficiency of single treatment mode of photodynamic therapy are solved.In order to solve the problem that photosensitizer and photothermal agent are easy to fall off in vivo by connecting up conversion particles or coating mesoporous silica,covalent coupling,electrostatic attraction and lipid micelle encapsulation,in the way of embedded method to design PDT,PTT and chemotherapy targeted anti-cancerdiagnosis and treatment system named as GNS@Gd OF-DOX-RB-FA.Firstly,gold nanoparticles are bound to the surface of microcapsules by electrostatic adsorption and grow in situ to form gold nanovesicles.The hydrothermal method for synthesis of Gd OF precursors with gold nanovesicles introduced to form precursors with microcapsules,Gd OF particles are prepared after calcining precursors and gold nanodisks are formed at internal Gd OF particles,which improves the stability of the composite system,gold nanodisks′embedded design with no reduction of fluorescence imaging results of Gd OF particles,which is beneficial for inducing diagnosis and treatment of integration.The gold nanodisks exhibit dual-absorptiometry of biological tissue optical windows at NIR-I and NIR-II regions which could modulate therapeutic light source according to the location of the lesion.Specifically,the second NIR window（1000-1350 nm,NIR-II）has received a lot of interest because it provides deeper tissue penetration depth,lower signal-to-noise ratio,and higher maximum permission exposure（MPE）to skin for cancer treatment at deep level.Subsequently,modificating bovine serum albumin（BSA）can make diagnosis and treatment system obtain the better biocompatibility,doxorubicin（DOX）,rose bengal（RB）and folic acid（FA）are introduced at the same time to realize chemotherapy,photodynamic therapy,targeted functionalization.Based on the rapid proliferation of tumor cells in the above studies,in order to solve the problem of existence of hypoxia area in the tumor,which seriously reduces the response of tumor tissue to conventional chemotherapy,radiotherapy,PDT and other treatment methods,upconversion nanoparticles cubic-crystalline-phasedα-Na Yb F₄:Tm nanoparticles are synthesized in this study,subsequently,loading with photosensitizers of Cu_2-xSe and coating Zn Fe₂O₄ shell by hydrothermal synthesis to construct safe and efficient nanoplatform of ferroptosis-apoptosis combined anticancer therapies.Converting near-infrared light to ultraviolet light addresses the issue of low efficiency of treatment caused from restricted depth of penetration and satisfies UV absorption range of Zn Fe₂O₄ with narrow forbidden gap,stimulated released ferrous ions occurry Fenton reaction with hydrogen peroxide around the cells to generate toxic hydroxyl radicals.Under NIR-laser irradiation,acheiving dual PTT effectiveness of Cu_2-xSe and Zn Fe₂O₄photothermal agents to realize ferroptosis and promote apoptosis of cancer cells.Cu_2-xSe as the CT constrat agent to architecture the PTT and PDT diagnosis and treatment system with UCL imaging and CT dual modality imaging guiding.The problems of high oxygen dependence and low efficiency of single treatment mode of photodynamic therapy are solved.