Cancer treatment is a multifaceted challenge,and therapeutic vaccines have emerged as a promising approach.The micellar preparation efficiently encapsulates antigen polypeptides and enhances antigen presentation throu...Cancer treatment is a multifaceted challenge,and therapeutic vaccines have emerged as a promising approach.The micellar preparation efficiently encapsulates antigen polypeptides and enhances antigen presentation through the major histocompatibility class I pathway,promoting cytotoxic T lymphocyte immune responses.Moreover,it enables codelivery of both antigen and adjuvant to the same target antigen-presenting cells.Combining themicellar vaccine with traditional cancer treatments(such as chemotherapy,radiotherapy,and surgery)has demonstrated improved efficacy in murine tumor models.Overall,the polyethylene glycol-phosphatidylethanolamine micelle-based vaccine presents a promising platformfor cancer therapeutic vaccines.By leveraging the strengths of various treatmentmodalities,this innovative vaccine approach holds the potential to revolutionize cancer therapy and bring new possibilities for cancer patients.展开更多
A novel amphiphilic cationic block copolymer polylysine-b-polyphenylalanine(PLL-b-PPhe)was synthesized and self-assembled into micelles in aqueous solution,then shielded with poly(glutamic acid)(marked as PG/PLL-b-PPh...A novel amphiphilic cationic block copolymer polylysine-b-polyphenylalanine(PLL-b-PPhe)was synthesized and self-assembled into micelles in aqueous solution,then shielded with poly(glutamic acid)(marked as PG/PLL-b-PPhe)to codeliver gene and drug for combination cancer therapy.Here,doxorubicin(DOX)was selected to be loaded into PLL-b-PPhe micelles and the drug loading efficiency was 8.0%.The drug release studies revealed that the PLL-b-PPhe micelles were pH sensitive and the released DOX could reach to 53.0%,65.0%,72.0%at pH 7.4,6.8 and 5.0,respectively.In order to reduce positive charge and cytotoxicity of PLL-b-PPhe micelles,PG was used as shelding,simultaneously condensed with Bcl2 siRNA to form gene carrier system.Compared with PEI,PG/PLL-b-PPhe had excellent gene transfection efficiency,especially when the molar ratio of PLL to PPhe was 30:60 and the mixed mass ratio of PLL-b-PPhe to gene was 5:1.More importantly,DOX and Bcl2 siRNA gene codelivery system displayed remarkable cytotoxicity against B16 F10 cells.Confocal laser scanning microscopy(CLSM)and flow cytometry were used to characterize endocytosis of the codelivery system,and confirmed that both DOX and Bcl2 siRNA had been endocytosed into B16 F10 cells.The above results indicated that gene and drug codelivery was a promising strategy in future cancer therapy.展开更多
Multidrug-resistance(MDR)featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic.Compound nanoparticles comprising multiple cytostatics with differen...Multidrug-resistance(MDR)featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic.Compound nanoparticles comprising multiple cytostatics with different mechanisms of action are commonly developed to tackle the multifaceted nature of clinical MDR.However,the different pharmacokinetics and release profiles of various drugs result in inconsistent drug internalization and suboptimal drug synergy at the tumor sites.In the present study,a type of self-targeting hyaluronate(HA)nanogels((CDDPH)^ANG/DOX)to reverse drug resistance through the synchronized pharmacokinetics,intratumoral distribution,and intracellular release of topoisomerase II inhibitor doxorubicin(DOX)and DNA-crosslinking agent cisplatin(CDDP)is developed.With prolonged circulation time and enhanced intratumoral accumulation in vivo,(CDDP)^HANG/DOX shows efficient drug delivery into the drug-resistant MCF-7/ADR breast cancer cells and enhanced antitumor activity.Besides,fluorescence imaging of DOX combined with the micro-computed tomography(micro-CT)imaging of CDDP facilitates the visualization of this combination tumor chemotherapy.With visualizable synchronized drug delivery,the self-targeting in situ crosslinked nanoplatform may hold good potential in future clinical therapy of advanced cancers.展开更多
Lung inflammation is an essential inducer of various diseases and is closely related to pulmonary-endothelium dysfunction.Herein,we propose a pulmonary endothelium-targeted codelivery system of anti-inflammatory indom...Lung inflammation is an essential inducer of various diseases and is closely related to pulmonary-endothelium dysfunction.Herein,we propose a pulmonary endothelium-targeted codelivery system of anti-inflammatory indomethacin(IND)and antioxidant superoxide dismutase(SOD)by assembling the biopharmaceutical SOD onto the“vector”of rod-like pure IND crystals,followed by coating with anti-ICAM-1 antibody(Ab)for targeting endothelial cells.The codelivery system has a 237 nm diameter in length and extremely high drug loading of 39%IND and 2.3%SOD.Pharmacokinetics and biodistribution studies demonstrate the extended blood circulation and the strong pulmonary accumulation of the system after intravenous injection in the lipopolysaccharide(LPS)-induced inflammatory murine model.Particularly,the system allows a robust capacity to target pulmonary endothelium mostly due to the rod-shape and Ab coating effect.In vitro,the preparation shows the synergistic antiinflammatory and antioxidant effects in LPS-activated endothelial cells.In vivo,the preparation exhibits superior pharmacodynamic efficacy revealed by significantly downregulating the inflammatory/oxidative stress markers,such as TNF-a,IL-6,COX-2,and reactive oxygen species(ROS),in the lungs.In conclusion,the codelivery system based on rod-like pure crystals could well target the pulmonary endothelium and effectively alleviate lung inflammation.The study offers a promising approach to combat pulmonary endothelium-associated diseases.展开更多
Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies.Heat shock protein 90(Hsp90)as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and ...Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies.Heat shock protein 90(Hsp90)as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance.Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance.In this study,a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX,and a COAmodified 4-arm PEG polymer(4PSC)was synthesized.COA,an active component in oleanolic acid that exerts strong antitumor activity by downregulating Hsp90 expression,was used as a structural and functional element to endow 4PSC with redox responsiveness and Hsp90 inhibitory activity.Our results showed that 4PSC/PTX nanomicelles efficiently delivered PTX and COA to tumor locations without inducing systemic toxicity.By blocking the Hsp90 signaling pathway,4PSC significantly enhanced the antitumor effect of PTX,inhibiting tumor proliferation and invasiveness as well as chemotherapy-induced resistance in vitro.Remarkable results were further confirmed in vivo with two preclinical tumor models.These findings demonstrate that the COA-modified 4PSC drug delivery nanosystem provides a potential platform for enhancing the efficacy of chemotherapies.展开更多
Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in...Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor immunosuppression.Therapeutic vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor immunosuppression.Chemically defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic heterogeneity.Here,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC subsets.These NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor immunosuppression.As a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy.展开更多
Codelivery of drugs by drug carriers is a promising strategy against several diseases such as infections and cancer.However,traditional drug carriers are typically characterized by low drug payload,limiting their trea...Codelivery of drugs by drug carriers is a promising strategy against several diseases such as infections and cancer.However,traditional drug carriers are typically characterized by low drug payload,limiting their treatment efficacy.Using nanocrystals of insoluble drug as carriers,a carrier free platform was developed previously to deliver a second insoluble drug for codelivery.To extend the concept,we hypothesized,herein,that the platform allows for codelivery of hydrophobic and hydrophilic drugs using a cocrystalization-like strategy.To obtain proof-of-concept,paclitaxel(PTX),an insoluble chemotherapeutic agent,and dichloroacetic acid(DCA),a water-soluble inhibitor of pyruvate dehydrogenase kinase,were utilized as model drugs.PTX-DCA hybrid nanocrystals(PTX-DCA NCs)were prepared by antisolvent precipitation and characterized.Their in vitro antitumor activity against cancer cells was evaluated.PTX-DCA NCs prepared from the optimized formulation had a diameter of 160 nm and a rodshape morphology and possessed encapsulated efficacy of approximately 30%for DCA.The use of the hybrid crystals enabled synergy to kill cancer cells,in particular in PTX-resistant cells in a dosedependent pattern.In conclusion,by using a cocrystalization-like strategy,a hydrophilic drug can be formulated into a drug’s nanocrystal for codelivery.展开更多
基金supported by a grant from the Strategic Priority Research Program of the Chinese Academy of Sciences(no.XDA09030303).
文摘Cancer treatment is a multifaceted challenge,and therapeutic vaccines have emerged as a promising approach.The micellar preparation efficiently encapsulates antigen polypeptides and enhances antigen presentation through the major histocompatibility class I pathway,promoting cytotoxic T lymphocyte immune responses.Moreover,it enables codelivery of both antigen and adjuvant to the same target antigen-presenting cells.Combining themicellar vaccine with traditional cancer treatments(such as chemotherapy,radiotherapy,and surgery)has demonstrated improved efficacy in murine tumor models.Overall,the polyethylene glycol-phosphatidylethanolamine micelle-based vaccine presents a promising platformfor cancer therapeutic vaccines.By leveraging the strengths of various treatmentmodalities,this innovative vaccine approach holds the potential to revolutionize cancer therapy and bring new possibilities for cancer patients.
