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
Controllably and efficaciously localized CRISPR/Cas9 plasmids transfection plays an essential role in genetic editing associated with various key human diseases.We employed near-infrared(NIR)light-responsive CRISPR/Ca...Controllably and efficaciously localized CRISPR/Cas9 plasmids transfection plays an essential role in genetic editing associated with various key human diseases.We employed near-infrared(NIR)light-responsive CRISPR/Cas9 plasmids delivery via a charge-reversal nanovector to achieve highly efficient and site-specific gene editing.The nanovector with abundant positive charges was fabricated on the basis of an ultraviolet-sensitive conjugated polyelectrolyte coated on an upconversion nanomaterial(UCNP-UVP-P),which can convert into negative charges upon 980 nm light irradiation.Using the as-prepared nanovector,we demonstrated the plasmids could be efficiency transfected into tumor cells(~63%±4%)in a time-contolled manner,and that functional CRISPR/Cas9 proteins could be successfully expressed in a selected NIR-irradiated region.Particularly,this strategy was successfully applied to the delivery of CRISPR/Cas9 gene to tumor cells in vivo,inducing high efficiency editing of the target gene PLK-1 under photolrradiation.Therefore,this precisely controlled gene regulation strategy has the potential to serve as a new paradigm for gene engineering in complex biological systems.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
Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles ha...Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment(TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a lightcontrollable charge-reversal nanoparticle(LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer(TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4 T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4 T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC.展开更多
Gene therapy is known highly effective for treatment of many diseases;however,its wide use has been severely bottlenecked by lack of safe and effective delivery vectors[1].Cationic polymers are safe nonviral gene vect...Gene therapy is known highly effective for treatment of many diseases;however,its wide use has been severely bottlenecked by lack of safe and effective delivery vectors[1].Cationic polymers are safe nonviral gene vectors with great potential for large-scale applications[2],and widely used to condense the large macromolecules into cationic polymer/DNA complexes(polyplexes)nanoparticles,protect-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
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
In this work,zwitterionic polymer(polyzwitterion)coated nanodiamonds(ND)with tumorous pH responsiveness were prepared for efficient application of commercial NDS in tumor cells imaging.Poly(carboxybetaine methacrylate...In this work,zwitterionic polymer(polyzwitterion)coated nanodiamonds(ND)with tumorous pH responsiveness were prepared for efficient application of commercial NDS in tumor cells imaging.Poly(carboxybetaine methacrylate)was firstly grafted on the pristine NDS(PCBMA-@-NDs)by surface-initiated reversible addition-fragmentation chain transfer(RAFT)polymerization.To achieve pH responsiveness and activated interaction with tumor cells,PCBMA-@-NDs were subsequently modified with benzene sulfonamide(PCBSA-@-NDs)via one step carbodiimide chemistry.The surface polymer functionalization was characterized by FTIR,1H NMR and TGA,and PCBMA-@-NDs and PCBSA-@-NDs showed great dispersibility,enhanced fluorescence intensity and excellent antifouling property in contrast to pristine NDs.Moreover,PCBSA-@-NDs was able to switch zwitterionic surface(at pH 7.4)reversibly into positive charge(at pH 6.5)via protonated or deprotonated acylsulfonamide.As expected,PCBSA-@-NDS demonstrated higher cell affinity and better imaging performance than those of zwitterionic NDS at tumor slight acid environment,proven by fluorescence microscopy and flow cytometry.Overall,we provide a feasible and valuable strategy to construct smart NDS,thus encouraging the application of cost-effective fluorescence nanomater-ials in biomedical fields.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This research was supported by the National Natural Science Foundation of China(Nos.21771065 and 81630046)the Guangdong Special Support Program(No.2017TQ04R138)+2 种基金the Natural Science Foundation of Guangdong(No.2019A1515012021)the Science and Technology Planning Project of Guangdong(No.2017A 020215088)Pearl River Nova Program of Guangzhou(No.201806010189).
文摘Controllably and efficaciously localized CRISPR/Cas9 plasmids transfection plays an essential role in genetic editing associated with various key human diseases.We employed near-infrared(NIR)light-responsive CRISPR/Cas9 plasmids delivery via a charge-reversal nanovector to achieve highly efficient and site-specific gene editing.The nanovector with abundant positive charges was fabricated on the basis of an ultraviolet-sensitive conjugated polyelectrolyte coated on an upconversion nanomaterial(UCNP-UVP-P),which can convert into negative charges upon 980 nm light irradiation.Using the as-prepared nanovector,we demonstrated the plasmids could be efficiency transfected into tumor cells(~63%±4%)in a time-contolled manner,and that functional CRISPR/Cas9 proteins could be successfully expressed in a selected NIR-irradiated region.Particularly,this strategy was successfully applied to the delivery of CRISPR/Cas9 gene to tumor cells in vivo,inducing high efficiency editing of the target gene PLK-1 under photolrradiation.Therefore,this precisely controlled gene regulation strategy has the potential to serve as a new paradigm for gene engineering in complex biological systems.
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.
基金Financial supports from the National Natural Science Foundation of China(81903548,81690265,81803444,81521005 and 32070927)the Youth Innovation Promotion Association of CAS(2019283)+3 种基金the Strategic Priority Research Program of CAS(XDA12050307)Shandong Provincial Natural Science Foundation(ZR2019ZD25)the International Partnership Program of CAS(153631KYSB20190013)the Shanghai Sailing Program(19YF1457300)。
文摘Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment(TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a lightcontrollable charge-reversal nanoparticle(LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer(TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4 T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4 T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC.
文摘Gene therapy is known highly effective for treatment of many diseases;however,its wide use has been severely bottlenecked by lack of safe and effective delivery vectors[1].Cationic polymers are safe nonviral gene vectors with great potential for large-scale applications[2],and widely used to condense the large macromolecules into cationic polymer/DNA complexes(polyplexes)nanoparticles,protect-
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the financial support from the National Natural Science Foundation of China(Project U1704150)the Scientifc and Technological Projects of Henan province(182102410017).
文摘In this work,zwitterionic polymer(polyzwitterion)coated nanodiamonds(ND)with tumorous pH responsiveness were prepared for efficient application of commercial NDS in tumor cells imaging.Poly(carboxybetaine methacrylate)was firstly grafted on the pristine NDS(PCBMA-@-NDs)by surface-initiated reversible addition-fragmentation chain transfer(RAFT)polymerization.To achieve pH responsiveness and activated interaction with tumor cells,PCBMA-@-NDs were subsequently modified with benzene sulfonamide(PCBSA-@-NDs)via one step carbodiimide chemistry.The surface polymer functionalization was characterized by FTIR,1H NMR and TGA,and PCBMA-@-NDs and PCBSA-@-NDs showed great dispersibility,enhanced fluorescence intensity and excellent antifouling property in contrast to pristine NDs.Moreover,PCBSA-@-NDs was able to switch zwitterionic surface(at pH 7.4)reversibly into positive charge(at pH 6.5)via protonated or deprotonated acylsulfonamide.As expected,PCBSA-@-NDS demonstrated higher cell affinity and better imaging performance than those of zwitterionic NDS at tumor slight acid environment,proven by fluorescence microscopy and flow cytometry.Overall,we provide a feasible and valuable strategy to construct smart NDS,thus encouraging the application of cost-effective fluorescence nanomater-ials in biomedical fields.