Radiation damage can cause a series of gastrointestinal(GI)tract diseases.The development of safe and effective GI tract radioprotectants still remains a great challenge clinically.Here,we firstly report an oral radio...Radiation damage can cause a series of gastrointestinal(GI)tract diseases.The development of safe and effective GI tract radioprotectants still remains a great challenge clinically.Here,we firstly report an oral radioprotectant Gel@GYY that integrates a porous gelatin-based(Gel)hydrogel and a pH-responsive hydrogen sulfide(H2S)donor GYY4137(morpholin-4-ium 4 methoxyphenyl(morpholino)phosphinodithioate).Gel@GYY has a remarkable adhesion ability and long retention time,which not only enables responsive release of low-dose H2S in stomach and subsequently sustained release of H2S in the whole intestinal tract especially in the colon,but also ensures a close contact between H2S and GI tract.The released H2S can effectively scavenge free radicals induced by X-ray radiation,reduce lipid peroxidation level,repair DNA damage and recover vital superoxide dismutase and glutathione peroxidase activities.Meanwhile,the released H2S inhibits radiation-induced activation of nuclear factorκB(NF-κB),thus reducing inflammatory cytokines levels in GI tract.After treatment,Gel@GYY displays efficient excretion from mice body due to its biodegradability.This work provides a new insight for therapeutic application of intelligent H2S-releasing oral delivery system and potential alternative to clinical GI physical damage protectant.展开更多
Photodynamic therapy (PDT) is a clinically approved cancer treatment that uses energy of light to generate active substances that cause damage to the cancer. Photosensitizers are employed to absorb light and generate ...Photodynamic therapy (PDT) is a clinically approved cancer treatment that uses energy of light to generate active substances that cause damage to the cancer. Photosensitizers are employed to absorb light and generate toxic reactive oxygen species (ROS) to damage biomolecules like DNA. At the same time, some chemotherapy drugs like nucleotide analogues can provide mechanism-guided promotion in the treatment efficacy of PDT. However, the photosensitizer and chemotherapy drugs used in PDT is usually organic molecules, which suffers from bad solubility, fast clearance, and acute toxicity. To achieve targeted treatment, a reasonable delivery system is necessary. Therefore, we reported a metal-phenolic network where IR780 and gemcitabine were coupled chemically to overcome these shortcomings. The enhanced PDT effects can be realized by the promoted cell death both in vitro and in vivo. Moreover, the synergistic therapy also induced T-cell mediated anti-tumor immune response, which was significant for the inhibition of distant tumor growth. This work expanded the biomedical application of metal-phenolic materials and contribute to the wider application of photodynamic cancer therapy.展开更多
Malignant melanoma cell-intrinsic PD-1:PD-L1 interaction thrusts tumorigenesis,angiogenesis,and radioresistance via mTOR hyperactivation to aggravate circumjacent aggression.Interdicting melanoma intrinsic growth sign...Malignant melanoma cell-intrinsic PD-1:PD-L1 interaction thrusts tumorigenesis,angiogenesis,and radioresistance via mTOR hyperactivation to aggravate circumjacent aggression.Interdicting melanoma intrinsic growth signals,including the blockade of PD-L1 and mTOR signaling concurrently,cooperative with radiotherapy may provide a vigorous repertoire to alleviate the tumor encumbrance.Thence,we design a three-pronged platinum@polymer-catechol nanobraker to deliver mTOR inhibitor TAK228 and anti-PD-L1 antibody(aPD-L1)for impeding the melanoma-PD-1-driven aggression and maximizing the melanoma eradication.The aPD-L1 collaborated with TAK228 restrains melanoma cell-intrinsic PD-1:PD-L1 tumorigenic interaction via blocking melanoma-PD-L1 ligand and the melanoma-PD-1 receptor-driven mTOR signaling;corresponding downregulation of mTOR downstream protumorigenic cellular MYC and proangiogenic hypoxia-inducible factor 1-alpha is conducive to preventing tumorigenesis and angiogenesis,respectively.Further,high-Z metal platinum sensitizing TAK228-enhanced radiotherapy confers the nanobraker on remarkable tumoricidal efficacy.Hereto,the customized three-pronged nanobrakers efficiently suppress melanoma tumorigenesis and angiogenesis concomitant with the amplification of radiotherapeutic efficacy.Such an ingenious tactic may provide substantial benefits to clinical melanoma patients.展开更多
