| Hypoxia is a common feature of most solid tumors and is mainly due to the increased oxygen consumption caused by the rapid,excessive growth of tumor cells.Hypoxia plays an important role in tumor invasion,metastasis and drug resistance,and is closely related to the progression process of tumors.Therefore,the detection of tumor hypoxic zone and the treatment targeting the hypoxic zone are of great importance.Nitroreductase（NTR）is overexpressed in the cells of hypoxic solid tumors and is an important tumor hypoxic target.Therefore,the construction of probes and delivery systems targeting NTR for tumor hypoxia detection and treatment is one of the hot spots of current research.However,the more widely studied NTR-responsive fluorescent probes are based on single-emission fluorescence intensity changes,which can be disturbed by the external environment,so that their detection sensitivity is affected.In addition,many chemotherapeutic drugs have relatively poor water solubility and are difficult to deliver effectively to the tumor hypoxic zone.Therefore,the development of highly sensitive NTR-based detection probes and delivery systems still faces significant challenges.Based on this,this thesis focuses on the following two parts of work:The first part:We have successfully prepared NTR-responsive molecular-mesoporous silica（Eos-NO2@MSN）ratio fluorescent probes for the first time using a photodynamic-mediated strategy.We loaded the monoclinic oxygen indicator 9,10-anthracenediyl-bis（methylene）dipropionic acid（ABDA）into the cavity of mesoporous silica nanoparticles（MSN）and modified the NTR-specific responsive fluorescent molecule Eos-NO2 on the surface of MSN to construct the Eos-NO2@MSN ratio fluorescent probe.The backbone of MSN carrier is stable and biocompatible.The water solubility of the responsive fluorescent molecule was improved,and the toxic side effects from the use of co-solvents were avoided.The Eos-NO2@MSN probe responded selectively to the NTR,and the fluorescence emission signal at 544 nm was recovered,while activating the photodynamic properties of the probe.Under laser irradiation at532 nm,the probe produced single-linear state oxygen and the fluorescence emission of the probe at 410 nm was extinction.Based on the change in fluorescence intensity ratio(λ544 nm/λ410 nm),the probe has been successfully applied to ratio detection of NTR in aqueous solution with a linear detection range of 0.2 to 1.0μg/m L.Finally,the probe also enables hypoxic fluorescence imaging in 4T1 tumor cells.This photodynamically mediated strategy is simple and easy to operate,and can be extended and applied to construct other response types of ratio fluorescent probes,providing a new idea for the construction of novel ratio fluorescent probes.The second part:Based on the overexpression of NTR in the tumor microenvironment,we constructed a hypoxia-responsive nanodelivery system（HS-HA@Cu-CUR NPs）loaded with copper curcumin complexes（Cu-CUR）.An amphiphilic macromolecular polymer was synthesized by grafting the NTR-responsive recognition group 2-nitroimidazole onto hyaluronic acid,and Cu-CUR was wrapped in the hydrophobic cavity formed by the polymer,resulting in the preparation of a well water-soluble hypoxia-responsive nanodelivery system.The NTR-responsive polymer shell of this system not only improved the water solubility of Cu-CUR,but also enhanced the enrichment of the complexes in the tumor hypoxia region.In the presence of NTR and reduced coenzyme I,the release of copper curcumin complexes from the nanoparticles in the hypoxia was successfully simulated in vitro.In addition,the photothermal warming performance of the nanoparticle sulfides was further tested after the hypoxia-responsive.The nanoparticles exhibited excellent photothermal performance and good photothermal stability after sulfidation,and the photothermal conversion efficiency could reach 17.28%,which has the potential to be applied to tumor endogenous hydrogen sulfide responsive photothermal therapy. |
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