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
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
pH-responsive charge reversal loaded miRNA nanocomposite was prepared by electrostatic self-assembly.The morphology,particle size and zeta potential of the nanocomposites were analyzed by transmission electron microsc...pH-responsive charge reversal loaded miRNA nanocomposite was prepared by electrostatic self-assembly.The morphology,particle size and zeta potential of the nanocomposites were analyzed by transmission electron microscopy and dynamic light scattering.The synthesis of the polymer was analyzed by^(1)H-NMR.The zeta-potential changes and cellular uptake effects of the nanocomplexes under different pH environments were investigated.The experimental results show that the surface morphology of the nanocomposite is spherical,and the average particle size is about 135 nm.As the pH value of the solution gradually decreases,the surface charge of the nanocomposite reverses from negative charge to positive charge(from-9.4 to+17.1 mV).Cellular uptake mediated by pH-responsive nanocomposite is selective for tumor cells,and the cellular uptake effect in tumor cells at pH 6.5 was approximately 3 times higher than that at pH 7.4.This pH responsive charge reversal nanocomposite has promising application prospects for gene delivery in the weak acid environment of tumors.展开更多
Nanopartide （NP） drug delivery systems have been successfully designed and implemented to orally deliver small interfering RNAs （siRNAs） for inflammatory disorders. However, the influence of surface charge on oral...Nanopartide （NP） drug delivery systems have been successfully designed and implemented to orally deliver small interfering RNAs （siRNAs） for inflammatory disorders. However, the influence of surface charge on orally administered siRNA nanocarriers has not been investigated. In this study, we prepared structurally related poly（ethylene glycol）-block-poly（lactic-co-glycolic acid） （PEG5K-b-PLGA10K） NPs with the assistance of a synthesized lipid featuring surface amine groups for subsequent charge tuning. NPs were prepared by a double emulsion method, and their surface charge could be tuned and controlled by a succinylation reaction to yield NPs with different surface charges, while maintaining their size and composition. The prepared NPs were termed as aminated NPs （ANPs）, plain NPs （PNPs）, or carboxylated NPs （CNPs） based on their surface charge. All NPs exhibited the desired structural stability and siRNA integrity after enzymatic degradation. In vivo studies showed that ANPs significantly accumulated in inflamed colons, and they were successful in decreasing TNF-α secretion and mRNA expression levels while maintaining colonic histology in a murine model of acute ulcerative colitis （UC）. This study described a methodology to modify the surface charge of siRNA-encapsulating polymeric NPs and highlighted the influence of surface charge on oral delivery of siRNA for localized inflammatory disorders.展开更多
Enhanced cellular uptake efficiency of nanoparticles is important for their biomedical applications, including photothermal therapy （PTT） for cancer. In this study, a one-pot method was used to construct a positivel...Enhanced cellular uptake efficiency of nanoparticles is important for their biomedical applications, including photothermal therapy （PTT） for cancer. In this study, a one-pot method was used to construct a positively charged and magnet-responsive nanocomposite comprising reduced graphene oxide anchoring iron oxide （RGI） with a polyethylenimine （PEI） modification, to improve the efficiency of cell internalization. The surface charge can be finely tuned using PEIs of different molecular weights. The obtained RGIlsk composite （RGI modified by 1.8 kDa PEI） could load indocyanine green （ICG） at a high mass ratio of 10：3 and ablate cancer cells using low-density laser irradiation because of its positively charged surface. In addition, the hybrids of RGI1.8k and ICG could kill most cancer cells at a laser density of 0.7 W/cm2 in vitro and 0.3 W/cm2 in vivo. At the same time, cell viability could be controlled by converting the external magnetic-field direction because of the enrichment of the magnet-responsive composite in vitro and in vivo. Furthermore, RGIr8k-ICGs could be used as T2-weighted magnetic resonance and infrared thermal imaging agents. Coupled with the magnetic target effect, the imaging signal could be improved significantly. Therefore, RGII^sk-ICGs represent a new highly efficient PTT and imaging agent with great potential for cancer treatment.展开更多
