In the treatment of breast cancer,the combination of glutamine metabolism inhibition and photothermal therapy(PTT)is gaining increasing attention.This study developed a Janus nanomotor to enhance permeability in tumor...In the treatment of breast cancer,the combination of glutamine metabolism inhibition and photothermal therapy(PTT)is gaining increasing attention.This study developed a Janus nanomotor to enhance permeability in tumor tissues for nanomedicine applications by using mesoporous organic silica(PMO)anisotropic ally grown on the surface of the platinum(Pt)nanoparticles(PMO@Pt).The prepared PMO@Pt had unique Janus structure with an average size of approximately 236 nm.The loading capacity of V9302 was evaluated to be 44.37%when the mass ratio of V9302 to PMO@Pt was maintained at 2.0 and in vitro release studies demonstrated that acidic environments significantly enhanced the drug release.Then this nanomotor was loaded with perfluorohexane(PFH),a phase-change material,and the glutamine inhibitor V9302(denoted as Janus PMO@Pt@PFH@V9302,JPV).Janus PMO@Pt@PFH(JPP)nanomotors demonstrated enhanced fluorescence intensity and distribution within 3D tumor spheroids compared to Janus PMO@Pt nanomotors,attributed to the photothermal-induced phase change of PFH.The nanomotors exhibited high biocompatibility,with cell viability exceeding 98%at high concentrations.However,the incorporation of V9302 into the nanomotors(JPV)significantly reduced 4T1 cell viability under laser irradiation,indicating a cytotoxic effect resulting from the synergy between photothermal therapy and glutamine metabolism inhibition.In vivo,JPV nanomotors effectively inhibited tumor growth and induced apoptosis without causing significant systemic toxicity,showcasing their potential as a therapeutic agent for breast cancer.This integrated nanomotor offers a promising approach for enhanced ultrasound imaging and photothermal therapy in cancer treatment.展开更多
The complexities of energy transfer mechanisms in the flagella of mammalian sperm flagella have been intensively investigated and demonstrate significant diversity across species.Enzymatic shuttles,particularly adenyl...The complexities of energy transfer mechanisms in the flagella of mammalian sperm flagella have been intensively investigated and demonstrate significant diversity across species.Enzymatic shuttles,particularly adenylate kinase(AK)and creatine kinase(CK),are pivotal in the efficient transfer of intracellular ATP,showing distinct tissue-and species-specificity.Here,the expression profiles of AK and CK were investigated in mice and found to fall into four subgroups,of which Subgroup III AKs were observed to be unique to the male reproductive system and conserved across chordates.Both AK8 and AK9 were found to be indispensable to male reproduction after analysis of an infertile male cohort.Knockout mouse models showed that AK8 and AK9 were central to promoting sperm motility.Immunoprecipitation combined with mass spectrometry revealed that AK8 and AK9 interact with the radial spoke(RS)of the axoneme.Examination of various human and mouse sperm samples with substructural damage,including the presence of multiple RS subunits,showed that the head of radial spoke 3 acts as an adapter for AK9 in the flagellar axoneme.Using an ATP probe together with metabolomic analysis,it was found that AK8 and AK9 cooperatively regulated ATP transfer in the axoneme,and were concentrated at sites associated with energy consumption in the flagellum.These findings indicate a novel function for RS beyond its structural role,namely,the regulation of ATP transfer.In conclusion,the results expand the functional spectrum of AK proteins and suggest a fresh model regarding ATP transfer within mammalian flagella.展开更多
Photothermal and photodynamic therapies(PTT/PDT)hold promise for localized tumor treatment,yet their full potential is hampered by limitations such as the hypoxic tumor microenvironment and inadequate systemic immune ...Photothermal and photodynamic therapies(PTT/PDT)hold promise for localized tumor treatment,yet their full potential is hampered by limitations such as the hypoxic tumor microenvironment and inadequate systemic immune activation.Addressing these challenges,we present a novel near-infrared(NIR)-triggered RNS nanoreactor(PBNO-Ce6)to amplify the photodynamic and photothermal therapy efficacy against triple-negative breast cancer(TNBC).The designed PBNOCe6 combines sodium nitroprusside-doped Prussian Blue nanoparticles with Chlorin e6 to enable on-site RNS production through NIR-induced concurrent NO release and ROS generation.This not only enhances tumor cell eradication but also potentiates local and systemic antitumor immune responses,protecting mice from tumor rechallenge.Our in vivo evaluations revealed that treatment with PBNO-Ce6 leads to a remarkable 2.7-fold increase in cytotoxic T lymphocytes and a 62%decrease in regulatory T cells in comparison to the control PB-Ce6(Prussian Blue nanoparticles loaded with Chlorin e6),marking a substantial improvement over traditional PTT/PDT.As such,the PBNO-Ce6 nanoreactor represents a transformative approach for improving outcomes in TNBC and potentially other malignancies affected by similar barriers.展开更多
基金financially supported by the Major Basic Research Fund of Jiangsu Province Hospital(No.TS202401)Jiangsu Province Hospital High-level Talent Cultivation Program(PhaseⅠ)(No.CZ0121002010039)
