BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erl...BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration.Nevertheless,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes.We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell death.Erlotinib has not been tested for this effect.AIM To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell death.METHODSΔψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell lines.The viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive MitoQ.The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0.The preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.RESULTS Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive agents.MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of MitoQ.SynergyFinder suggested that these drugs synergistically induced tumor cell lethality.Consistent with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.展开更多
Black phosphorus(BP)nano-materials,especially BP quantum dots(BPQDs),performs outstanding photothermal antitumor effects,excellent biocompatibility and biodegradability.However,there are several challenges to overcome...Black phosphorus(BP)nano-materials,especially BP quantum dots(BPQDs),performs outstanding photothermal antitumor effects,excellent biocompatibility and biodegradability.However,there are several challenges to overcome before offering real benefits,such as poor stability,poor dispersibility as well as difficulty in tailoring other functions.Here,a“three-in-one”mitochondria-targeted BP nano-platform,called as BPQD-PEG-TPP,was designed.In this nano-platform,BPQDs were covalently grafted with a heterobifunctional PEG,in which one end was an aryl diazo group capable of reacting with BPQDs to form a covalent bond and the other end was a mitochondria-targeted triphenylphosphine(TPP)group.In addition to its excellent near-infrared photothermal properties,BPQD-PEG-TPP had much enhanced stability and dispersibility under physiological conditions,efficient mitochondria targeting and promoted ROS production through a photothermal effect.Both in vitro and in vivo experiments demonstrated that BPQD-PEG-TPP performed much superior photothermal cytotoxicity than BPQDs and BPQD-PEG as the mitochondria targeted PTT.Thus this“three-in-one”nanoplatform fabricated through polymer grafting,with excellent stability,dispersibility and negligible side effects,might be a promising strategy for mitochondria-targeted photothermal cancer therapy.展开更多
Human salivary histatin 1(Hst1)exhibits a series of cell-activating properties,such as promoting cell spreading,migration,and metabolic activity.We recently have shown that fluorescently labeled Hst1(F-Hst1)targets an...Human salivary histatin 1(Hst1)exhibits a series of cell-activating properties,such as promoting cell spreading,migration,and metabolic activity.We recently have shown that fluorescently labeled Hst1(F-Hst1)targets and activates mitochondria,presenting an important molecular mechanism.However,its regulating signaling pathways remain to be elucidated.We investigated the influence of specific inhibitors of G protein-coupled receptors(GPCR),endocytosis pathways,extracellular signal-regulated kinases1/2(ERK1/2)signaling,p38 signaling,mitochondrial respiration and Na+/K+-ATPase activity on the uptake,mitochondria-targeting and-activating properties of F-Hst1.We performed a si RNA knockdown(KD)to assess the effect of Sigma-2 receptor(S2R)/Transmembrane Protein 97(TMEM97)—a recently identified target protein of Hst1.We also adopted live cell imaging to monitor the whole intracellular trafficking process of F-Hst1.Our results showed that the inhibition of cellular respiration hindered the internalization of F-Hst1.The inhibitors of GPCR,ERK1/2,phagocytosis,and clathrin-mediated endocytosis(CME)as well as siRNA KD of S2R/TMEM97 significantly reduced the uptake,which was accompanied by the nullification of the promoting effect of F-Hst1 on cell metabolic activity.Only the inhibitor of CME and KD of S2R/TMEM97 significantly compromised the mitochondria-targeting of Hst1.We further showed the intracellular trafficking and targeting process of F-Hst1,in which early endosome plays an important role.Overall,phagocytosis,CME,GPCR,ERK signaling,and S2R/TMEM97 are involved in the internalization of Hst1,while only CME and S2R/TMEM97 are critical for its subcellular targeting.The inhibition of either internalization or mitochondria-targeting of Hst1 could significantly compromise its mitochondria-activating property.展开更多