Nanomedicine has revolutionized disease theranostics by the accurate diagnosis and efficient therapy.Here,the PAMAM dendrimer decorated PVCL-GMA nanogels(NGs)were developed for favorable biodistribution in vivo and en...Nanomedicine has revolutionized disease theranostics by the accurate diagnosis and efficient therapy.Here,the PAMAM dendrimer decorated PVCL-GMA nanogels(NGs)were developed for favorable biodistribution in vivo and enhanced antitumor efficacy of ovarian carcinoma.By an ingenious design,the NGs with a unique structure that GMA-rich domains were localized on the surface were synthesized via precipitation polymerization.After G2 dendrimer decoration,the overall charge is changed from neutral to positive,and the NGs-G2 display the whole charge nature of positively charged corona and neutral core.Importantly,the unique architecture and charge conversion of NGs-G2 have a profound impact on the biodistribution and drug delivery in vivo.As a consequence of this alteration,the NGs-G2 as nanocarriers emerge the highly sought biodistribution of reduced liver accumulation,enhanced tumor uptake,and promoted drug release,resulting in the significantly augmented antitumor efficacy with low side effects.Remarkably,this finding is contrary to some reported work that the nanocarriers with positive charge have preferential liver uptake.Moreover,the NGs-G2 also displayed thermal/pH dual-responsive behaviors,excellent biocompatibility,improved cellular uptake,and stimuli-responsive drug release.Encouragingly,this work demonstrates a novel insight into the strategy for optimizing design,improving biodistribution and enhancing theranostic efficacy of nanocarriers.展开更多
Although anti-cancer nanotherapeutics have made breakthroughs,many remain clinically unsatisfactory due to limited delivery efficiency and complicated biological barriers.Here,we prepared charge-reversible crosslinked...Although anti-cancer nanotherapeutics have made breakthroughs,many remain clinically unsatisfactory due to limited delivery efficiency and complicated biological barriers.Here,we prepared charge-reversible crosslinked nanoparticles(PDC NPs)by supramolecular self-assembly of pro-apoptotic peptides and photosensitizers,followed by crosslinking the self-assemblies with polyethylene glycol to impart tumor microenvironment responsiveness and charge-reversibility.The resultant PDC NPs have a high drug loading of 68.3%,substantially exceeding that of 10%–15%in conventional drug delivery systems.PDC NPs can overcome the delivery hurdles to significantly improve the tumor accumulation and endocytosis of payloads by surface charge reversal and responsive crosslinking strategy.Pro-apoptotic peptides target the mitochondrial membranes and block the respiratory effect to reduce local oxygen consumption,which extensively augments oxygen-dependent photodynamic therapy(PDT).The photosensitizers around mitochondria increased along with the peptides,allowing PDT to work with pro-apoptotic peptides synergistically to induce tumor cell death by mitochondria-dependent apoptotic pathways.Our strategy would provide a valuable reference for improving the delivery efficiency of hydrophilic peptides and developing mitochondrial-targeting cancer therapies.展开更多
Dansylamide(DNSA) is a typical ICT probe that has a favorable serum albumin sensitivity. Inspired by this, we designed a microenvironment sensitive fluorescent probe 4 C-G through introducing DNSA into pillar[5]arene....Dansylamide(DNSA) is a typical ICT probe that has a favorable serum albumin sensitivity. Inspired by this, we designed a microenvironment sensitive fluorescent probe 4 C-G through introducing DNSA into pillar[5]arene. Unlike DNSA, 4 C-G displayed differentiated sensitivity to multiple proteins, which was benefit from pillar[5]arene assisted the probe to form complexes with proteins. 4 C-G could not only be applied in imaging of Hep G2, but also act as a favorable drug carrier for regorafenib(REG) encapsulation.The 4 C-G-REG complex would aggregate into high drug-loading fluorescent nanoparticles in a physiological environment(pH 7.4). Such nanoparticles exhibited p H-triggered enrichment ability, which rapidly enriched REG in the acidic environment(pH 6.0). Furthermore, the complexation between 4 C-G and REG maintained the imaging property of the probe and the excellent anticancer activity of the drug on Hep G2.展开更多
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
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Funded by the National Key R&D Program of China(No.2023YFC2412300)the Natural Science Foundation of Hubei Province(No.2022CFB386)the National Natural Science Foundation of China(No.52073222)。
文摘pH-responsive charge reversal loaded miRNA nanocomposite was prepared by electrostatic self-assembly.The morphology,particle size and zeta potential of the nanocomposites were analyzed by transmission electron microscopy and dynamic light scattering.The synthesis of the polymer was analyzed by^(1)H-NMR.The zeta-potential changes and cellular uptake effects of the nanocomplexes under different pH environments were investigated.The experimental results show that the surface morphology of the nanocomposite is spherical,and the average particle size is about 135 nm.As the pH value of the solution gradually decreases,the surface charge of the nanocomposite reverses from negative charge to positive charge(from-9.4 to+17.1 mV).Cellular uptake mediated by pH-responsive nanocomposite is selective for tumor cells,and the cellular uptake effect in tumor cells at pH 6.5 was approximately 3 times higher than that at pH 7.4.This pH responsive charge reversal nanocomposite has promising application prospects for gene delivery in the weak acid environment of tumors.
