The acidic microenvironments of tumor tissue and cells provide an opportunity for the development of pHresponsive drug delivery systems in cancer therapy.In this work,we designed a calcium carbonate(CaCO3)-corecrossli...The acidic microenvironments of tumor tissue and cells provide an opportunity for the development of pHresponsive drug delivery systems in cancer therapy.In this work,we designed a calcium carbonate(CaCO3)-corecrosslinked nanoparticle of methoxy poly(ethylene glycol)-block-poly(L-glutamic acid)through mineralization for intracellular delivery of doxorubicin(DOX),referred to as CaNP/DOX.CaNP/DOX exhibited high drug loading capability,uniform nanoparticle size,and pH-dependent DOX release.In the meantime,the enhanced cell uptake,superior cytotoxicity toward mouse osteosarcoma K7 cells,extended circulation half-life,and improved accumulation of DOX in K7 allograft tumor from CaNP/DOX were also demonstrated.More interestingly,CaNP/DOX displayed improved antitumor effect and reduced side effects against the K7 osteosarcoma-allografted mouse model and the 143B orthotopic osteosarcoma mouse model.Given the superior properties of Ca-mineralized polypeptide nanoparticle for intracellular drug delivery,the smart drug delivery system showed strong competitiveness in clinical chemotherapy of cancers.展开更多
Cancer the rapy with nanoscale drug formulations has made significant progress in the past few decades.However,the selective accumulation and release of therapeutic agents in the lesion sites are still great challenge...Cancer the rapy with nanoscale drug formulations has made significant progress in the past few decades.However,the selective accumulation and release of therapeutic agents in the lesion sites are still great challenges.To this end,we developed a cRGD-decorated pH-responsive polyion complex(PIC)micelle for intracellular targeted delivery of doxorubicin(DOX)to upregulate tumor inhibition and reduce toxicity.The PIC micelle was self-assembled via the electrostatic interaction between the positively charged cRGD-modified poly(ethylene glycol)-block-poly(L-lysine)and the anionic acid-sensitive 2,3-dimethylmaleic anhydride-modified doxorubicin(DAD).The decoration of cRGD enhanced the cell internalization of PIC micelle through the specific recognition ofαvβ3 integrin on the membrane of tumor cells.The active DOX was released under intracellular acidic microenvironment after endocytosis following the decomposition of DAD.Moreover,the targeted PIC micelle exhibited enhanced inhibition efficacies toward hepatoma in vitro and in vivo compared with the insensitive controls.The smart multifunctional micelle provides a promising platform for target intracellular delivery of therapeutic agent in cancer therapy.展开更多
A novel host-guest recognition motif based on a water-soluble pillar[7]arene （WP7） and a 2,7-diazapyrenium salt （DMDAP） was prepared. According to the integrated results of ^1H NMR, 2D NOESY, UV-vis spectroscopy a...A novel host-guest recognition motif based on a water-soluble pillar[7]arene （WP7） and a 2,7-diazapyrenium salt （DMDAP） was prepared. According to the integrated results of ^1H NMR, 2D NOESY, UV-vis spectroscopy and fluorescence titration experiments, we demonstrated that the molecular recognition of WP7 to DMDAP in water not only has high association constant but also has pH-responsiveness. Subsequently, we took advantage of this molecular recognition motif to fabricate a supra-amphiphile based on WP7 and an amphiphilic 2,7-diazapyrenium derivative DAPAC. Its controllable self-assembly in water was also investigated by means of TEM and DLS techniques.展开更多
PEGylated prodrug,covalent attaching polyethylene glycol(PEG) polymer chains to therapeutic drugs,is one of the most promising techniques to improve the water-solubility,stability,and therapeutic effect of drugs.In th...PEGylated prodrug,covalent attaching polyethylene glycol(PEG) polymer chains to therapeutic drugs,is one of the most promising techniques to improve the water-solubility,stability,and therapeutic effect of drugs.In this study,three PEGylated acid-sensitive prodrugs DOX-PEG-DOX with different molecular weights,were prepared via Schiff-base reaction between aldehyde-modified PEG and the amino groups of doxorubicin(DOX).This kind of amphiphilic polymeric prodrug could be self-assemble into nanoparticles in aqueous solution.The average particle size and morphologies of the prodrug nanoparticles under different pH conditions were observed by dynamic light scattering(DLS) and transmission electron microscopy(TEM),re s pectively.It turned out that the nanoparticles could be kept stable in the physiological environment,but degraded in acidic medium.Subsequently,we also investigated in vitro drug release behavior and found that the prodrug had acid-sensitive property.The cytotoxicity and intracellular uptake assays revealed that the prodrugs could rapidly internalized by HeLa or HepG2 cells to release DOX and effectively inhibited the proliferation of the tumor cells,which have the potential for use in cancer therapy.展开更多
Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during c...Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment.Herein,we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method,thereby enabling effective co-encapsulation of both doxorubicin(DOX),an immunogenic cell death(ICD)inducer,and alkylated NLG919(aNLG919),an inhibitor of indoleamine 2,3-dioxygenase 1(IDO1).The obtained DOX/aNLG919-loaded CaCO3 nanoparticles(DNCaNPs)are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1.Upon intravenous injection,such DNCaNPs show efficient tumor accumulation,improved tumor penetration of therapeutics and neutralization of acidic TME.As a result,those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells(Tregs),thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy&immunotherapy.This study presents a compendious strategy for construction of pH-responsive nanoparticles,endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.展开更多
Peptide amphiphiles with well-organized secondary structure are an important family of molecules that are known to assemble into a variety of nanostructures.In this work,we present three guanidiniocarbonylpyrrole(GCP)...Peptide amphiphiles with well-organized secondary structure are an important family of molecules that are known to assemble into a variety of nanostructures.In this work,we present three guanidiniocarbonylpyrrole(GCP)containing peptide amphiphiles,which show versatile morphology and secondary structure changes as a result of different chain lengths and in different concentration regimes.The random coil conformation,α-helix,andβ-sheet are obtained for peptide 1,peptide 2,and peptide 3,respectively under neutral aqueous conditions.Furthermore,all peptide amphiphiles can aggregate to form nanoparticles at low concentrations.However,at high concentrations,peptide 1 selfassembles into left-ha nded twisted helical fibers,while longer bamboo-like mo rphology can be obse rved exclusively for peptide 2.For peptide 3,freshly prepared samples show uniform spherical morphology,whereas an obvious morphological transition from original nanoparticles to disordered fibers was realized after incubating for one week.These fascinating morphology changes were determined by the combination of circular dichroism,dynamic light scattering,transmission electron microscopy,atomic force microscopy,and theoretical calculations.展开更多
Tumor cells undergoing immunogenic cell death (ICD) have emerged as an in situ therapeutic vaccine helping to activate a persistent anti-tumor response. Several chemotherapeutic agents have been demonstrated to induce...Tumor cells undergoing immunogenic cell death (ICD) have emerged as an in situ therapeutic vaccine helping to activate a persistent anti-tumor response. Several chemotherapeutic agents have been demonstrated to induce ICD, however accompanied with severe adverse effects in the clinic, weakening its immune responses. Herein, to elicit an intensive ICD while minimizing the systemic toxicity, we introduce a tumor targeting peptide modified bortezomib (BTZ) loading nanomedicine (i-NPBTZ) for the efficient delivery and controlled release of BTZ in tumors. This system is constructed by conjugating BTZ to PEGylated polyphenols via a pH-sensitive covalent boronate-phenol bond that allows them to self-assemble into nanovesicles in neutral condition with high drug loading efficiency. Once accumulated in acidic environment, BTZ-phenolic network is disassembled and thereby accelerates the release of BTZ from nanocarriers. The released BTZ selectively kill tumor cells with a concomitant evocation of tumor-specific cytotoxic T cells by triggering ICD in vivo. This can finally lead to an extended tumor ablation and prevention of distant metastasis in a syngeneic tumor mouse model, while reducing the systemic toxicity of BTZ. In general, our system offers a novel concept with clinical potential to exploit ICD for potentiating tumor immunotherapy and also provides an excellent example of the application of polymer-drug interaction for efficient drug delivery and controllable release.展开更多