Hepatic ischemia-reperfusion injury(HIRI)is the cause of postoperative hepatic dysfunction and failure,and even death.As an important biological effector molecule,hydrogen sulfide(H_(2)S)of mitochondria as a gasotrans...Hepatic ischemia-reperfusion injury(HIRI)is the cause of postoperative hepatic dysfunction and failure,and even death.As an important biological effector molecule,hydrogen sulfide(H_(2)S)of mitochondria as a gasotransmitter that is usually used to protect against acute HIRI injury.However,the exact relationship between HIRI and mitochondrial H_(2)S remains tangled due to the lack of an effective analytical method.Herein,we have fabricated a mitochondria-targeted H_(2)S-activatable fluorogenic probe(Mito-GW)to explore the stability of mitochondrial H_(2)S and track the changes of mitochondrial H_(2)S during the HIRI.By virtue of pyridinium electropositivity and its amphiphilicity,Mito-GW could accumulate in mitochondria.It goes through an analyte-prompted immolation when reacts with H_(2)S,resulting in the releasing of the fluorophore(GW).Therefore,the extent of Mito-GW conversion to GW can be used to evaluate the changes of mitochondrial H_(2)S level in living cells and tissues.As proof-of-principle,we have used MitoGW to demonstrate the mitochondria H_(2)S-levels increase and then decrease during HIRI in vitro and in vivo.Our research highlights the tremendous potential of Mito-GW as a mitochondrial H_(2)S fluorogenic probe in elucidating the pathogenesis of HIRI,providing a powerful tool for promoting future research on hepatology.展开更多
Glioblastoma(GBM)is the most aggressive malignant brain tumor and has a high mortality rate.Photodynamic therapy(PDT)has emerged as a promising approach for the treatment of malignant brain tumors.However,the use of P...Glioblastoma(GBM)is the most aggressive malignant brain tumor and has a high mortality rate.Photodynamic therapy(PDT)has emerged as a promising approach for the treatment of malignant brain tumors.However,the use of PDT for the treatment of GBM has been limited by its low blood-brain barrier(BBB)permeability and lack of cancer-targeting ability.Herein,brain endothelial cell-derived extracellular vesicles(bEVs)were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the BBB.To enhance PDT efficacy,the photosensitizer chlorin e6(Ce6)was linked to mitochondria-targeting triphenylphosphonium(TPP)and entrapped into bEVs.TPPconjugated Ce6(TPP-Ce6)selectively accumulated in the mitochondria,which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light irradiation.Moreover,the encapsulation of TPP-Ce6 into b EVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6,leading to significantly enhanced PDT efficacy in U87MG GBM cells.An in vivo biodistribution study using orthotopic GBM-xenografted mice showed that b EVs containing TPP-Ce6[b EV(TPP-Ce6)]substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated transcytosis.As such,b EV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity,suggesting that mitochondria are an effective target for photodynamic GBM therapy.展开更多
mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium(TPP), which is a delocalized cationic...mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium(TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides,dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively,compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated in vitro and in vivo, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors.展开更多
Subcellular organelle-specific nanoparticles for simultaneous tumor targeting, imaging, and drug delivery are of enormous interest in cancer therapy. Herein, we report a selective mitochondria-targeting probe 1, which...Subcellular organelle-specific nanoparticles for simultaneous tumor targeting, imaging, and drug delivery are of enormous interest in cancer therapy. Herein, we report a selective mitochondria-targeting probe 1, which was synthesized by incorporating a triphenyl phosphine with a cyanostilbene and a long alkyl chain moiety. Probe 1 was found to display fluorescence via aggregation-induced emission （AIE）. The low molecular-weight cyanostilbene-based probe 1, with and without an anticancer drug, formed a narrow homogeneous nanorod with ca. 110 nm of length or nanopartides with ca. 20 nm diameter in aqueous media. The self-assembled cyanostilbene nanoparticles （N1） selectively accumulated in the mitochondria of cancer cells and emitted fluorescence. N1 was also able to deliver an anticancer drug, doxorubicin （DOX）, to the mitochondria with high efficiency. More importantl~ N1 exhibited highly selective cytotoxicity for cancer cells over normal cells. The great potential applications of this self-assembled nanoparticle to biological systems result from its ability to aggregate in the mitochondria. This aggregation led to a significant increase in the generation of intraceUular reactive oxygen species and to a decrease in the mitochondrial membrane potential in cancer cells. Furthermore, tumor tissue uptake experiments in mice proposed that the self-assembled N1 had the ability to internalize and deliver the anticancer drug into tumor tissues effectively. Moreover, both N1 and Nl-encapsulated doxorubicin （N1-DOX） effectively suppressed tumor growth in a xenograft model in vivo. Taken together, our findings indicate that applications of N1 as a mitochondrial targeting probe, drug delivery platform, and chemotherapeutic agent provide a unique strategy for potential image-guided therapy as well as a site-specific delivery system to cancer cells.展开更多
Hypochlorous acid（HOCl） plays a vital role in many physiological and pathological processes as one of reactive oxygen species（ROS）. Developing highly sensitive and selective methods for HOCl detection is of signif...Hypochlorous acid（HOCl） plays a vital role in many physiological and pathological processes as one of reactive oxygen species（ROS）. Developing highly sensitive and selective methods for HOCl detection is of significant interest. In this work, we developed a benzothiazole based probe 1 for ratiometric fluorescence detection of hypochlorite in living cells. The probe can detect HOCl with high selectivity, fast response（within 30 s） as well as low detection limit（0.18 mmol/L）. Fluorescence co-localization studies demonstrated that probe 1 was a mitochondria-targeted fluorescent probe. Furthermore, confocal fluorescence images of He La cell indicated that probe 1 could be used for monitoring intracellular HOCl in living cells. Finally, test strips experiment suggests that the probe 1 can detect the hypochlorous acid in tap water accompanied by remarkable color change.展开更多
An Ir8 Pd4-heteronuclear metal-organic cage(MOC-51)was assembled from bipodal metalloligand[Ir(ppy)2(qpy)(BF4)](qpy=4,4′:2′,2″:4″,4′′′-quaterpyridine;ppy-2-phenylpridine)with Pd(Ⅱ)salt.The cubic barrel shaped ...An Ir8 Pd4-heteronuclear metal-organic cage(MOC-51)was assembled from bipodal metalloligand[Ir(ppy)2(qpy)(BF4)](qpy=4,4′:2′,2″:4″,4′′′-quaterpyridine;ppy-2-phenylpridine)with Pd(Ⅱ)salt.The cubic barrel shaped MOC shows one-photon and two-photon excited deep-red emission,as well as large singlet oxygen quantum yields under visible light irradiation,therefore exhibiting great potentials in organelles-targeted cell imaging and photodynamic therapy(PDT).Compared with the Ir(Ⅲ)metalloligand,the Ir8 Pd4-MOC showed less dark toxicity and higher mitochondria-targeting efficiency.The localization in mitochondria overco mes the limitation of short lifetime and diffusion distance of ROS in cell,thus improved PDT effect can be obtained in low light dose usage of the MOC.This study presents the first case of Ir-based metal-organic cages for bio-applications in successful integration of imaging diagnosis and photodynamic therapy.展开更多
Targetingmitochondria via nano platform emerged as an attractive anti-tumor pathway due to the central regulation role in cellar apoptosis and drug resistance.Here,a mitochondria-targeting nanoparticle(TOS-PDA-PEG-TPP...Targetingmitochondria via nano platform emerged as an attractive anti-tumor pathway due to the central regulation role in cellar apoptosis and drug resistance.Here,a mitochondria-targeting nanoparticle(TOS-PDA-PEG-TPP)was designed to precisely deliver polydopamine(PDA)as the photothermal agent and alphatocopherol succinate(α-TOS)as the chemotherapeutic drug to the mitochondria of the tumor cells,which inhibits the tumor growth through chemo-and photothermal-synergistic therapies.TOSPDA-PEG-TPP was constructed by coating PDA on the surface of TOS NPs self-assembled byα-TOS,followed by grafting PEGand triphenylphosphonium(TPP)on their surface to prolong the blood circulation time and target delivery of TOS and PDA to the mitochondria of tumor cells.In vitro studies showed that TOS-PDA-PEGTPP could be efficiently internalized by tumor cells and accumulated atmitochondria,resulting in cellular apoptosis and synergistic inhibition of tumor cell proliferation.In vivo studies demonstrated that TOS-PDA-PEG-TPP could be efficiently localized at tumor sites and significantly restrain the tumor growth under NIR irradiation without apparent toxicity or deleterious effects.Conclusively,the combination strategy adopted for functional nanodrugs construction aimed at target-delivering therapeutic agents with different action mechanisms to the same intracellular organelles can be extended to other nanodrugs-dependent therapeutic systems.展开更多