文摘In the treatment of breast cancer,the combination of glutamine metabolism inhibition and photothermal therapy(PTT)is gaining increasing attention.This study developed a Janus nanomotor to enhance permeability in tumor tissues for nanomedicine applications by using mesoporous organic silica(PMO)anisotropic ally grown on the surface of the platinum(Pt)nanoparticles(PMO@Pt).The prepared PMO@Pt had unique Janus structure with an average size of approximately 236 nm.The loading capacity of V9302 was evaluated to be 44.37%when the mass ratio of V9302 to PMO@Pt was maintained at 2.0 and in vitro release studies demonstrated that acidic environments significantly enhanced the drug release.Then this nanomotor was loaded with perfluorohexane(PFH),a phase-change material,and the glutamine inhibitor V9302(denoted as Janus PMO@Pt@PFH@V9302,JPV).Janus PMO@Pt@PFH(JPP)nanomotors demonstrated enhanced fluorescence intensity and distribution within 3D tumor spheroids compared to Janus PMO@Pt nanomotors,attributed to the photothermal-induced phase change of PFH.The nanomotors exhibited high biocompatibility,with cell viability exceeding 98%at high concentrations.However,the incorporation of V9302 into the nanomotors(JPV)significantly reduced 4T1 cell viability under laser irradiation,indicating a cytotoxic effect resulting from the synergy between photothermal therapy and glutamine metabolism inhibition.In vivo,JPV nanomotors effectively inhibited tumor growth and induced apoptosis without causing significant systemic toxicity,showcasing their potential as a therapeutic agent for breast cancer.This integrated nanomotor offers a promising approach for enhanced ultrasound imaging and photothermal therapy in cancer treatment.
基金supported by National Key Research and Development Program of China(2022YFC2702702,2021YFC2700901)the National Natural Science Foundation of China(81971441,82171607,32000584)+3 种基金the University Outstanding Young Talents Support Program(gxyq2021174)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT310002)Anhui Provincial Natural Science Foundation(2208085Y31)the Natural Science Foundation of Jiangsu Province(BK20230004).
文摘The complexities of energy transfer mechanisms in the flagella of mammalian sperm flagella have been intensively investigated and demonstrate significant diversity across species.Enzymatic shuttles,particularly adenylate kinase(AK)and creatine kinase(CK),are pivotal in the efficient transfer of intracellular ATP,showing distinct tissue-and species-specificity.Here,the expression profiles of AK and CK were investigated in mice and found to fall into four subgroups,of which Subgroup III AKs were observed to be unique to the male reproductive system and conserved across chordates.Both AK8 and AK9 were found to be indispensable to male reproduction after analysis of an infertile male cohort.Knockout mouse models showed that AK8 and AK9 were central to promoting sperm motility.Immunoprecipitation combined with mass spectrometry revealed that AK8 and AK9 interact with the radial spoke(RS)of the axoneme.Examination of various human and mouse sperm samples with substructural damage,including the presence of multiple RS subunits,showed that the head of radial spoke 3 acts as an adapter for AK9 in the flagellar axoneme.Using an ATP probe together with metabolomic analysis,it was found that AK8 and AK9 cooperatively regulated ATP transfer in the axoneme,and were concentrated at sites associated with energy consumption in the flagellum.These findings indicate a novel function for RS beyond its structural role,namely,the regulation of ATP transfer.In conclusion,the results expand the functional spectrum of AK proteins and suggest a fresh model regarding ATP transfer within mammalian flagella.
基金the financial support from the National Natural Science Foundation of China (No. 82372019, 82022034, 82173327)Jiangsu Province Natural Science Foundation of China (BK20200032)Double First Class Foundation of China Pharmaceutical University(CPUQNJC22_03)
文摘Photothermal and photodynamic therapies(PTT/PDT)hold promise for localized tumor treatment,yet their full potential is hampered by limitations such as the hypoxic tumor microenvironment and inadequate systemic immune activation.Addressing these challenges,we present a novel near-infrared(NIR)-triggered RNS nanoreactor(PBNO-Ce6)to amplify the photodynamic and photothermal therapy efficacy against triple-negative breast cancer(TNBC).The designed PBNOCe6 combines sodium nitroprusside-doped Prussian Blue nanoparticles with Chlorin e6 to enable on-site RNS production through NIR-induced concurrent NO release and ROS generation.This not only enhances tumor cell eradication but also potentiates local and systemic antitumor immune responses,protecting mice from tumor rechallenge.Our in vivo evaluations revealed that treatment with PBNO-Ce6 leads to a remarkable 2.7-fold increase in cytotoxic T lymphocytes and a 62%decrease in regulatory T cells in comparison to the control PB-Ce6(Prussian Blue nanoparticles loaded with Chlorin e6),marking a substantial improvement over traditional PTT/PDT.As such,the PBNO-Ce6 nanoreactor represents a transformative approach for improving outcomes in TNBC and potentially other malignancies affected by similar barriers.
