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
Carrier-free drug self-delivery systems consisting of amphiphilic drug-drug conjugate(ADDC)with well-defined structure and nanoscale features have drawn much attention in tumor drug delivery.Herein,we report a simple ...Carrier-free drug self-delivery systems consisting of amphiphilic drug-drug conjugate(ADDC)with well-defined structure and nanoscale features have drawn much attention in tumor drug delivery.Herein,we report a simple and effective strategy to prepare ADDC using derivatives of cisplatin(CP)and dasatinib(DAS),which further selfassembled to form reduction-responsive nanoparticles(CP-DDA NPs).DAS was modified with succinic anhydride and then connected with CP derivative by ester bonds.The size,micromorphology and in vitro drug release of CP-DDA NPs were characterized.The biocompatibility and bioactivity of these carrier-free nanoparticles were then investigated by HepG2 cells and H22-tumor bearing mice.In vitro and in vivo experiments proved that CPDDA NPs had excellent anti-tumor activity and significantly reduced toxicities.This study provides a new strategy to design the carrier-free nanomedicine composed of CP and DAS for synergistic tumor treatment.展开更多
Ultrasound(US)has been applied in clinical practice for its non-invasive and high selectivity.However,it is difficult to achieve a satisfactory anti-tumor effect with US alone.Meanwhile,the use of US therapy alone can...Ultrasound(US)has been applied in clinical practice for its non-invasive and high selectivity.However,it is difficult to achieve a satisfactory anti-tumor effect with US alone.Meanwhile,the use of US therapy alone can exacerbate tumor hypoxia.In this study,we prepared hypoxia-activated 6-diazo-5-oxo-L-norleucine(DON)prodrug nanoparticles(HDON-NPs)to improve US therapeutic effects.In an H22 murine liver cancer model,US therapy selectively disrupted tumor blood vessels,leading to increased tumor hypoxia and a 1.67-fold increase in the expression of nitroreductase(NTR).The combination therapy of US and HDON-NPs demonstrated a synergistic effect,resulting in a tumor suppression rate(TSR)of 90.2%±6.4%,which was 5.93-fold higher than that of US therapy alone.The combined treatment selectively blocked the glutamine metabolism of the tumor cells while simultaneously activating the T cells in the tumor microenvironment,thereby exerting a robust anti-tumor effect.展开更多
The combinational chemo-immunotherapy as a novel treatment strategy has been widely studied and applied in clinic to enhance antitumor therapeutic efficacy and relieve side effects.RNA interference(RNAi)targeting PD-L...The combinational chemo-immunotherapy as a novel treatment strategy has been widely studied and applied in clinic to enhance antitumor therapeutic efficacy and relieve side effects.RNA interference(RNAi)targeting PD-L1 via inhibiting novo production of PD-L1 will overcome the innate and adaptive PD-L1 expression during chemotherapy,thus enable sustained and efficient immune checkpoint blockade(ICB)to active antitumor immune response.Herein,we designed a glutathione(GSH)-responsive camptothecin(CPT)prodrug-based hybrid micellar nanoparticles(siPD-L1@HM-CPT)to achieve synergistic antitumor chemoimmunotherapy by PD-L1 knockdown.siPD-L1@HM-CPT derived from the one-step loading PD-L1 siRNA(siPD-L1)into the CPT prodrug-based hybrid micelles(HM-CPT)which were co-assembled from biodegradable polyphosphoesters-based prodrug CPT-ss-PAEEP15 and stabilizer DSPE-PEG,showed high loading efficiency,GSH-responsive drug release,and excellent stability and biosafety.siPD-L1@HM-CPT achieved simultaneously the co-delivery of CPT and siPD-L1 in vitro and in vivo,high accumulation at the tumor sites,and rapid intracellular release to promote antitumor efficacy via sensitizing CPT chemotherapy,inducing strong immunogenic cell death(ICD)and sustained ICB to improve intratumoral CD8+T cells infiltration.In addition,the antitumor immunity response limited by the differentiated immunogenicity,intrinsic PD-L1 expression,and intracellular GSH level was facilitated by efficient ICD and ICB from silencing PD-L1 and synergistic CPT chemosensitization in our experimental B16-F10 and 4T1 tumor models.Our study might offer a perspective on designing novel co-delivery nanoparticles by convenient and controllable preparation for antitumor chemo-immunotherapy.展开更多
PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles(prodrug-SANPs).However,the impacts of the amount of PEG on the self-assemble stability,cellular uptake,...PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles(prodrug-SANPs).However,the impacts of the amount of PEG on the self-assemble stability,cellular uptake,pharmacokinetics,and antitumor efficacy of prodrug-SANPs are still unknown.Herein,selenoether bond bridged docetaxel dimeric prodrug was synthesized as the model prodrug.Five prodrug-SANPs were designed by using different mass ratios of prodrugs to PEG(W_(prodrug)/W_(DSPE-mPEG2000)=10:0,9:1,8:2,7:3 and 6:4),and defined as Pure drug NPs,9:1NPs,8:2NPs,7:3 NPs and 6:4 NPs,respectively.Interestingly,8:2 NPs formed the most compact nanostructure,thus improving the self-assemble stability and pharmacokinetics behavior.In addition,the difference of these prodrug-SANPs in cellular uptake was investigated,and the influence of PEG on cytotoxicity and antitumor efficacy was also clarified in details.The 8:2 NPs exhibited much better antitumor efficacy than other prodrug-SANPs and even commercial product.Our findings demonstrated the pivotal role of the amount of PEG on prodrug-SANPs.展开更多
Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance.Herein,a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune...Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance.Herein,a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms.A disulfide bond-linked bispecific prodrug of NLG919 and JQ1(namely NJ) was synthesized and self-assembled into a prodrug nanoparticle,which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ.Upon tumor accumulation via passive tumor targeting,the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug.NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond.JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1.In contrast,NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment,which thus restores robust antitumor immune responses.Photodynamic therapy(PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells.The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.展开更多
In spired by the clinically approved albumin based PTX formulatio n(Abraxa ne)and high-drug-loading dimeric prodrug tactics,herein we report a theranostic HAbraxane-likeH prodrug formulation,which is comprised of huma...In spired by the clinically approved albumin based PTX formulatio n(Abraxa ne)and high-drug-loading dimeric prodrug tactics,herein we report a theranostic HAbraxane-likeH prodrug formulation,which is comprised of human serum albumin(HSA),a paclitaxel(PTX)dimer bridged with thioether liner(PTX2-S),and photosensitizer IR780 iodide.Nanoparticles(NPs)with PTX2-S and IR780 as the core and HSA as the stealth shell are formed.Compared with HSA-based PTX clinical formulation(Abraxane),the dimeric molecules not only constitute the bulk structure of the particles,but also act as crossi ng age nt,thus realizing drug loadi ng content in creasi ng from 6.6 wt.%to 48.7 wt.%with high loadi ng efficie ncy(>90%)and excellent stability in biological conditions.Importa ntly,the thioether lin kage dually resp onds to the tumor redox heteroge neity and the NPs gradually releases the pare nt drug PTX for chemotherapy.Mea nwhile,PTX2-S facilitates the en capsulatio n of IR780 iodide due to their π-π stacki ng interaction and IR780 iodide gen erates spatio-temporal hyperthermia un der light irradiation to kill cancer cells for photothermal therapy.The described craft integrates the biomimetic trait of HSA,high drug loading,tumor redox heterogeneity-initiated on-dema nd drug release,and combi nation therapy into one formulati on and the developed nan oparticles are promising for cancer treatment.展开更多
Chemotherapy combined with photodynamic therapy has emerged as a promising strategy for cancer treatment.However,simultaneously delivering chemotherapeutic drugs and photosensitizers and precisely adjusting the ratio ...Chemotherapy combined with photodynamic therapy has emerged as a promising strategy for cancer treatment.However,simultaneously delivering chemotherapeutic drugs and photosensitizers and precisely adjusting the ratio of the two components as needed remains a challengeable task.Herein,novel supramolecular nanoparticles(donated as BODIPY-CPT-NPs)for chemo-photodynamic combination cancer therapy are constructed from a glutathione-responsive camptothecin-based prodrug,BODIPY photosensitizer,and dimacrocyclic host molecule through orthogonal host-guest recognitions and co-assembly.With this strategy,the ratio of prodrugs and photosensitizers in nanoparticles can be easily and precisely controlled as needed.Benefiting from the strong host-guest interactions and stable self-assembly,the nanoparticles exhibit excellent stability and photobleaching resistance.Furthermore,camptothecin can be released from nanoparticles for chemotherapy in the presence of reduction agent and single oxygen can be efficiently generated for PDT with light irradiation.The combined effects of the BODIPY-CPT-NPs have been verified in CT26 and HeLa cancer cells.展开更多
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supported by the National Natural Science Foundation of China(No.51803001 and 51503001)the Natural Science Foundation of Anhui Province(No.2008085ME136 and 2008085QE210)+1 种基金the Research Foundation of Education Department of Anhui Province of China(No.KJ2018ZD003,KJ2018A0006 and KJ2019A0015)the Academic and Technology Introduction Project of Anhui University(AU02303203)grant.
