Spurred by significant progress in materials chemistry and drug delivery, charge-reversal nanocarriers are being developed to deliver anticancer formulations in spatial-, temporal- and dosagecontrolled approaches. Cha...Spurred by significant progress in materials chemistry and drug delivery, charge-reversal nanocarriers are being developed to deliver anticancer formulations in spatial-, temporal- and dosagecontrolled approaches. Charge-reversal nanoparticles can release their drug payload in response to specific stimuli that alter the charge on their surface. They can elude clearance from the circulation and be activated by protonation, enzymatic cleavage, or a molecular conformational change. In this review, we discuss the physiological basis for, and recent advances in the design of charge-reversal nanoparticles that are able to control drug biodistribution in response to specific stimuli, endogenous factors(changes in p H,redox gradients, or enzyme concentration) or exogenous factors(light or thermos-stimulation).展开更多
Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the re...Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac(Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species(ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A(LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1a(HIF-1a) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.展开更多
Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the a...Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6(Ce6), hydrophilic chemotherapeutic drug berberrubine(BBR) and matrix metalloproteinase-2(MMP-2) response peptide(PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6(BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine(PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively,we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.展开更多
Due to the limitations of conventional chemotherapy including side effects,poor prognosis,and drug resistance,there is an urgent need for the development of a novel multi-functional combined therapy strategy.Dopamine-...Due to the limitations of conventional chemotherapy including side effects,poor prognosis,and drug resistance,there is an urgent need for the development of a novel multi-functional combined therapy strategy.Dopamine-modified oxaliplatin prodrug(OXA-DA)was successfully synthesized in this study to ameliorate the organ distribution of oxaliplatin for improving the drug efficacy and reducing toxic side effects,and OXA-DA was applied to develop a porous oxaliplatin cross-linked polydopamine nanoparticle for loading siPD-L1 to construct multifunctional nanoplatform.The multifunctional nanoplatform was modified with poly(2-ethyl-2-oxazoline)(PEOz),which occurred charge reversal in the tumor microenvironment,and exerted the lysosomal escape effect in tumor cells to improve the bioavailability of small interfering RNA targeting programmed cell death-ligand 1(siPD-L1).The pH-responsive charge reversal,photothermal,biodegradation,lysosomal escape ability,PD-L1 protein degradation,toxicity properties and multiple antitumor effects were comprehensively evaluated in vitro and in vivo experiments.The findings indicated that OXA-DA-siPD-L1@PDA-PEOz excellently induced tumor cell necrosis and apoptosis as a result of the synergistic effect of chemo-photothermal therapy,and upregulated CD8+T cells produced interferon-γ(IFN-γ)to further attack the tumor cells.In conclusion,the novel nanoplatform-mediated chemo/photothermal/immunotherapy has promising clinical applications in the treatment of malignant tumors.展开更多
Unique physiopathological characteristics of tumor tissues impose obstacles to the sufficient penetration of traditional nanomedicines,resulting in undesirable drug delivery efficacy and therapeutic outcomes.Here,we c...Unique physiopathological characteristics of tumor tissues impose obstacles to the sufficient penetration of traditional nanomedicines,resulting in undesirable drug delivery efficacy and therapeutic outcomes.Here,we constructed TRAIL-[NDHCPT]^(GAC),a synergistic hydroxycamptothecin(HCPT)and tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)protein co-loaded disk-shaped nanocarrier withγ-glutamyl transpeptidase responsiveness.When the novel nanodisks extravasated into the tumor interstitium,theγ-glutamyl transpeptidase overexpressed on the tumor cell membranes cleaved theγ-glutamyl portions of the nanodisk surface to produce positively charged amino groups.As a result,the cationic nanodisks possessed stronger tumor infiltration ability through transcytosis than anionic nanodisks.HCPT and TRAIL exerted synergistic antitumor effects with better overall therapeutic efficacy.This TRAIL-[ND-HCPT]^(GAC)system performed significantly better than free HCPT and remarkably prolonged the survival of breast tumor-bearing mice with no significant toxicity.展开更多
