Construction And Evaluation Of Antitumor Upconversion Nanoparticles As Theranostic Agents Based On Hypoxia And Near Infrared Light Dual Control

Theranostics has become a frontier and hotspot in the field of pharmacy,medicine,and chemistry.Theranostic reagents can provide a multifunctional platform for treatment of cancer,which included real-time monitoring,positioning diagnosis and personalized treatment.Stimulus-triggered drug release by the unique extracellular environment（such as hypoxia,p H et al.）or the external stimuli（such as light,magnetic force et al.）is a special approach to control drug release.Hypoxia has been used for theranostic research of solid tumor.However,it also occurs during other situations which induced drug release and lead to unexpected cytotoxicity.Light has attracted great attention due to its advantages in highly specific spatial and temporal control drug release.Lanthanide ions doped upconversion nanoparticles（UCNPs）are used to convert near-infrared（NIR）light into ultraviolet（UV）or visible emissions.Compared to UV light,NIR light have high tissue penetration depth,inert to ambient interference and minimized photodamage to tissues.However,it cannot avoid drug release in normal tissue where illuminated in the optical path to the tumor locaization.If we can design a theranostic reagent which fused the tumor hypoxic condition（tissue microenvironment）and light triggerable advantage（external stimuli）,we can achieve a highly precise release anticancer drug and reduce its poison side effect.Herein we report a novel theranostic reagent（UCNP-CAE-FDU/NO₂）which based on hypoxia and near-infrared（NIR）light dual control.The theranostic reagent is designed based on the following considerations:（1）Floxuridine（FDU）is anticancer drug which was masked by ester functional group.（2）Upconversion nanoparticles（UCNPs）consist of a crystalline host matrix（NaYF₄）doped with lanthanide ions(Yb³⁺,Tm³⁺).（3）（E）-o-Hydroxycinnamic acid was introduced as the procursor of fluorescence dye.（4）The 4-nitrobenzyl ether as the hypoxia response group.The TEM、NMR、MS and IR characterization comfirmed the structures of the intermediate and the theranostic reagent.HPLC and HRMS were used to evaluate the anticancer drug release mechanism.We explored drug released property of hypoxia incubating time and illuminating time through fluorescence spectrum analysis.The cytotoxicity profile of the theranostic reagent to MCF-7 cells by a MTT assay was tested in different conditions.Lsaer scanning confocal microcope was used to monitor the release of anticancer drug in hypoxia tumor cells.The results showed that UCN P-CAE-FDU/NO₂ was well dispersed and dimensioned.The average particle size of it was 30 nm.The result revealed that the theranostic reagent could release anticancer drug FDU and the coumarin derivative under hypoxia condition after illumination with NIR light.Fluorescence intensity of the coumarin derivative could report the quantification of anticancer drug which increased with the hypoxia incubation and illumination time.The MTT exhibited that the theranostic reagent had cytotoxicity to MCF-7 cells in hypoxic and NIR irradiated conditions.The coumarin derivative could diagnose the hypoxia cells and monitor release of the drug.The theranostic reagent（UCN P-CAE-FDU/NO₂）own diagnosis and therapy dual function with precisely releasing drug.It provide a new approach to the integration of diagnosis and therapy of hypoxic tumor.