Tumor-targeted delivery of nanomedicine is of great importance to improve therapeutic efficacy of cancer and minimize systemic side effects.Unfortunately,nowadays the targeting efficiency of nanomedicine toward tumor ...Tumor-targeted delivery of nanomedicine is of great importance to improve therapeutic efficacy of cancer and minimize systemic side effects.Unfortunately,nowadays the targeting efficiency of nanomedicine toward tumor is still quite limited and far from clinical requirements.In this work,we develop an innovative peptide-based nanoparticle to realize light-triggered nitric oxide(NO)release and structural transformation for enhanced intratumoral retention and simultaneously sensitizing photodynamic therapy(PDT).The designed nanoparticle is self-assembled from a chimeric peptide monomer,TPP-RRRKLVFFK-Ce6,which contains a photosensitive moiety(chlorin e6,Ce6),aβ-sheet-forming peptide domain(Lys-Leu-Val-Phe-Phe,KLVFF),an oligoarginine domain(RRR)as NO donor and a triphenylphosphonium(TPP)moiety for targeting mitochondria.When irradiated by light,the constructed nanoparticles undergo rapid structural transformation from nanosphere to nanorod,enabling to achieve a significantly higher intratumoral accumulation by 3.26 times compared to that without light irradiation.More importantly,the conversion of generated NO and reactive oxygen species(ROS)in a light-responsive way to peroxynitrite anions(ONOO)with higher cytotoxicity enables NO to sensitize PDT in cancer treatment.Both in vitro and in vivo studies demonstrate that NO sensitized PDT based on the well-designed transformable nanoparticles enables to eradicate tumors efficiently.The light-triggered transformable nanoplatform developed in this work provides a new strategy for enhanced intratumoral retention and improved therapeutic outcome.展开更多
Interferon-γ(IFN-γ),secreted by activated T cells predominantly,plays a crucial performance in the tumoricidal immune response.Unfortunately,a high level of IFN-γseverely ignites the immunosuppressive response,espe...Interferon-γ(IFN-γ),secreted by activated T cells predominantly,plays a crucial performance in the tumoricidal immune response.Unfortunately,a high level of IFN-γseverely ignites the immunosuppressive response,especially by increasing the expression of immune checkpoint programmed death-ligand 1(PD-L1)and immunoregulatory enzyme indoleamine 2,3-dioxygenase 1(IDO-1).Herein,we have explored a versatile IFN-γ-nano-integrator(aPD-L1-SH@Ce6@NLG919-PEG,simplified as CNDP)to establish a positive anti-tumor feedback loop to amplify the IFN-γ-mediated tumoricidal effect.In this nanointegrator,photosensitizer chlorin e6(Ce6)mediates photodynamic therapy(PDT)to re-shape immunogenicity and activate the adaptive immune response,followed by the secretion of high-level IFN-γto struggle tumor cells.IDO-1 inhibitor(NLG919)afterwards mitigates the immunosuppressive behavior of IFN-γby neutralizing the function of IDO-1.To turn“waste”into wealth,anti-PD-L1(aPD-L1)antibodies are technically integrated into the nano-integrator to propel the precise attack of breast cancer through ascending PD-L1 blockade.Together,this“three musketeers”nano-integrator tumoricidal tactic may give a unique insight into the clinical anti-tumor therapy.展开更多
Despite tremendous advances in gas therapy,there are major concerns about the inevitable concentration of toxicity and the ability to perform real-time tracking of drug delivery.Second near-infrared(NIR-Ⅱ)window abso...Despite tremendous advances in gas therapy,there are major concerns about the inevitable concentration of toxicity and the ability to perform real-time tracking of drug delivery.Second near-infrared(NIR-Ⅱ)window absorbing nanoplatforms hold great promise for precision medicine because of their excellent tissue penetration of light and non-invasive nature.In this study,we engineered an NIR-Ⅱlaser-activated theranostic agent(named CP-bF@PEG)that was composed of amphiphilic