Tumor-promoting inflammation is accompanied by cancer initiation,progression,and metastasis.Cyclooxygenase-2(COX-2)and its downstream product,prostaglandin E2(PGE2),play critical roles in tumor-promoting inflammation....Tumor-promoting inflammation is accompanied by cancer initiation,progression,and metastasis.Cyclooxygenase-2(COX-2)and its downstream product,prostaglandin E2(PGE2),play critical roles in tumor-promoting inflammation.Several studies have revealed the potential of COX-2 inhibition in improving cancer response to chemotherapy,as well as immunotherapy.Aspirin,a nonsteroidal anti-inflammatory drug,has been reported as a COX-2 inhibitor.However,as a small molecule drug with a carboxyl group,there is still the lack of effective methods of preparing polymer–aspirin conjugates with tumor stimuli-responsive release properties.Herein,we synthesized a reactive oxygen species(ROS)-responsive aspirin polymeric prodrug(P3C-Asp)via Passerini three-component reaction between aspirin,4-formylbenzeneboronic acid pinacol ester,and 5-isocyanopent-1-yne,followed by copper(I)-catalyzed alkyne-azide cycloaddition“click”reaction of the aspirin prodrug with dextran(DEX).The P3C-Asp could release aspirin and salicylic acid in response to tumor-specific stimuli.In the murine colorectal cancer model,P3C-Asp suppressed tumor growth effectively without significant side effects and eradicated tumors when combined with the immune checkpoint inhibitor,anti-PD-1 antibody(aPD-1).Further analysis revealed that the suppression was attributable to changes in the immune microenvironment,including reduced PGE2 content,as well as increased infiltration of CD8+T cells and M1 macrophages.The results mentioned above proved that targeting COX-2 pathway with a proper polymeric prodrug might be a useful strategy for cancer immunotherapy.展开更多
Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by ...Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.展开更多
An acid-sensitive delivery system based on acylhydrazone bond was developed for high loading and efficient delivery of doxorubicin.Doxorubicin(DOX)was covalently combined with dihydrazide adipate to form acid-sensitiv...An acid-sensitive delivery system based on acylhydrazone bond was developed for high loading and efficient delivery of doxorubicin.Doxorubicin(DOX)was covalently combined with dihydrazide adipate to form acid-sensitive hydrazone bond based on Schiff base reaction,then the intermediate was covalently combined with carboxymethyl chitosan through amide bond to form polymeric prodrugs,and nanoparticles were formed through self-assembling.Moreover,the structural and particle properties of CMCS-ADH-DOX were characterized by ultraviolet visible near infrared spectrophotometry(UV),nuclear magnetic resonance spectroscopy(^(1)H-NMR),fourier transform infrared spectroscopy(FT-IR),dynamic light scattering(DLS),and transmission electron microscopy(TEM).The mean diameter of the self-assembled nanoparticles is 165 nm,while the morphology is a relatively uniform spherical shape.Moreover,these DOXloaded nanoparticles showed pH-triggered drug release behavior.Compared with free DOX,CAD NPs showed lower toxic side effects in L929 cells and similar toxicity in 4T1 cells.The experimental results indicate that the CMCS-ADH-DOX nanoparticles may be used as an acid-sensitive targeted delivery system with good application prospect for cancer.展开更多
Chitosan-stavudine （d4T） conjugate with a succinic spacer was synthesized via carbodiimide coupling reaction and structurally characterized. In order to nanosize it for improving its therapeutic properties, the chit...Chitosan-stavudine （d4T） conjugate with a succinic spacer was synthesized via carbodiimide coupling reaction and structurally characterized. In order to nanosize it for improving its therapeutic properties, the chitosan-5＇-O-succinyl-d4T conjugate was crosslinked with sodium tripolyphosphate （TPP） to obtain the chitosan-d4T conjugate nano-prodrug. The morphologies of chitosan-d4T conjugate nanoparticles were observed by transmission electron microscopy （TEM）, and their zeta potential, particle size, and polydispersity （size distribution） were measured by the dynamic light scattering （DLS） techniques. In vitro drug release studies at pH 1.1 and pH 7.4 indicate that the crosslinked chitosan-d4T conjugate nano-prodrug can prevent the coupled d4T from leaking out before entering the target viral reservoirs and provide a mild sustained release without the burst release. The results reveal that constructing conjugated chitosan nano-prodrugs may be a promising approach for improving the therapy efficacy of drugs in antiviral treatment.展开更多
A polymeric polyethylenimine(PEI)-based prodrug of anticancer doxorubicin(DOX)(PEI-hyd-DOX) was designed by attaching DOX to PEI via an acid-labile hydrazone bond, for the achievement of biocontrollable gene and drug ...A polymeric polyethylenimine(PEI)-based prodrug of anticancer doxorubicin(DOX)(PEI-hyd-DOX) was designed by attaching DOX to PEI via an acid-labile hydrazone bond, for the achievement of biocontrollable gene and drug co-delivery in response to the intracellular acid microenvironments in the late endosome/lysosome compartments. The cytotoxicity of PEI-hyd-DOX was evaluated by the MTT assay and the cellular uptake was monitored using confocal laser scanning microscopy. The polymeric prodrug can respond with a high sensitivity to the specific acid condition inside cells, thus permitting the precise biocontrol over intracellular drug liberation with high drug efficacy. The chemical attachment of drug molecules also led to the relatively reduced toxicity and the enhanced transfection efficiency compared with parent PEI. The resulting data adumbrated the potential of PEI-hyd-DOX to co-deliver DOX and therapeutic gene for the combination of chemotherapy and gene therapy.展开更多
基金supported by the National Natural Science Foundation of China(51673185,51973215,51673189,51833010,51829302,and 51520105004)the Jilin Province Science and Technology Development Plan(20170101100JC and 20190103112JH)Ministry of Science and Technology of China(2016YFC1100701).