基金This work was supported by the National Basic Research Program of China （No. 2015CB932100）, the National Natural Science Foundation of China （Nos. 51503195, 51390482 and 51633008）, the National Key R＆D Program of China （No. 2017YFA0205600）, the Fundamental Research Funds for the Central Universities, and 111 Project （No. B17018）. S. I. is also grateful for the CAS-TWAS president fellowship.
文摘Nanopartide （NP） drug delivery systems have been successfully designed and implemented to orally deliver small interfering RNAs （siRNAs） for inflammatory disorders. However, the influence of surface charge on orally administered siRNA nanocarriers has not been investigated. In this study, we prepared structurally related poly（ethylene glycol）-block-poly（lactic-co-glycolic acid） （PEG5K-b-PLGA10K） NPs with the assistance of a synthesized lipid featuring surface amine groups for subsequent charge tuning. NPs were prepared by a double emulsion method, and their surface charge could be tuned and controlled by a succinylation reaction to yield NPs with different surface charges, while maintaining their size and composition. The prepared NPs were termed as aminated NPs （ANPs）, plain NPs （PNPs）, or carboxylated NPs （CNPs） based on their surface charge. All NPs exhibited the desired structural stability and siRNA integrity after enzymatic degradation. In vivo studies showed that ANPs significantly accumulated in inflamed colons, and they were successful in decreasing TNF-α secretion and mRNA expression levels while maintaining colonic histology in a murine model of acute ulcerative colitis （UC）. This study described a methodology to modify the surface charge of siRNA-encapsulating polymeric NPs and highlighted the influence of surface charge on oral delivery of siRNA for localized inflammatory disorders.
基金The work was supported by the National Natural Science Foundation of China （Nos. 31301177, 21427811, and 91430217）, and MOST China （No. 2013YQ170585）. J. W. also appreciated NSF.
文摘Enhanced cellular uptake efficiency of nanoparticles is important for their biomedical applications, including photothermal therapy （PTT） for cancer. In this study, a one-pot method was used to construct a positively charged and magnet-responsive nanocomposite comprising reduced graphene oxide anchoring iron oxide （RGI） with a polyethylenimine （PEI） modification, to improve the efficiency of cell internalization. The surface charge can be finely tuned using PEIs of different molecular weights. The obtained RGIlsk composite （RGI modified by 1.8 kDa PEI） could load indocyanine green （ICG） at a high mass ratio of 10：3 and ablate cancer cells using low-density laser irradiation because of its positively charged surface. In addition, the hybrids of RGI1.8k and ICG could kill most cancer cells at a laser density of 0.7 W/cm2 in vitro and 0.3 W/cm2 in vivo. At the same time, cell viability could be controlled by converting the external magnetic-field direction because of the enrichment of the magnet-responsive composite in vitro and in vivo. Furthermore, RGIr8k-ICGs could be used as T2-weighted magnetic resonance and infrared thermal imaging agents. Coupled with the magnetic target effect, the imaging signal could be improved significantly. Therefore, RGII^sk-ICGs represent a new highly efficient PTT and imaging agent with great potential for cancer treatment.