polymers(Pluronic F127,with polyethylene glycol,PEG,moieties)coated with an NIR-Ⅱ-absorbing conjugated polymer(PTTBBT,CP)and nitric oxide(NO)donor(benzofuroxan,bF),which served as an NIR-Ⅱphotothermal inducer and NO nanogenerator.Under deep tissue penetration of NIR-Ⅱlaser irradiation,CP-bF@PEG was found to possess fluorescence imaging ability to accurately identify tumor and excellent photothermal effect.Moreover,CP-bF@PEG could generate NO via glutathione activation in the tumor microenvironment in a controllable manner.This NIR-Ⅱ-absorbing polymer for high-contrast NIR-Ⅱfluorescence imaging-guided precision photothermal therapy achieved synergistic effects with NO therapy,as evidenced by pronounced tumor therapeutic efficacy and few side effects.This nanotheranostic agent is a highly promising candidate for high-contrast NIR-Ⅱimaging-guided precision photothermal therapy combined with gas therapy against cancer.展开更多
基金the National Natural Science Foundation of China(Nos.22175182,21471103)Sheng Yuan Cooperation(No.2021SYHZ0048)+1 种基金Beijing Natural Science Foundation(No.2202064)the directional institutionalized scientific research platform relies on Beijing Synchrotron Radiation Facility of Chinese Academy of Sciences.
文摘Radiation damage can cause a series of gastrointestinal(GI)tract diseases.The development of safe and effective GI tract radioprotectants still remains a great challenge clinically.Here,we firstly report an oral radioprotectant Gel@GYY that integrates a porous gelatin-based(Gel)hydrogel and a pH-responsive hydrogen sulfide(H2S)donor GYY4137(morpholin-4-ium 4 methoxyphenyl(morpholino)phosphinodithioate).Gel@GYY has a remarkable adhesion ability and long retention time,which not only enables responsive release of low-dose H2S in stomach and subsequently sustained release of H2S in the whole intestinal tract especially in the colon,but also ensures a close contact between H2S and GI tract.The released H2S can effectively scavenge free radicals induced by X-ray radiation,reduce lipid peroxidation level,repair DNA damage and recover vital superoxide dismutase and glutathione peroxidase activities.Meanwhile,the released H2S inhibits radiation-induced activation of nuclear factorκB(NF-κB),thus reducing inflammatory cytokines levels in GI tract.After treatment,Gel@GYY displays efficient excretion from mice body due to its biodegradability.This work provides a new insight for therapeutic application of intelligent H2S-releasing oral delivery system and potential alternative to clinical GI physical damage protectant.
基金the National Natural Science Foundation of China(NSFC,Nos.32171318,32222090 and 32101069)the Faculty of Health Sciences,University of Macao,the Multi-Year Research Grant(MYRG)of University of Macao(No.MYRG2022-00011-FHS)+2 种基金the Science and Technology Development Fund,Macao SAR(Nos.0103/2021/A and 0002/2021/AKP)Shenzhen Science and Technology Innovation Commission,Shenzhen-Hong Kong-Macao Science and Technology Plan C(No.SGDX20201103093600004)Dr.Stanley Ho Medical Development Foundation(No.SHMDF-OIRFS/2022/002)。
文摘Photodynamic therapy (PDT) is a clinically approved cancer treatment that uses energy of light to generate active substances that cause damage to the cancer. Photosensitizers are employed to absorb light and generate toxic reactive oxygen species (ROS) to damage biomolecules like DNA. At the same time, some chemotherapy drugs like nucleotide analogues can provide mechanism-guided promotion in the treatment efficacy of PDT. However, the photosensitizer and chemotherapy drugs used in PDT is usually organic molecules, which suffers from bad solubility, fast clearance, and acute toxicity. To achieve targeted treatment, a reasonable delivery system is necessary. Therefore, we reported a metal-phenolic network where IR780 and gemcitabine were coupled chemically to overcome these shortcomings. The enhanced PDT effects can be realized by the promoted cell death both in vitro and in vivo. Moreover, the synergistic therapy also induced T-cell mediated anti-tumor immune response, which was significant for the inhibition of distant tumor growth. This work expanded the biomedical application of metal-phenolic materials and contribute to the wider application of photodynamic cancer therapy.