文摘Carrier-free drug self-delivery systems consisting of amphiphilic drug-drug conjugate(ADDC)with well-defined structure and nanoscale features have drawn much attention in tumor drug delivery.Herein,we report a simple and effective strategy to prepare ADDC using derivatives of cisplatin(CP)and dasatinib(DAS),which further selfassembled to form reduction-responsive nanoparticles(CP-DDA NPs).DAS was modified with succinic anhydride and then connected with CP derivative by ester bonds.The size,micromorphology and in vitro drug release of CP-DDA NPs were characterized.The biocompatibility and bioactivity of these carrier-free nanoparticles were then investigated by HepG2 cells and H22-tumor bearing mice.In vitro and in vivo experiments proved that CPDDA NPs had excellent anti-tumor activity and significantly reduced toxicities.This study provides a new strategy to design the carrier-free nanomedicine composed of CP and DAS for synergistic tumor treatment.
基金financially supported by the Ministry of Science and Technology of China(No.2022YFE0110200)the Natural Science Foundation of Jilin Province(No.20230101037JC)the National Natural Science Foundation of China(Nos.52203198 and 52025035).
文摘Ultrasound(US)has been applied in clinical practice for its non-invasive and high selectivity.However,it is difficult to achieve a satisfactory anti-tumor effect with US alone.Meanwhile,the use of US therapy alone can exacerbate tumor hypoxia.In this study,we prepared hypoxia-activated 6-diazo-5-oxo-L-norleucine(DON)prodrug nanoparticles(HDON-NPs)to improve US therapeutic effects.In an H22 murine liver cancer model,US therapy selectively disrupted tumor blood vessels,leading to increased tumor hypoxia and a 1.67-fold increase in the expression of nitroreductase(NTR).The combination therapy of US and HDON-NPs demonstrated a synergistic effect,resulting in a tumor suppression rate(TSR)of 90.2%±6.4%,which was 5.93-fold higher than that of US therapy alone.The combined treatment selectively blocked the glutamine metabolism of the tumor cells while simultaneously activating the T cells in the tumor microenvironment,thereby exerting a robust anti-tumor effect.
基金The authors acknowledge the support by the National Basic Research Program of China(Nos.2020YFA0710700 and 2018YFA0208900)the National Natural Science Foundation of China(No.31470968).
文摘The combinational chemo-immunotherapy as a novel treatment strategy has been widely studied and applied in clinic to enhance antitumor therapeutic efficacy and relieve side effects.RNA interference(RNAi)targeting PD-L1 via inhibiting novo production of PD-L1 will overcome the innate and adaptive PD-L1 expression during chemotherapy,thus enable sustained and efficient immune checkpoint blockade(ICB)to active antitumor immune response.Herein,we designed a glutathione(GSH)-responsive camptothecin(CPT)prodrug-based hybrid micellar nanoparticles(siPD-L1@HM-CPT)to achieve synergistic antitumor chemoimmunotherapy by PD-L1 knockdown.siPD-L1@HM-CPT derived from the one-step loading PD-L1 siRNA(siPD-L1)into the CPT prodrug-based hybrid micelles(HM-CPT)which were co-assembled from biodegradable polyphosphoesters-based prodrug CPT-ss-PAEEP15 and stabilizer DSPE-PEG,showed high loading efficiency,GSH-responsive drug release,and excellent stability and biosafety.siPD-L1@HM-CPT achieved simultaneously the co-delivery of CPT and siPD-L1 in vitro and in vivo,high accumulation at the tumor sites,and rapid intracellular release to promote antitumor efficacy via sensitizing CPT chemotherapy,inducing strong immunogenic cell death(ICD)and sustained ICB to improve intratumoral CD8+T cells infiltration.In addition,the antitumor immunity response limited by the differentiated immunogenicity,intrinsic PD-L1 expression,and intracellular GSH level was facilitated by efficient ICD and ICB from silencing PD-L1 and synergistic CPT chemosensitization in our experimental B16-F10 and 4T1 tumor models.Our study might offer a perspective on designing novel co-delivery nanoparticles by convenient and controllable preparation for antitumor chemo-immunotherapy.