Fe-based Fenton agents can generate highly reactive and toxic hydroxyl radicals(·OH)in the tumor microenvironment(TME)for chemodynamic therapy(CDT)with high specificity.However,the low pH environment and insuffic...Fe-based Fenton agents can generate highly reactive and toxic hydroxyl radicals(·OH)in the tumor microenvironment(TME)for chemodynamic therapy(CDT)with high specificity.However,the low pH environment and insufficient endogenous hydrogen peroxide(H_(2)O_(2))of the highly efficient Fenton reaction limits its practical application in clinic.Here,a Cu(Ⅱ)-doped mesoporous silica nanoagent(Cu-MSN)with excellent dispersity was successfully developed.After loaded with doxorubicin(DOX)and ascorbate(AA),Cu-MSN@DA was coated with active targeting ligand folic acid(FA),dimethyl maleic an-hydride(DMMA)and carboxymethyl chitosan(CMC)to obtain an active transporting nanoagent(FCDC@Cu-MSN@DA)with tunable charge-reversal property,which is more adaptable to the pH value of TME than Fe-based Fenton agents,and can self-supply exogenous H_(2)O_(2)by ascorbate to produce more toxic·OH to trigger the apoptosis of cancer cells.Meanwhile,the high level of glutathione(GSH)in TME can reduce Cu(Ⅱ)to Cu(I)by Fenton-like reaction,increasing the generation rate of·OH and relieving tumor antioxidant ability.The supply of exogenous H_(2)O_(2)significantly enhanced the synergistic effect of CDT by oxidative damage.Together with DOX-induced cell apoptosis,this novel nanoagent FCDC@Cu-MSN@DA can achieve maximum therapeutic efficacy,creating a new model of safe and effective tumor treatment with high specificity.展开更多
Nanodrug carriers with fluorescence radiation are widely used in cancer diagnosis and therapy due to their real-time imaging,less side effect,better drug utilization as well as the good bioimaging ability.However,trad...Nanodrug carriers with fluorescence radiation are widely used in cancer diagnosis and therapy due to their real-time imaging,less side effect,better drug utilization as well as the good bioimaging ability.However,traditional nanocarriers still suffer from unexpectable drug leakage,unsatisfactory tumor-targeted drug delivery and shallow imaging depth,which limit their further application in cancer theranostics.In this study,an integrated nanoplatform is constructed by polymeric prodrug micelles with two-photon and aggregation-induced emission bioimaging,charge reversal and drug delivery triggered by acidic pH.The prodrug micelles can be self-assembled by the TPPEI(DA/DOX)-PEG prodrug polymer,which consists of the two-photon fluorophore(TP),dimethylmaleic anhydride(DA)grafted polyethyleneimine(PEI)and polyethylene glycol(PEG).The PEG segment,DOX and DA are bridged to polymer by acid cleavable bonds,which provides the micelles a‘stealth’property and a satisfactory stability during blood circulation,while the outside PEG segment is abandoned along with the DA protection in the tumor acidic microenvironment,thus leading to charge reversal-mediated accelerated endocytosis and tumor-targeted drug delivery.The great antitumor efficacy and reduced side effect of these pH-sensitive prodrug micelles are confirmed by antitumor assays in vitro and in vivo.Meanwhile,these micelles exhibited great deep-tissue two-photon bioimaging ability up to 150 lm in depth.The great antitumor efficacy,reduced side effect and deep two-photon tissue imaging make the TP-PEI(DA/DOX)-PEG prodrug micelles would be an efficient strategy for theranostic nanoplatform in cancer treatment.展开更多