基金This research was financially supported by the Sino-German Center for Research Promotion(GZ1505),DFG(SFB 985,Functional Microgels and Microgel Systems),National Natural Science Foundation of China(81801704 and 81761148028)Science and Technology Commission of Shanghai Municipality(18520750400)Shanghai Sailing Program(18YF1415300)。
文摘Nanomedicine has revolutionized disease theranostics by the accurate diagnosis and efficient therapy.Here,the PAMAM dendrimer decorated PVCL-GMA nanogels(NGs)were developed for favorable biodistribution in vivo and enhanced antitumor efficacy of ovarian carcinoma.By an ingenious design,the NGs with a unique structure that GMA-rich domains were localized on the surface were synthesized via precipitation polymerization.After G2 dendrimer decoration,the overall charge is changed from neutral to positive,and the NGs-G2 display the whole charge nature of positively charged corona and neutral core.Importantly,the unique architecture and charge conversion of NGs-G2 have a profound impact on the biodistribution and drug delivery in vivo.As a consequence of this alteration,the NGs-G2 as nanocarriers emerge the highly sought biodistribution of reduced liver accumulation,enhanced tumor uptake,and promoted drug release,resulting in the significantly augmented antitumor efficacy with low side effects.Remarkably,this finding is contrary to some reported work that the nanocarriers with positive charge have preferential liver uptake.Moreover,the NGs-G2 also displayed thermal/pH dual-responsive behaviors,excellent biocompatibility,improved cellular uptake,and stimuli-responsive drug release.Encouragingly,this work demonstrates a novel insight into the strategy for optimizing design,improving biodistribution and enhancing theranostic efficacy of nanocarriers.
基金support from the National Natural Science Foundation of China(Nos.82172084 and 81803002)STI2030-Major Projects(No.2022ZD0212500)。
文摘Although anti-cancer nanotherapeutics have made breakthroughs,many remain clinically unsatisfactory due to limited delivery efficiency and complicated biological barriers.Here,we prepared charge-reversible crosslinked nanoparticles(PDC NPs)by supramolecular self-assembly of pro-apoptotic peptides and photosensitizers,followed by crosslinking the self-assemblies with polyethylene glycol to impart tumor microenvironment responsiveness and charge-reversibility.The resultant PDC NPs have a high drug loading of 68.3%,substantially exceeding that of 10%–15%in conventional drug delivery systems.PDC NPs can overcome the delivery hurdles to significantly improve the tumor accumulation and endocytosis of payloads by surface charge reversal and responsive crosslinking strategy.Pro-apoptotic peptides target the mitochondrial membranes and block the respiratory effect to reduce local oxygen consumption,which extensively augments oxygen-dependent photodynamic therapy(PDT).The photosensitizers around mitochondria increased along with the peptides,allowing PDT to work with pro-apoptotic peptides synergistically to induce tumor cell death by mitochondria-dependent apoptotic pathways.Our strategy would provide a valuable reference for improving the delivery efficiency of hydrophilic peptides and developing mitochondrial-targeting cancer therapies.
基金supported by the Scientific Research Staring Foundation of Yangzhou UniversityYangzhou Green Yang Gold Phoenix plansJiangsu Shuangchuang Project。
文摘Dansylamide(DNSA) is a typical ICT probe that has a favorable serum albumin sensitivity. Inspired by this, we designed a microenvironment sensitive fluorescent probe 4 C-G through introducing DNSA into pillar[5]arene. Unlike DNSA, 4 C-G displayed differentiated sensitivity to multiple proteins, which was benefit from pillar[5]arene assisted the probe to form complexes with proteins. 4 C-G could not only be applied in imaging of Hep G2, but also act as a favorable drug carrier for regorafenib(REG) encapsulation.The 4 C-G-REG complex would aggregate into high drug-loading fluorescent nanoparticles in a physiological environment(pH 7.4). Such nanoparticles exhibited p H-triggered enrichment ability, which rapidly enriched REG in the acidic environment(pH 6.0). Furthermore, the complexation between 4 C-G and REG maintained the imaging property of the probe and the excellent anticancer activity of the drug on Hep G2.
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).