Delivery systems based on nanoparticles(NPs)have shown great potential to reduce side effects and improve the therapeutic efficacy.Herein,we report the one-pot synthesis of poly(ethylene glycol)-mediated zeolitic imid...Delivery systems based on nanoparticles(NPs)have shown great potential to reduce side effects and improve the therapeutic efficacy.Herein,we report the one-pot synthesis of poly(ethylene glycol)-mediated zeolitic imidazolate framework-8(ZIF-8)NPs for the co-delivery of an anticancer drug(i.e.,doxorubicin)and a cell penetrating peptide containing histidine and arginine(i.e.,H4 R4)to improve the efficacy of therapeutic delive ry.The cargo-encapsulated ZIF-8 NPs are pH-responsive,which are stable at neutral pH and degradable at acidic pH to release the encapsulated cargos.The released H4 R4 can help for endosome/lysosome escape to enhance the cytotoxicity of the encapsulated drugs.In vivo studies demonstrate that the co-delivery of doxo rubicin and H4 R4 peptides can efficiently inhibit tumor growth without significant side effects.The reported strategy provides a new perspective on the design of drug delivery systems and brings more opportunities for biomedical applications.展开更多
基金financially supported by the National Natural Science Foundation of China(Grant No.51803006)the Scientific Development Program of Liaoning Province(Grant No.20170541058)the China Postdoctoral Science Foundation(Grant No.2019M650297).
文摘The acidic microenvironments of tumor tissue and cells provide an opportunity for the development of pHresponsive drug delivery systems in cancer therapy.In this work,we designed a calcium carbonate(CaCO3)-corecrosslinked nanoparticle of methoxy poly(ethylene glycol)-block-poly(L-glutamic acid)through mineralization for intracellular delivery of doxorubicin(DOX),referred to as CaNP/DOX.CaNP/DOX exhibited high drug loading capability,uniform nanoparticle size,and pH-dependent DOX release.In the meantime,the enhanced cell uptake,superior cytotoxicity toward mouse osteosarcoma K7 cells,extended circulation half-life,and improved accumulation of DOX in K7 allograft tumor from CaNP/DOX were also demonstrated.More interestingly,CaNP/DOX displayed improved antitumor effect and reduced side effects against the K7 osteosarcoma-allografted mouse model and the 143B orthotopic osteosarcoma mouse model.Given the superior properties of Ca-mineralized polypeptide nanoparticle for intracellular drug delivery,the smart drug delivery system showed strong competitiveness in clinical chemotherapy of cancers.
基金financially supported by the National Natural Science Foundation of China(Nos.51973216,51873207,51833010,51703225,51673190,51673187,51603204 and 51520105004)the Science and Technology Development Program of Jilin Province(No.20190201068JC)+2 种基金the National Key Research and Development Program of China(No.2016YFC1100701)the Youth Talents Promotion Project of Jilin Province(No.181909)the Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2019005)。
文摘Cancer the rapy with nanoscale drug formulations has made significant progress in the past few decades.However,the selective accumulation and release of therapeutic agents in the lesion sites are still great challenges.To this end,we developed a cRGD-decorated pH-responsive polyion complex(PIC)micelle for intracellular targeted delivery of doxorubicin(DOX)to upregulate tumor inhibition and reduce toxicity.The PIC micelle was self-assembled via the electrostatic interaction between the positively charged cRGD-modified poly(ethylene glycol)-block-poly(L-lysine)and the anionic acid-sensitive 2,3-dimethylmaleic anhydride-modified doxorubicin(DAD).The decoration of cRGD enhanced the cell internalization of PIC micelle through the specific recognition ofαvβ3 integrin on the membrane of tumor cells.The active DOX was released under intracellular acidic microenvironment after endocytosis following the decomposition of DAD.Moreover,the targeted PIC micelle exhibited enhanced inhibition efficacies toward hepatoma in vitro and in vivo compared with the insensitive controls.The smart multifunctional micelle provides a promising platform for target intracellular delivery of therapeutic agent in cancer therapy.