The interaction between metal and support is critical in oxygen catalysis as it governs the charge transfer between these two entities,influences the electronic structures of the supported metal,affects the adsorption...The interaction between metal and support is critical in oxygen catalysis as it governs the charge transfer between these two entities,influences the electronic structures of the supported metal,affects the adsorption energies of reaction intermediates,and ultimately impacts the catalytic performance.In this study,we discovered a unique charge transfer reversal phenomenon in a metal/carbon nanohybrid system.Specifically,electrons were transferred from the metal-based species to N-doped carbon,while the carbon support reciprocally donated electrons to the metal domain upon the introduction of nickel.This led to the exceptional electrocatalytic performances of the resulting Ni-Fe/Mo_(2)C@nitrogen-doped carbon catalyst,with a half-wave potential of 0.91 V towards oxygen reduction reaction(ORR)and a low overpotential of 290 m V at 10 mA cm^(-2)towards oxygen evolution reaction(OER)under alkaline conditions.Additionally,the Fe-Ni/Mo_(2)C@carbon heterojunction catalyst demonstrated high specific capacity(794 mA h g_(Zn)~(-1))and excellent cycling stability(200 h)in a Zn-air battery.Theoretical calculations revealed that Mo_(2)C effectively inhibited charge transfer from Fe to the support,while secondary doping of Ni induced a charge transfer reversal,resulting in electron accumulation in the Fe-Ni alloy region.This local electronic structure modulation significantly reduced energy barriers in the oxygen catalysis process,enhancing the catalytic efficiency of both ORR and OER.Consequently,our findings underscore the potential of manipulating charge transfer reversal between the metal and support as a promising strategy for developing highly-active and durable bi-functional oxygen electrodes.展开更多
Due to better penetrating abilities of near-infrared (NIR) light and lower autofluorescence of biological tissue at NIR region, the combination of NIR fluorescent imaging with therapeutic abilities has gradually emerg...Due to better penetrating abilities of near-infrared (NIR) light and lower autofluorescence of biological tissue at NIR region, the combination of NIR fluorescent imaging with therapeutic abilities has gradually emerged as a promising strategy for cancer therapy. Herein, tumor microenvironment (TME) sensitive nanocarriers based on doxorubicin hydrochloride (DOX), NIR emitting carbon dots (C-dots), hollow mesoporous silica nanoparticles (HMSN) and anionic polymer citraconic anhydride-modified polylysine (PLL(cit)) are fabricated for imaging guided drug delivery. The NIR emitting C-dots were conjugated onto the surface of HMSN via disulfide bonds which can be reduced by intracellular glutathione (GSH) and result in the release of DOX into cells. And then the PLL(cit) was grafted on the surface of the nanocarriers to endow the nanocarriers with charge convertible property in mildly acidic TME (pH = 6.50) which results in prolonged blood circulation time and enhanced cellular internalization. The in vitro and in vivo experiments confirmed that the dual pH/GSH responsive features of nanocarriers can eliminate the tumor tissues effectively and elicit much slighter side effects. Moreover, since the fluorescence of C-dots can be recovered after the reduction of disulfide bonds and selectively accumulation of nanocarriers around tumor tissue, the DOX@HMSN-SS-C-dots-PLL(cit) can be served as a promising NIR fluorescence probe for targeted imaging of tumor tissue. As a kind of multifunctional nanocarrier with NIR fluorescent imaging and therapeutic functions, the theranostic nanocarriers hold great potential for tumor therapy and in vivo imaging of tumor tissue.展开更多
The strategy of pH-responsive aggregation in tumor micro-environment(TME)provides an intriguing platform for enhancing tumor retention and exerting therapeutic effects sufficiently.In this work,we have designed an int...The strategy of pH-responsive aggregation in tumor micro-environment(TME)provides an intriguing platform for enhancing tumor retention and exerting therapeutic effects sufficiently.In this work,we have designed an intelligent dual pH-responsive self-aggregating nano gold system(Au@PAH-Pt/DMMA)for the combined chemo-radiotherapy,in which a“charge-reversal like”strategy was utilized to realize irreversible stable aggregation and pH-specific release of cisplatin prodrug in TME.Responsive aggregation increases the cellular uptake of Au@PAH-Pt/DMMA by 55%–60%,and the cellular uptake of Pt after X-ray irradiation can be further enhanced by 80%.Additionally,responsive aggregation greatly slows down the rate of efflux from tumor in vivo.This system not only promotes B16 cell apoptosis as a chemotherapeutic agent(30.4%),it also enhances the effect of chemo-radiotheray(CRT)by promoting apoptosis as a radiosensitizer(55.3%).The colony formation assay results were fitted to cell survival curve of B16 cells and the sensitization enhancement ratio(SER)was calculated to be 1.29,which shows a good radiosensitizing ability.When exposed to X-ray,this nanoplatform reached the ideal therapeutic effect,and the tumor inhibition rate of Au@PAH-Pt/DMMA reached 91.6%with low drug administration frequency and dose of X-ray.Overall,the dual pH-responsive nanoparticles Au@PAH-Pt/DMMA could effectively enhance tumor therapeutic efficiency by combined chemo-radiotherapy,which provides a potential method for clinical transformation of cancer treatment.展开更多