基金This work was supported by the National Natural Science Foundation of China(NSFC 32171318 and 32101069)the Faculty of Health Sciences,University of Macao,the Science and Technology Development Fund,Macao SAR(File no.0109/2018/A3,0011/2019/AKP,0113/2019/A2,0103/2021/A,and 0002/2021/AKP)+1 种基金the Multi-Year Research Grant(MYRG)of University of Macao(File no.MYRG2022-00011-FHS)Shenzhen Science and Technology Innovation Commission,Shenzhen-Hong Kong-Macao Science and Technology Plan C(No.SGDX20201103093600004).
文摘Malignant melanoma cell-intrinsic PD-1:PD-L1 interaction thrusts tumorigenesis,angiogenesis,and radioresistance via mTOR hyperactivation to aggravate circumjacent aggression.Interdicting melanoma intrinsic growth signals,including the blockade of PD-L1 and mTOR signaling concurrently,cooperative with radiotherapy may provide a vigorous repertoire to alleviate the tumor encumbrance.Thence,we design a three-pronged platinum@polymer-catechol nanobraker to deliver mTOR inhibitor TAK228 and anti-PD-L1 antibody(aPD-L1)for impeding the melanoma-PD-1-driven aggression and maximizing the melanoma eradication.The aPD-L1 collaborated with TAK228 restrains melanoma cell-intrinsic PD-1:PD-L1 tumorigenic interaction via blocking melanoma-PD-L1 ligand and the melanoma-PD-1 receptor-driven mTOR signaling;corresponding downregulation of mTOR downstream protumorigenic cellular MYC and proangiogenic hypoxia-inducible factor 1-alpha is conducive to preventing tumorigenesis and angiogenesis,respectively.Further,high-Z metal platinum sensitizing TAK228-enhanced radiotherapy confers the nanobraker on remarkable tumoricidal efficacy.Hereto,the customized three-pronged nanobrakers efficiently suppress melanoma tumorigenesis and angiogenesis concomitant with the amplification of radiotherapeutic efficacy.Such an ingenious tactic may provide substantial benefits to clinical melanoma patients.
基金financially supported by National Natural Science Foundation of China(51872188)Shenzhen Basic Research Program(SGDX20201103093600004)+3 种基金Special Funds for the Development of Strategic Emerging Industries in Shenzhen(20180309154519685)SZU Top Ranking Project(860-00000210)Basic and Applied Basic Research Foundation of Guangdong Province(2019A1515110294)the Postdoctoral Science Foundation of China(2020M672798).
文摘Tumor-targeted delivery of nanomedicine is of great importance to improve therapeutic efficacy of cancer and minimize systemic side effects.Unfortunately,nowadays the targeting efficiency of nanomedicine toward tumor is still quite limited and far from clinical requirements.In this work,we develop an innovative peptide-based nanoparticle to realize light-triggered nitric oxide(NO)release and structural transformation for enhanced intratumoral retention and simultaneously sensitizing photodynamic therapy(PDT).The designed nanoparticle is self-assembled from a chimeric peptide monomer,TPP-RRRKLVFFK-Ce6,which contains a photosensitive moiety(chlorin e6,Ce6),aβ-sheet-forming peptide domain(Lys-Leu-Val-Phe-Phe,KLVFF),an oligoarginine domain(RRR)as NO donor and a triphenylphosphonium(TPP)moiety for targeting mitochondria.When irradiated by light,the constructed nanoparticles undergo rapid structural transformation from nanosphere to nanorod,enabling to achieve a significantly higher intratumoral accumulation by 3.26 times compared to that without light irradiation.More importantly,the conversion of generated NO and reactive oxygen species(ROS)in a light-responsive way to peroxynitrite anions(ONOO)with higher cytotoxicity enables NO to sensitize PDT in cancer treatment.Both in vitro and in vivo studies demonstrate that NO sensitized PDT based on the well-designed transformable nanoparticles enables to eradicate tumors efficiently.The light-triggered transformable nanoplatform developed in this work provides a new strategy for enhanced intratumoral retention and improved therapeutic outcome.