文摘Tumor-promoting inflammation is accompanied by cancer initiation,progression,and metastasis.Cyclooxygenase-2(COX-2)and its downstream product,prostaglandin E2(PGE2),play critical roles in tumor-promoting inflammation.Several studies have revealed the potential of COX-2 inhibition in improving cancer response to chemotherapy,as well as immunotherapy.Aspirin,a nonsteroidal anti-inflammatory drug,has been reported as a COX-2 inhibitor.However,as a small molecule drug with a carboxyl group,there is still the lack of effective methods of preparing polymer–aspirin conjugates with tumor stimuli-responsive release properties.Herein,we synthesized a reactive oxygen species(ROS)-responsive aspirin polymeric prodrug(P3C-Asp)via Passerini three-component reaction between aspirin,4-formylbenzeneboronic acid pinacol ester,and 5-isocyanopent-1-yne,followed by copper(I)-catalyzed alkyne-azide cycloaddition“click”reaction of the aspirin prodrug with dextran(DEX).The P3C-Asp could release aspirin and salicylic acid in response to tumor-specific stimuli.In the murine colorectal cancer model,P3C-Asp suppressed tumor growth effectively without significant side effects and eradicated tumors when combined with the immune checkpoint inhibitor,anti-PD-1 antibody(aPD-1).Further analysis revealed that the suppression was attributable to changes in the immune microenvironment,including reduced PGE2 content,as well as increased infiltration of CD8+T cells and M1 macrophages.The results mentioned above proved that targeting COX-2 pathway with a proper polymeric prodrug might be a useful strategy for cancer immunotherapy.
基金financially supported by the National Natural Science Foundation of China(82073790,51873120,51673127,and 81621003)1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University,China(ZYJC21013,ZYGD18028)。
文摘Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.
基金Funded by the Industrial Technology Research Institute of Hubei Provincial Department of Science and Technology(No.2020DEB012)the Hubei Provincial Department of Science and Technology Support Enterprise Technology Innovation Development Project(No.2021BAB119)。
文摘An acid-sensitive delivery system based on acylhydrazone bond was developed for high loading and efficient delivery of doxorubicin.Doxorubicin(DOX)was covalently combined with dihydrazide adipate to form acid-sensitive hydrazone bond based on Schiff base reaction,then the intermediate was covalently combined with carboxymethyl chitosan through amide bond to form polymeric prodrugs,and nanoparticles were formed through self-assembling.Moreover,the structural and particle properties of CMCS-ADH-DOX were characterized by ultraviolet visible near infrared spectrophotometry(UV),nuclear magnetic resonance spectroscopy(^(1)H-NMR),fourier transform infrared spectroscopy(FT-IR),dynamic light scattering(DLS),and transmission electron microscopy(TEM).The mean diameter of the self-assembled nanoparticles is 165 nm,while the morphology is a relatively uniform spherical shape.Moreover,these DOXloaded nanoparticles showed pH-triggered drug release behavior.Compared with free DOX,CAD NPs showed lower toxic side effects in L929 cells and similar toxicity in 4T1 cells.The experimental results indicate that the CMCS-ADH-DOX nanoparticles may be used as an acid-sensitive targeted delivery system with good application prospect for cancer.
基金Funded by the National Natural Science Foundation of China(Nos.20504018,20972014,20604010,20872010 and 20732004)the National Basic Research Program of China(No.2009CB930203)
文摘Chitosan-stavudine （d4T） conjugate with a succinic spacer was synthesized via carbodiimide coupling reaction and structurally characterized. In order to nanosize it for improving its therapeutic properties, the chitosan-5＇-O-succinyl-d4T conjugate was crosslinked with sodium tripolyphosphate （TPP） to obtain the chitosan-d4T conjugate nano-prodrug. The morphologies of chitosan-d4T conjugate nanoparticles were observed by transmission electron microscopy （TEM）, and their zeta potential, particle size, and polydispersity （size distribution） were measured by the dynamic light scattering （DLS） techniques. In vitro drug release studies at pH 1.1 and pH 7.4 indicate that the crosslinked chitosan-d4T conjugate nano-prodrug can prevent the coupled d4T from leaking out before entering the target viral reservoirs and provide a mild sustained release without the burst release. The results reveal that constructing conjugated chitosan nano-prodrugs may be a promising approach for improving the therapy efficacy of drugs in antiviral treatment.
基金supported by the National Natural Science Foundation of China (21374085, 21174110, 51233003)the Natural Science Foundation of Hubei Province of China (2014CFB697)the Fundamental Research Funds for the Central Universities (2042014kf0193)
文摘A polymeric polyethylenimine(PEI)-based prodrug of anticancer doxorubicin(DOX)(PEI-hyd-DOX) was designed by attaching DOX to PEI via an acid-labile hydrazone bond, for the achievement of biocontrollable gene and drug co-delivery in response to the intracellular acid microenvironments in the late endosome/lysosome compartments. The cytotoxicity of PEI-hyd-DOX was evaluated by the MTT assay and the cellular uptake was monitored using confocal laser scanning microscopy. The polymeric prodrug can respond with a high sensitivity to the specific acid condition inside cells, thus permitting the precise biocontrol over intracellular drug liberation with high drug efficacy. The chemical attachment of drug molecules also led to the relatively reduced toxicity and the enhanced transfection efficiency compared with parent PEI. The resulting data adumbrated the potential of PEI-hyd-DOX to co-deliver DOX and therapeutic gene for the combination of chemotherapy and gene therapy.