文摘Spurred by significant progress in materials chemistry and drug delivery, charge-reversal nanocarriers are being developed to deliver anticancer formulations in spatial-, temporal- and dosagecontrolled approaches. Charge-reversal nanoparticles can release their drug payload in response to specific stimuli that alter the charge on their surface. They can elude clearance from the circulation and be activated by protonation, enzymatic cleavage, or a molecular conformational change. In this review, we discuss the physiological basis for, and recent advances in the design of charge-reversal nanoparticles that are able to control drug biodistribution in response to specific stimuli, endogenous factors(changes in p H,redox gradients, or enzyme concentration) or exogenous factors(light or thermos-stimulation).
基金supported by National Natural Science Foundation of China(81961138009,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(No.2020YFS0570,China)+2 种基金111 Project(B18035,China)the Fundamental Research Funds for the Central Universities(China)the Open Research Fund of Chengdu University of Traditional Chinese Medicine State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China(China)。
文摘Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac(Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species(ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A(LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1a(HIF-1a) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.
基金supported by National Natural Science Foundation of China (82173762)111 Project (B18035,China)+1 种基金the Key Research and Development Program of Science and Technology Department of Sichuan Province (2022JDJQ0050,2022YFS0334)the Open Research Fund of Chengdu University of Traditional Chinese Medicine State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China。
文摘Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6(Ce6), hydrophilic chemotherapeutic drug berberrubine(BBR) and matrix metalloproteinase-2(MMP-2) response peptide(PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6(BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine(PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively,we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.
基金the National Natural Science Foundation of China(Nos.32071342 and 32101065)the Natural Science Foundation of Guangdong Province(Nos.2023A1515012015,2022A1515110271 and 2020A1515011353).
文摘Due to the limitations of conventional chemotherapy including side effects,poor prognosis,and drug resistance,there is an urgent need for the development of a novel multi-functional combined therapy strategy.Dopamine-modified oxaliplatin prodrug(OXA-DA)was successfully synthesized in this study to ameliorate the organ distribution of oxaliplatin for improving the drug efficacy and reducing toxic side effects,and OXA-DA was applied to develop a porous oxaliplatin cross-linked polydopamine nanoparticle for loading siPD-L1 to construct multifunctional nanoplatform.The multifunctional nanoplatform was modified with poly(2-ethyl-2-oxazoline)(PEOz),which occurred charge reversal in the tumor microenvironment,and exerted the lysosomal escape effect in tumor cells to improve the bioavailability of small interfering RNA targeting programmed cell death-ligand 1(siPD-L1).The pH-responsive charge reversal,photothermal,biodegradation,lysosomal escape ability,PD-L1 protein degradation,toxicity properties and multiple antitumor effects were comprehensively evaluated in vitro and in vivo experiments.The findings indicated that OXA-DA-siPD-L1@PDA-PEOz excellently induced tumor cell necrosis and apoptosis as a result of the synergistic effect of chemo-photothermal therapy,and upregulated CD8+T cells produced interferon-γ(IFN-γ)to further attack the tumor cells.In conclusion,the novel nanoplatform-mediated chemo/photothermal/immunotherapy has promising clinical applications in the treatment of malignant tumors.