基金This work was supported by the National Natural Science Foundation of China(NSFC)(Nos.32171318 and 32101069)the Faculty of Health Sciences,University of Macao,the Start-up Research Grant(SRG)of University of Macao(No.SRG2018-00130-FHS)+2 种基金the Science and Technology Development Fund,Macao SAR(Nos.0109/2018/A3,0011/2019/AKP,0113/2019/A2,and 0103/2021/A)Shenzhen Science and Technology Innovation Commission,Shenzhen-Hong Kong-Macao Science and Technology Plan C(No.SGDX20201103093600004)We appreciate the assistance and support from the Proteomics,Metabolomics and Drug Development Core,Animal Research Core,and Biological Imaging and Stem Cell Core in the Faculty of Health Sciences,University of Macao.
文摘Interferon-γ(IFN-γ),secreted by activated T cells predominantly,plays a crucial performance in the tumoricidal immune response.Unfortunately,a high level of IFN-γseverely ignites the immunosuppressive response,especially by increasing the expression of immune checkpoint programmed death-ligand 1(PD-L1)and immunoregulatory enzyme indoleamine 2,3-dioxygenase 1(IDO-1).Herein,we have explored a versatile IFN-γ-nano-integrator(aPD-L1-SH@Ce6@NLG919-PEG,simplified as CNDP)to establish a positive anti-tumor feedback loop to amplify the IFN-γ-mediated tumoricidal effect.In this nanointegrator,photosensitizer chlorin e6(Ce6)mediates photodynamic therapy(PDT)to re-shape immunogenicity and activate the adaptive immune response,followed by the secretion of high-level IFN-γto struggle tumor cells.IDO-1 inhibitor(NLG919)afterwards mitigates the immunosuppressive behavior of IFN-γby neutralizing the function of IDO-1.To turn“waste”into wealth,anti-PD-L1(aPD-L1)antibodies are technically integrated into the nano-integrator to propel the precise attack of breast cancer through ascending PD-L1 blockade.Together,this“three musketeers”nano-integrator tumoricidal tactic may give a unique insight into the clinical anti-tumor therapy.
基金J.L.and L.X.contributed equally to this work.This work was sup-ported by the Faculty of Health Sciences,University of Macao,the Start-up Research Grant(SRG)of University of Macao(File No.SRG2018-00130-FHS)the Science and Technology Development Fund,Macao SAR(File Nos.0109/2018/A3 and 0011/2019/AKP)+1 种基金Shenzhen Science and Technology Innovation Commission,Shenzhen-Hong Kong-Macao Science and Technology Plan C,No.SGDX20201103093600004)The authors thank the Animal Research Core and Biological Imaging and Stem Cell Core in the Faculty of Health Sciences,University of Macao.The animal experimental procedures were conducted following an es-tablished protocol(UMARE-030-2018)that had previously been ap-proved by the University of Macao Animal Ethics Committee.
文摘Despite tremendous advances in gas therapy,there are major concerns about the inevitable concentration of toxicity and the ability to perform real-time tracking of drug delivery.Second near-infrared(NIR-Ⅱ)window absorbing nanoplatforms hold great promise for precision medicine because of their excellent tissue penetration of light and non-invasive nature.In this study,we engineered an NIR-Ⅱlaser-activated theranostic agent(named CP-bF@PEG)that was composed of amphiphilic polymers(Pluronic F127,with polyethylene glycol,PEG,moieties)coated with an NIR-Ⅱ-absorbing conjugated polymer(PTTBBT,CP)and nitric oxide(NO)donor(benzofuroxan,bF),which served as an NIR-Ⅱphotothermal inducer and NO nanogenerator.Under deep tissue penetration of NIR-Ⅱlaser irradiation,CP-bF@PEG was found to possess fluorescence imaging ability to accurately identify tumor and excellent photothermal effect.Moreover,CP-bF@PEG could generate NO via glutathione activation in the tumor microenvironment in a controllable manner.This NIR-Ⅱ-absorbing polymer for high-contrast NIR-Ⅱfluorescence imaging-guided precision photothermal therapy achieved synergistic effects with NO therapy,as evidenced by pronounced tumor therapeutic efficacy and few side effects.This nanotheranostic agent is a highly promising candidate for high-contrast NIR-Ⅱimaging-guided precision photothermal therapy combined with gas therapy against cancer.