| Cancer is the second leading cause of death in the world and has been threatening people’s health.Therefore,it is of great importance to develop effective analytical methods for cancer treatment.Hypoxia is a typical feature of most solid tumors and plays a crucial role in drug resistance,invasion,and migration.Additionally,studying the expression levels of biomolecules at the subcellular organelle level helps us to understand the mechanism of disease initiation as well as the process of development and,in turn,to investigate suitable therapeutic strategies.However,current studies investigating hypoxia-related pathologies at the subcellular level is still relatively scarce.Based on this,we have constructed a hypoxia-responsive mitochondrion-targeted nanoprobe for imaging biomolecules in mitochondria as well as for mitochondrion-targeted tumor therapy.The specific research contents are as follows:（1）We proposed a smart nanodevice via integrating light-responsive DNA probes into hypoxia-responsive metal-organic framework（MOF）,for spatiotemporally controlled biorecognition in mitochondria under hypoxic conditions.Mitochondrial ATP under hypoxic conditions was chosen as a model.Once the constructed nanodevice（MOF@Y-apt）entered the hypoxic cancer cells,MOF@Y-apt was degraded by the hypoxia-related high expressed reductases and thus cause the release of Y-apt.Significantly,cyanine dyes,possess the ability to specifically target mitochondria in cancer cells.Therefore,the released spatiotemporally controlled Y-apt can response to mitochondrial ATP and output fluorescent signal under the targeting effect of cyanine dyes.Additionally,the fluorescence of Cy5.5 labeled on Yc-PC was available as an internal standard for Cy3 fluorescence self-correction which can effectively improve the accuracy of the imaging results.More importantly,compared with some previous works using PC linker as spatiotemporally controlled element,our scheme further utilized TP excitation which can avoid cell damage and possess ideal tissue penetration depth to achieve the purpose of photolysis.The nanodevice had superior detection performance in vitro and in mouse tumor tissues.（2）We report a hypoxia-activated and mitochondrion-targeted DNA nanotrain for enhanced photodynamic therapy（PDT）.This DNA nanotrain was prepared by self-assembly of two relatively short DNA hairpin monomers（H1 and H2）through hybridization chain reaction（HCR）.Cyanine structural dye（Cy3）and black hole quencher 2（BHQ2）,which were employed as a fluorescent mitochondrion-targeted molecule and azoreductase-responsive element,respectively,covalently attached to the DNA hairpin monomers.The extended guanine（G）-rich sequence at the end of the DNA hairpin monomer（H2）served as a nanocarrier for the photosensitizers.Upon initiation between the DNA hairpin monomer and initiation probe,the fluorescence of Cy3 and the singlet oxygen（1O2）generation in the nanotrain were effectively quenched by BHQ2through the fluorescence resonance energy transfer（FRET）process.Once the nanotrain entered cancer cells,the azo bond in BHQ2 will be reduced by the high expression of azoreductase under hypoxia conditions;then,the fluorescence of Cy3 and the 1O2generation will significantly be restored.Furthermore,due to the mitochondrion-targeting characteristic endowed by Cy3,the photosensitizer-loaded nanotrain would accumulate in the mitochondria of cancer cells and then demonstrate enhanced PDT efficacy under light irradiation. |
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