基金The Regional Innovation and Development Joint Fund(No.U20A20411)the National Science Fund for Excellent Young Scholars(No.82022070)provided funding for this work。
文摘Unique physiopathological characteristics of tumor tissues impose obstacles to the sufficient penetration of traditional nanomedicines,resulting in undesirable drug delivery efficacy and therapeutic outcomes.Here,we constructed TRAIL-[NDHCPT]^(GAC),a synergistic hydroxycamptothecin(HCPT)and tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)protein co-loaded disk-shaped nanocarrier withγ-glutamyl transpeptidase responsiveness.When the novel nanodisks extravasated into the tumor interstitium,theγ-glutamyl transpeptidase overexpressed on the tumor cell membranes cleaved theγ-glutamyl portions of the nanodisk surface to produce positively charged amino groups.As a result,the cationic nanodisks possessed stronger tumor infiltration ability through transcytosis than anionic nanodisks.HCPT and TRAIL exerted synergistic antitumor effects with better overall therapeutic efficacy.This TRAIL-[ND-HCPT]^(GAC)system performed significantly better than free HCPT and remarkably prolonged the survival of breast tumor-bearing mice with no significant toxicity.
基金financially supported by the National Key Research and Development Program of China(No.2019YFA0705803)the National Natural Science Foundation of China Youth Fund(Nos.51803174,82102470)+4 种基金the Natural Science Foundation of Sichuan Province(No.24NSFSC4798)the Foundation of Sichuan Engineering Technology Research Center of Basalt Fiber Composites Development and Application of Southwest Petroleum University(No.2022SCXWYXWFC002)the support from the School of New Energy and Materials of Southwest Petroleum UniversitySichuan International Science and Technology Cooperation BaseDalian Institute of Chemical Physics of Chinese Academy of Sciences。
文摘Fe-based Fenton agents can generate highly reactive and toxic hydroxyl radicals(·OH)in the tumor microenvironment(TME)for chemodynamic therapy(CDT)with high specificity.However,the low pH environment and insufficient endogenous hydrogen peroxide(H_(2)O_(2))of the highly efficient Fenton reaction limits its practical application in clinic.Here,a Cu(Ⅱ)-doped mesoporous silica nanoagent(Cu-MSN)with excellent dispersity was successfully developed.After loaded with doxorubicin(DOX)and ascorbate(AA),Cu-MSN@DA was coated with active targeting ligand folic acid(FA),dimethyl maleic an-hydride(DMMA)and carboxymethyl chitosan(CMC)to obtain an active transporting nanoagent(FCDC@Cu-MSN@DA)with tunable charge-reversal property,which is more adaptable to the pH value of TME than Fe-based Fenton agents,and can self-supply exogenous H_(2)O_(2)by ascorbate to produce more toxic·OH to trigger the apoptosis of cancer cells.Meanwhile,the high level of glutathione(GSH)in TME can reduce Cu(Ⅱ)to Cu(I)by Fenton-like reaction,increasing the generation rate of·OH and relieving tumor antioxidant ability.The supply of exogenous H_(2)O_(2)significantly enhanced the synergistic effect of CDT by oxidative damage.Together with DOX-induced cell apoptosis,this novel nanoagent FCDC@Cu-MSN@DA can achieve maximum therapeutic efficacy,creating a new model of safe and effective tumor treatment with high specificity.