基金financially supported by National Natural Science Foundation of China (no. 81872816)Doctoral Scientific Research Staring Foundation of Liaoning Province (no. 2021BS-130)General Program of Department of Education of Liaoning Province (no. LJKZ0953)
文摘PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles(prodrug-SANPs).However,the impacts of the amount of PEG on the self-assemble stability,cellular uptake,pharmacokinetics,and antitumor efficacy of prodrug-SANPs are still unknown.Herein,selenoether bond bridged docetaxel dimeric prodrug was synthesized as the model prodrug.Five prodrug-SANPs were designed by using different mass ratios of prodrugs to PEG(W_(prodrug)/W_(DSPE-mPEG2000)=10:0,9:1,8:2,7:3 and 6:4),and defined as Pure drug NPs,9:1NPs,8:2NPs,7:3 NPs and 6:4 NPs,respectively.Interestingly,8:2 NPs formed the most compact nanostructure,thus improving the self-assemble stability and pharmacokinetics behavior.In addition,the difference of these prodrug-SANPs in cellular uptake was investigated,and the influence of PEG on cytotoxicity and antitumor efficacy was also clarified in details.The 8:2 NPs exhibited much better antitumor efficacy than other prodrug-SANPs and even commercial product.Our findings demonstrated the pivotal role of the amount of PEG on prodrug-SANPs.
基金supported by the National Natural Science Foundation of China(51873228,22074043)International Cooperation Project of Science and Technology Commission of Shanghai Municipality(20430711800,China)+1 种基金the Youth Innovation Promotion Association of CAS(2014218,China)the Fusion Grant between Fudan University and Shanghai Institute of Materia Medica,CAS(No.FU-SIMM-20182006,China)。
文摘Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance.Herein,a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms.A disulfide bond-linked bispecific prodrug of NLG919 and JQ1(namely NJ) was synthesized and self-assembled into a prodrug nanoparticle,which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ.Upon tumor accumulation via passive tumor targeting,the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug.NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond.JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1.In contrast,NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment,which thus restores robust antitumor immune responses.Photodynamic therapy(PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells.The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.
基金National Natural Science Foundation of China (Nos. 51773197 and 51522307).
文摘In spired by the clinically approved albumin based PTX formulatio n(Abraxa ne)and high-drug-loading dimeric prodrug tactics,herein we report a theranostic HAbraxane-likeH prodrug formulation,which is comprised of human serum albumin(HSA),a paclitaxel(PTX)dimer bridged with thioether liner(PTX2-S),and photosensitizer IR780 iodide.Nanoparticles(NPs)with PTX2-S and IR780 as the core and HSA as the stealth shell are formed.Compared with HSA-based PTX clinical formulation(Abraxane),the dimeric molecules not only constitute the bulk structure of the particles,but also act as crossi ng age nt,thus realizing drug loadi ng content in creasi ng from 6.6 wt.%to 48.7 wt.%with high loadi ng efficie ncy(>90%)and excellent stability in biological conditions.Importa ntly,the thioether lin kage dually resp onds to the tumor redox heteroge neity and the NPs gradually releases the pare nt drug PTX for chemotherapy.Mea nwhile,PTX2-S facilitates the en capsulatio n of IR780 iodide due to their π-π stacki ng interaction and IR780 iodide gen erates spatio-temporal hyperthermia un der light irradiation to kill cancer cells for photothermal therapy.The described craft integrates the biomimetic trait of HSA,high drug loading,tumor redox heterogeneity-initiated on-dema nd drug release,and combi nation therapy into one formulati on and the developed nan oparticles are promising for cancer treatment.
基金supported by National Natural Science Foundation of China(Nos.21702153 and 21801194)Wuhan Science and Technology Bureau(No.whkxjsj009)the support of the Core Facility of Wuhan University and the Large-scale Instrument and Equipment Sharing Foundation of Wuhan University.
文摘Chemotherapy combined with photodynamic therapy has emerged as a promising strategy for cancer treatment.However,simultaneously delivering chemotherapeutic drugs and photosensitizers and precisely adjusting the ratio of the two components as needed remains a challengeable task.Herein,novel supramolecular nanoparticles(donated as BODIPY-CPT-NPs)for chemo-photodynamic combination cancer therapy are constructed from a glutathione-responsive camptothecin-based prodrug,BODIPY photosensitizer,and dimacrocyclic host molecule through orthogonal host-guest recognitions and co-assembly.With this strategy,the ratio of prodrugs and photosensitizers in nanoparticles can be easily and precisely controlled as needed.Benefiting from the strong host-guest interactions and stable self-assembly,the nanoparticles exhibit excellent stability and photobleaching resistance.Furthermore,camptothecin can be released from nanoparticles for chemotherapy in the presence of reduction agent and single oxygen can be efficiently generated for PDT with light irradiation.The combined effects of the BODIPY-CPT-NPs have been verified in CT26 and HeLa cancer cells.