基金the National Natural Science Foundation of China(No.51873208)the National Science and Technology Major Projects for Major New Drugs Innovation and Development(No.2018ZX09711003-012)National Program for Support of Top-notch Young Professionals,Jilin Province Science and Technology Development Program(No.20180414027GH)for financial support to this work。
文摘A novel amphiphilic cationic block copolymer polylysine-b-polyphenylalanine(PLL-b-PPhe)was synthesized and self-assembled into micelles in aqueous solution,then shielded with poly(glutamic acid)(marked as PG/PLL-b-PPhe)to codeliver gene and drug for combination cancer therapy.Here,doxorubicin(DOX)was selected to be loaded into PLL-b-PPhe micelles and the drug loading efficiency was 8.0%.The drug release studies revealed that the PLL-b-PPhe micelles were pH sensitive and the released DOX could reach to 53.0%,65.0%,72.0%at pH 7.4,6.8 and 5.0,respectively.In order to reduce positive charge and cytotoxicity of PLL-b-PPhe micelles,PG was used as shelding,simultaneously condensed with Bcl2 siRNA to form gene carrier system.Compared with PEI,PG/PLL-b-PPhe had excellent gene transfection efficiency,especially when the molar ratio of PLL to PPhe was 30:60 and the mixed mass ratio of PLL-b-PPhe to gene was 5:1.More importantly,DOX and Bcl2 siRNA gene codelivery system displayed remarkable cytotoxicity against B16 F10 cells.Confocal laser scanning microscopy(CLSM)and flow cytometry were used to characterize endocytosis of the codelivery system,and confirmed that both DOX and Bcl2 siRNA had been endocytosed into B16 F10 cells.The above results indicated that gene and drug codelivery was a promising strategy in future cancer therapy.
基金This study was financially supported by the National Key Research and Development Program of China(No.2016YFC1100701)the National Natural Science Foundation of China(Nos.52022095,51973216,and 51873207)+1 种基金the Science and Technology Development Program of jilin Province(No.20200404182YY)the Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2019005)。
文摘Multidrug-resistance(MDR)featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic.Compound nanoparticles comprising multiple cytostatics with different mechanisms of action are commonly developed to tackle the multifaceted nature of clinical MDR.However,the different pharmacokinetics and release profiles of various drugs result in inconsistent drug internalization and suboptimal drug synergy at the tumor sites.In the present study,a type of self-targeting hyaluronate(HA)nanogels((CDDPH)^ANG/DOX)to reverse drug resistance through the synchronized pharmacokinetics,intratumoral distribution,and intracellular release of topoisomerase II inhibitor doxorubicin(DOX)and DNA-crosslinking agent cisplatin(CDDP)is developed.With prolonged circulation time and enhanced intratumoral accumulation in vivo,(CDDP)^HANG/DOX shows efficient drug delivery into the drug-resistant MCF-7/ADR breast cancer cells and enhanced antitumor activity.Besides,fluorescence imaging of DOX combined with the micro-computed tomography(micro-CT)imaging of CDDP facilitates the visualization of this combination tumor chemotherapy.With visualizable synchronized drug delivery,the self-targeting in situ crosslinked nanoplatform may hold good potential in future clinical therapy of advanced cancers.
基金supported by the National Natural Science Foundation of China,China (Nos.81872823,82073782 and 82241002)the Shanghai Science and Technology Committee,China (No.19430741500)the Key Laboratory of Modern Chinese Medicine Preparation of Ministry of Education of Jiangxi University of Traditional Chinese Medicine,China (zdsys202103)。
文摘Lung inflammation is an essential inducer of various diseases and is closely related to pulmonary-endothelium dysfunction.Herein,we propose a pulmonary endothelium-targeted codelivery system of anti-inflammatory indomethacin(IND)and antioxidant superoxide dismutase(SOD)by assembling the biopharmaceutical SOD onto the“vector”of rod-like pure IND crystals,followed by coating with anti-ICAM-1 antibody(Ab)for targeting endothelial cells.The codelivery system has a 237 nm diameter in length and extremely high drug loading of 39%IND and 2.3%SOD.Pharmacokinetics and biodistribution studies demonstrate the extended blood circulation and the strong pulmonary accumulation of the system after intravenous injection in the lipopolysaccharide(LPS)-induced inflammatory murine model.Particularly,the system allows a robust capacity to target pulmonary endothelium mostly due to the rod-shape and Ab coating effect.In vitro,the preparation shows the synergistic antiinflammatory and antioxidant effects in LPS-activated endothelial cells.In vivo,the preparation exhibits superior pharmacodynamic efficacy revealed by significantly downregulating the inflammatory/oxidative stress markers,such as TNF-a,IL-6,COX-2,and reactive oxygen species(ROS),in the lungs.In conclusion,the codelivery system based on rod-like pure crystals could well target the pulmonary endothelium and effectively alleviate lung inflammation.The study offers a promising approach to combat pulmonary endothelium-associated diseases.