基金supported by the National Natural Science Foundation of China(Projects No.21502129)the National 111 Project of Introducing Talents of Discipline to Universities(No.B16033)+1 种基金China Postdoctoral Science Foundation Funded Project(Nos.2017M612956,2018T110969)the State Key Laboratory of Polymer Materials Engineering(No.sklpme2018-3-05)。
文摘Nanodrug carriers with fluorescence radiation are widely used in cancer diagnosis and therapy due to their real-time imaging,less side effect,better drug utilization as well as the good bioimaging ability.However,traditional nanocarriers still suffer from unexpectable drug leakage,unsatisfactory tumor-targeted drug delivery and shallow imaging depth,which limit their further application in cancer theranostics.In this study,an integrated nanoplatform is constructed by polymeric prodrug micelles with two-photon and aggregation-induced emission bioimaging,charge reversal and drug delivery triggered by acidic pH.The prodrug micelles can be self-assembled by the TPPEI(DA/DOX)-PEG prodrug polymer,which consists of the two-photon fluorophore(TP),dimethylmaleic anhydride(DA)grafted polyethyleneimine(PEI)and polyethylene glycol(PEG).The PEG segment,DOX and DA are bridged to polymer by acid cleavable bonds,which provides the micelles a‘stealth’property and a satisfactory stability during blood circulation,while the outside PEG segment is abandoned along with the DA protection in the tumor acidic microenvironment,thus leading to charge reversal-mediated accelerated endocytosis and tumor-targeted drug delivery.The great antitumor efficacy and reduced side effect of these pH-sensitive prodrug micelles are confirmed by antitumor assays in vitro and in vivo.Meanwhile,these micelles exhibited great deep-tissue two-photon bioimaging ability up to 150 lm in depth.The great antitumor efficacy,reduced side effect and deep two-photon tissue imaging make the TP-PEI(DA/DOX)-PEG prodrug micelles would be an efficient strategy for theranostic nanoplatform in cancer treatment.
基金financially supported by the Outstanding Youth Scientific Research Project for Colleges and Universities of Anhui Province of China (2022AH020054)the Anhui Provincial Natural Science Foundation (2208085Y06)+2 种基金the National Natural Science Foundation of China (Nos.21975001 and U2002213)the Support Program of Excellent Young Talents in Anhui Provincial Colleges and Universities (gxyq ZD2022034)the Double Tops Joint Fund of the Yunnan Science and Technology Bureau and Yunnan University (2019FY003025)。
文摘The interaction between metal and support is critical in oxygen catalysis as it governs the charge transfer between these two entities,influences the electronic structures of the supported metal,affects the adsorption energies of reaction intermediates,and ultimately impacts the catalytic performance.In this study,we discovered a unique charge transfer reversal phenomenon in a metal/carbon nanohybrid system.Specifically,electrons were transferred from the metal-based species to N-doped carbon,while the carbon support reciprocally donated electrons to the metal domain upon the introduction of nickel.This led to the exceptional electrocatalytic performances of the resulting Ni-Fe/Mo_(2)C@nitrogen-doped carbon catalyst,with a half-wave potential of 0.91 V towards oxygen reduction reaction(ORR)and a low overpotential of 290 m V at 10 mA cm^(-2)towards oxygen evolution reaction(OER)under alkaline conditions.Additionally,the Fe-Ni/Mo_(2)C@carbon heterojunction catalyst demonstrated high specific capacity(794 mA h g_(Zn)~(-1))and excellent cycling stability(200 h)in a Zn-air battery.Theoretical calculations revealed that Mo_(2)C effectively inhibited charge transfer from Fe to the support,while secondary doping of Ni induced a charge transfer reversal,resulting in electron accumulation in the Fe-Ni alloy region.This local electronic structure modulation significantly reduced energy barriers in the oxygen catalysis process,enhancing the catalytic efficiency of both ORR and OER.Consequently,our findings underscore the potential of manipulating charge transfer reversal between the metal and support as a promising strategy for developing highly-active and durable bi-functional oxygen electrodes.
基金This study was funded by National Natural Science Foundation of China (Nos. 51773055, 51973053, and 22073025)Natural Science Foundation of Hubei Province of China (No. 2019CFB748).