基金This work was supported by National Basic Research Program （2013CB834502）, the National Natural Science Foundation of China （21125417, 21434005） and the Fundamental Research Funds for the Central Universities.
文摘A novel host-guest recognition motif based on a water-soluble pillar[7]arene （WP7） and a 2,7-diazapyrenium salt （DMDAP） was prepared. According to the integrated results of ^1H NMR, 2D NOESY, UV-vis spectroscopy and fluorescence titration experiments, we demonstrated that the molecular recognition of WP7 to DMDAP in water not only has high association constant but also has pH-responsiveness. Subsequently, we took advantage of this molecular recognition motif to fabricate a supra-amphiphile based on WP7 and an amphiphilic 2,7-diazapyrenium derivative DAPAC. Its controllable self-assembly in water was also investigated by means of TEM and DLS techniques.
基金the financial supports from the National Natural Science Foundation of China(No.21374066)the Major Program of the Natural Science Project of Jiangsu Higher Education Institutions(No.15KJA150007)+2 种基金Natural Science Foundation of Jiangsu Province(No.BK20171212)the Project Funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education InstitutionsSoochow-Waterloo University Joint Project for Nanotechnology from Suzhou Industrial Park
文摘PEGylated prodrug,covalent attaching polyethylene glycol(PEG) polymer chains to therapeutic drugs,is one of the most promising techniques to improve the water-solubility,stability,and therapeutic effect of drugs.In this study,three PEGylated acid-sensitive prodrugs DOX-PEG-DOX with different molecular weights,were prepared via Schiff-base reaction between aldehyde-modified PEG and the amino groups of doxorubicin(DOX).This kind of amphiphilic polymeric prodrug could be self-assemble into nanoparticles in aqueous solution.The average particle size and morphologies of the prodrug nanoparticles under different pH conditions were observed by dynamic light scattering(DLS) and transmission electron microscopy(TEM),re s pectively.It turned out that the nanoparticles could be kept stable in the physiological environment,but degraded in acidic medium.Subsequently,we also investigated in vitro drug release behavior and found that the prodrug had acid-sensitive property.The cytotoxicity and intracellular uptake assays revealed that the prodrugs could rapidly internalized by HeLa or HepG2 cells to release DOX and effectively inhibited the proliferation of the tumor cells,which have the potential for use in cancer therapy.
基金partially supported by the National Natural Science Foundation of China(51802209,22077093,51761145041,51525203)the National Research Programs from Ministry of Science and Technology(MOST)of China(2016YFA0201200)+3 种基金the Natural Science Foundation of Jiangsu Province(BK20180848)the Jiangsu Social Development Project(BE2019658)Collaborative Innovation Center of Suzhou Nano Science and Technologythe 111 Program from the Ministry of Education of China.
文摘Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment.Herein,we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method,thereby enabling effective co-encapsulation of both doxorubicin(DOX),an immunogenic cell death(ICD)inducer,and alkylated NLG919(aNLG919),an inhibitor of indoleamine 2,3-dioxygenase 1(IDO1).The obtained DOX/aNLG919-loaded CaCO3 nanoparticles(DNCaNPs)are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1.Upon intravenous injection,such DNCaNPs show efficient tumor accumulation,improved tumor penetration of therapeutics and neutralization of acidic TME.As a result,those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells(Tregs),thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy&immunotherapy.This study presents a compendious strategy for construction of pH-responsive nanoparticles,endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.