基金supported by the National Natural Science Foundation of China(Nos.3210110581373339)+6 种基金the 2021 Natural Science Foundation of Guangdong Province(Nos.2021A1515011367,China)the Southern Hospital Matching Fund(Nos.2013001,China)the High-Level university Academic Backbone and Training program in Guangzhou Medical University(Nos.B185004199,China)2022 City school joint funding project(Nos.202201020394,China)the 2018 Guangdong Key Discipline Construction Project of Pharmacy(Nos.Q185031010,China)the 2019 Undergraduate Laboratory Open Project(Nos.C195015003,China)Guangzhou Science and Technology Planning Project(Nos.202201010783,China)。
文摘Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies.Heat shock protein 90(Hsp90)as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance.Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance.In this study,a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX,and a COAmodified 4-arm PEG polymer(4PSC)was synthesized.COA,an active component in oleanolic acid that exerts strong antitumor activity by downregulating Hsp90 expression,was used as a structural and functional element to endow 4PSC with redox responsiveness and Hsp90 inhibitory activity.Our results showed that 4PSC/PTX nanomicelles efficiently delivered PTX and COA to tumor locations without inducing systemic toxicity.By blocking the Hsp90 signaling pathway,4PSC significantly enhanced the antitumor effect of PTX,inhibiting tumor proliferation and invasiveness as well as chemotherapy-induced resistance in vitro.Remarkable results were further confirmed in vivo with two preclinical tumor models.These findings demonstrate that the COA-modified 4PSC drug delivery nanosystem provides a potential platform for enhancing the efficacy of chemotherapies.
基金G.Z.acknowledges funding support from NIH(R01CA266981,R01AI168684,R35GM143014,R21NS114455)DoD CDMRP Breast Cancer Breakthrough Award Level II(BC210931/P1)+3 种基金NIH-NCATS KL2 scholarship(KL2TR002648)via VCU C.Kenneth and Dianne Wright Center for Clinical and Translational Research(UL1TR002649)American Cancer Society Research Scholar Grant(RSG-22-055-01-IBCD)METAvivor Early Career Investigator Award,among others.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.T.S.and F.C.acknowledge the National Natural Science Foundation of China(52103199,82102203)Guangdong Basic and Applied Basic Research Foundation(2020A1515110811).
文摘Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor immunosuppression.Therapeutic vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor immunosuppression.Chemically defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic heterogeneity.Here,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC subsets.These NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor immunosuppression.As a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy.
基金supported by the National Natural Science Foundation of China(Nos.81872823,81871477 and 82073782)the Double First-Class(CPU2018PZQ13,China)of the China Pharmaceutical University+1 种基金the Shanghai Science and Technology Committee(No.19430741500)the Key Laboratory of Modern Chinese Medicine Preparation of Ministry of Education of Jiangxi University of Traditional Chinese Medicine,China(No.TCM-201905)。
文摘Codelivery of drugs by drug carriers is a promising strategy against several diseases such as infections and cancer.However,traditional drug carriers are typically characterized by low drug payload,limiting their treatment efficacy.Using nanocrystals of insoluble drug as carriers,a carrier free platform was developed previously to deliver a second insoluble drug for codelivery.To extend the concept,we hypothesized,herein,that the platform allows for codelivery of hydrophobic and hydrophilic drugs using a cocrystalization-like strategy.To obtain proof-of-concept,paclitaxel(PTX),an insoluble chemotherapeutic agent,and dichloroacetic acid(DCA),a water-soluble inhibitor of pyruvate dehydrogenase kinase,were utilized as model drugs.PTX-DCA hybrid nanocrystals(PTX-DCA NCs)were prepared by antisolvent precipitation and characterized.Their in vitro antitumor activity against cancer cells was evaluated.PTX-DCA NCs prepared from the optimized formulation had a diameter of 160 nm and a rodshape morphology and possessed encapsulated efficacy of approximately 30%for DCA.The use of the hybrid crystals enabled synergy to kill cancer cells,in particular in PTX-resistant cells in a dosedependent pattern.In conclusion,by using a cocrystalization-like strategy,a hydrophilic drug can be formulated into a drug’s nanocrystal for codelivery.