文摘Due to better penetrating abilities of near-infrared (NIR) light and lower autofluorescence of biological tissue at NIR region, the combination of NIR fluorescent imaging with therapeutic abilities has gradually emerged as a promising strategy for cancer therapy. Herein, tumor microenvironment (TME) sensitive nanocarriers based on doxorubicin hydrochloride (DOX), NIR emitting carbon dots (C-dots), hollow mesoporous silica nanoparticles (HMSN) and anionic polymer citraconic anhydride-modified polylysine (PLL(cit)) are fabricated for imaging guided drug delivery. The NIR emitting C-dots were conjugated onto the surface of HMSN via disulfide bonds which can be reduced by intracellular glutathione (GSH) and result in the release of DOX into cells. And then the PLL(cit) was grafted on the surface of the nanocarriers to endow the nanocarriers with charge convertible property in mildly acidic TME (pH = 6.50) which results in prolonged blood circulation time and enhanced cellular internalization. The in vitro and in vivo experiments confirmed that the dual pH/GSH responsive features of nanocarriers can eliminate the tumor tissues effectively and elicit much slighter side effects. Moreover, since the fluorescence of C-dots can be recovered after the reduction of disulfide bonds and selectively accumulation of nanocarriers around tumor tissue, the DOX@HMSN-SS-C-dots-PLL(cit) can be served as a promising NIR fluorescence probe for targeted imaging of tumor tissue. As a kind of multifunctional nanocarrier with NIR fluorescent imaging and therapeutic functions, the theranostic nanocarriers hold great potential for tumor therapy and in vivo imaging of tumor tissue.
基金This work was financially supported by the National Natural Science Foundation of China(Nos.51433004,51773096,and 21604095)Natural Science Foundation of Tianjin(Nos.17JCZDJC33500 and 18JCQNJC14500)+1 种基金Program for Innovative Research Team in Peking Union Medical College,CAMS Initiative for Innovative Medicine(No.2017-I2M-3-022)Specific Program for High-Tech Leader&Team of Tianjin Government,Tianjin innovation and promotion plan key innovation team of immunoreactive biomaterials.We would like to thank Qiang Wu for FTIR spectroscopy and the guidance,Zhiqing Qiao and Lei Chen for ICP-OES,Yujun Yan and Jie Gu for radiotherapy experiments,Yajuan Wan and Rui Wang for flow cytometry,and Mengyue Pei for in vitro experiments.
文摘The strategy of pH-responsive aggregation in tumor micro-environment(TME)provides an intriguing platform for enhancing tumor retention and exerting therapeutic effects sufficiently.In this work,we have designed an intelligent dual pH-responsive self-aggregating nano gold system(Au@PAH-Pt/DMMA)for the combined chemo-radiotherapy,in which a“charge-reversal like”strategy was utilized to realize irreversible stable aggregation and pH-specific release of cisplatin prodrug in TME.Responsive aggregation increases the cellular uptake of Au@PAH-Pt/DMMA by 55%–60%,and the cellular uptake of Pt after X-ray irradiation can be further enhanced by 80%.Additionally,responsive aggregation greatly slows down the rate of efflux from tumor in vivo.This system not only promotes B16 cell apoptosis as a chemotherapeutic agent(30.4%),it also enhances the effect of chemo-radiotheray(CRT)by promoting apoptosis as a radiosensitizer(55.3%).The colony formation assay results were fitted to cell survival curve of B16 cells and the sensitization enhancement ratio(SER)was calculated to be 1.29,which shows a good radiosensitizing ability.When exposed to X-ray,this nanoplatform reached the ideal therapeutic effect,and the tumor inhibition rate of Au@PAH-Pt/DMMA reached 91.6%with low drug administration frequency and dose of X-ray.Overall,the dual pH-responsive nanoparticles Au@PAH-Pt/DMMA could effectively enhance tumor therapeutic efficiency by combined chemo-radiotherapy,which provides a potential method for clinical transformation of cancer treatment.