基金supported by the National Natural Science Foundation of China(No.21572101)the Natural Science Foundation of Jiangsu Province(No.BK20180055)+1 种基金Qinghai Provincial Key Laboratory of Tibetan Medicine Research(No.2017-ZJ-Y11)funding by the Fonds der Chemischen Industrie(Liebig-Fellowship)。
文摘Peptide amphiphiles with well-organized secondary structure are an important family of molecules that are known to assemble into a variety of nanostructures.In this work,we present three guanidiniocarbonylpyrrole(GCP)containing peptide amphiphiles,which show versatile morphology and secondary structure changes as a result of different chain lengths and in different concentration regimes.The random coil conformation,α-helix,andβ-sheet are obtained for peptide 1,peptide 2,and peptide 3,respectively under neutral aqueous conditions.Furthermore,all peptide amphiphiles can aggregate to form nanoparticles at low concentrations.However,at high concentrations,peptide 1 selfassembles into left-ha nded twisted helical fibers,while longer bamboo-like mo rphology can be obse rved exclusively for peptide 2.For peptide 3,freshly prepared samples show uniform spherical morphology,whereas an obvious morphological transition from original nanoparticles to disordered fibers was realized after incubating for one week.These fascinating morphology changes were determined by the combination of circular dichroism,dynamic light scattering,transmission electron microscopy,atomic force microscopy,and theoretical calculations.
基金This work was supported by the National Key R&D Program of China(Nos.2017YFA0205200 and 2020YFA0710700)the National Natural Science Foundation of China(Nos.81771957,51903105,51961145109,and 51773191)+1 种基金the China Postdoctoral Science Foundation(Nos.2019TQ0400 and 2019M663362)All animals received are in compliance with the guidelines outlined in the Guide for the Care and Use of Laboratory Animals,and all procedures were approved by the University of Science and Technology of China Animal Care and Use Committee(No.USTCACUC1801006).
文摘Tumor cells undergoing immunogenic cell death (ICD) have emerged as an in situ therapeutic vaccine helping to activate a persistent anti-tumor response. Several chemotherapeutic agents have been demonstrated to induce ICD, however accompanied with severe adverse effects in the clinic, weakening its immune responses. Herein, to elicit an intensive ICD while minimizing the systemic toxicity, we introduce a tumor targeting peptide modified bortezomib (BTZ) loading nanomedicine (i-NPBTZ) for the efficient delivery and controlled release of BTZ in tumors. This system is constructed by conjugating BTZ to PEGylated polyphenols via a pH-sensitive covalent boronate-phenol bond that allows them to self-assemble into nanovesicles in neutral condition with high drug loading efficiency. Once accumulated in acidic environment, BTZ-phenolic network is disassembled and thereby accelerates the release of BTZ from nanocarriers. The released BTZ selectively kill tumor cells with a concomitant evocation of tumor-specific cytotoxic T cells by triggering ICD in vivo. This can finally lead to an extended tumor ablation and prevention of distant metastasis in a syngeneic tumor mouse model, while reducing the systemic toxicity of BTZ. In general, our system offers a novel concept with clinical potential to exploit ICD for potentiating tumor immunotherapy and also provides an excellent example of the application of polymer-drug interaction for efficient drug delivery and controllable release.
基金supported by the National Natural Science Foundation of China(Nos.21872085 and 21902088)the Project for Scientific Research Innovation Team of Young Scholar in Colleges and Universities of Shandong Province(No.2020KJC001)。
文摘Delivery systems based on nanoparticles(NPs)have shown great potential to reduce side effects and improve the therapeutic efficacy.Herein,we report the one-pot synthesis of poly(ethylene glycol)-mediated zeolitic imidazolate framework-8(ZIF-8)NPs for the co-delivery of an anticancer drug(i.e.,doxorubicin)and a cell penetrating peptide containing histidine and arginine(i.e.,H4 R4)to improve the efficacy of therapeutic delive ry.The cargo-encapsulated ZIF-8 NPs are pH-responsive,which are stable at neutral pH and degradable at acidic pH to release the encapsulated cargos.The released H4 R4 can help for endosome/lysosome escape to enhance the cytotoxicity of the encapsulated drugs.In vivo studies demonstrate that the co-delivery of doxo rubicin and H4 R4 peptides can efficiently inhibit tumor growth without significant side effects.The reported strategy provides a new perspective on the design of drug delivery systems and brings more opportunities for biomedical applications.
