Preparation And Application Of Tumor Microenvironment Responsive "Dual-Locking" And "Dual-Drug" Prodrugs

Among various cancer treatments,chemotherapy based on highly cytotoxic chemotherapeutic drugs is an indispensable choice due to its high efficiency.However,conventional chemotherapy causes severe side effects in healthy tissues.Therefore,it is important to overcome multiple obstacles to successfully deliver drugs to tumor sites.The stimulus-responsive drug delivery systems provide a promising strategy for target-specific delivery of drug.However,most of the currently stimulus-responsive nanomaterials only respond to a single stimulus,which may not be robust enough to distinguish cancer tissue.In addition,the application of advanced nanocarriers to deliver multiple drugs has become a popular trend,and many carriers achieve better tumor targeting or reduce toxic side effects,thereby improving therapeutic outcomes to a certain extent.However,although many advanced nanoparticles have been successfully applied for delivery of multiple drugs,few can maintain a constant and precise drug release ratio due to the different physicochemical properties of the drugs and premature drug release.To solve these problems,this thesis designed two nanoparticles to improve the treatment efficacy of chemotherapy of tumors.Specific research contents were as the followings:1、Herein,we report a novel dual-locking theranostic nanoprobe（DL-P）based on near-infrared（NIR）hemicyanine CyNH₂with two orthogonal stimuli of cancer cell lysosomal pH（first“lock”）-and lysosome-overexpressed cathepsin B（CTB,second“lock”）-triggered NIR fluorescence turn-on and drug activation to improve the specificity of cancer imaging and therapy.The fluorescence of CyNH₂was initially quenched due to intramolecular charge transfer（ICT）but could be selectively activated under the dual-key stimulation of lysosomal pH and CTB to liberate CyNH₂,resulting in strong NIR fluorescence turn-on for cancer imaging.Moreover,CyNH₂caused mitochondrial dysfunction to inhibit cancer cell proliferation for cancer therapy.Compared with previously reported probes that respond to a single stimulus,this dual-locking nanoprobe that is responsive to two orthogonal stimuli triggers with integrated imaging and therapy function in a single agent exhibits increased imaging and therapy function in a single agent exhibits increased selectivity and specificity,which provides a prospective strategy for precise cancer imaging and therapy.2、A simple dual-drug delivery system with a flexible and controllable drug release ratio was constructed to deliver two anticancer drugs,doxorubicin（DOX）and curcumin（CUR）.The DOX and CUR drug ratio can be easily tuned for an enhanced synergistic effect,and the drugs can be released at predesigned ratios due to synchronous drug activation and nanoparticle collapse.Drug release at predefined ratios for synergistic anticancer therapy was demonstrated via in vitro and in vivo experiments.Therefore,the dual drug delivery system developed in this work provides a simple and efficient strategy for combination chemotherapy.