Nitroxyl(HNO)has been reported to possess unique biological and pharmacological performances,and emerged as a novel therapy for congestive heart failure.Recent studies also suggest that HNO may be produced and involve...Nitroxyl(HNO)has been reported to possess unique biological and pharmacological performances,and emerged as a novel therapy for congestive heart failure.Recent studies also suggest that HNO may be produced and involved in important metabolisms in mitochondria.However,due to its high reactivity and short life properties,fast,sensitive and selective observation and monitoring of HNO related dynamic changes in mitochondria still remains a great challenge.Herein,we synthesized a mitochondria-targeting near-infrared(NIR)fluorescent probe(DCMHNO)for rapid detection of HNO with remarkably high sensitivity,selectivity and photostability.DCMHNO shows fast response(about 4 min)towards HNO via 2-(diphenylphosphino)benzoyl group through the Staudinger reaction to boost the bright NIR emission(700 nm)with excellent sensitivity(detection limit of 13 nM),high p H stability and very low interference from other species.DCMHNO can selectively locate in mitochondria and visualize exogenous and endogenous HNO in live He La cells with high biocompatibility and photostability.The probe could also monitor the interaction between NO and H2 S that gives rise to the generation of HNO in live He La cells.In addition,DCMHNO was further utilized in ex vivo NIR imaging of HNO in live mouse liver tissues at the depth of about 50μm.In vivo imaging of HNO with high signal-to-noise ratio in live mice was also realized by using DCMHNO.These remarkable imaging performances could render NIR DCMNHNO as a useful tool to reveal HNO related dynamic changes in live samples.展开更多
Cancer phototheranostics involving optical imaging-guided photodynamic therapy(PDT)and photothermal therapy(PTT)is a localized noninvasive approach in treating cancer.Mitochondria-targeted near-infrared(NIR)cyanines a...Cancer phototheranostics involving optical imaging-guided photodynamic therapy(PDT)and photothermal therapy(PTT)is a localized noninvasive approach in treating cancer.Mitochondria-targeted near-infrared(NIR)cyanines are excellent therapeutic photosensitizers of cancer.However,most mitochondria-targeted cyanines exist in the form of hydrophobic structures,which in vivo may cause cyanine aggregation during blood circulation,resulting in poor biocompatibility and limited therapeutic efficacy.Therefore,we developed a trade-off strategy by encapsulating mitochondria-targeted cyanines into liposomal bilayers(CyBI7-LPs),which balanced hydrophilicity that favored blood circulation and hydrophobicity that enhanced mitochondria tumor targeting.Moreover,CyBI7-LPs greatly minimized photobleaching of cyanine as self-generated reactive oxygen species(ROS)could rapidly escape from the liposomal bilayer,affording enhanced PTT/PDT efficacy.Bioorthogonal-mediated targeting strategy was further employed to improve uptake of tumor cells by modifying the liposomal surface to generate CyBI7-LPB.The CyBI7-LPB probe produced a tumor-to-background ratio(TBR)of approximately 6.4 at 24 HPI.Guiding by highly sensitive imaging resulted in excellent anti-tumor therapy outcomes using CyBI7-LPB due to the enhanced photothermal and photodynamic effects.This proposed liposomal nanoplatform exhibited a simple and robust approach as an imaging-guided synergistic anti-tumor therapeutic strategy.展开更多
Mitochondria are a novel and promising therapeutic target for diagnosis, treatment and prevention of a lot of human diseases such as cancer, metabolic diseases and neurodegenerative disease. Owing to the mitochondrial...Mitochondria are a novel and promising therapeutic target for diagnosis, treatment and prevention of a lot of human diseases such as cancer, metabolic diseases and neurodegenerative disease. Owing to the mitochondrial special bilayer structure and highly negative potential nature, therapeutic molecules have multiple difficulties in reaching mitochondria. To overcome multiple barriers for targeting mitochondria, the researchers developed various pharmaceutical preparations such as liposomes, polymeric nanoparticles and inorganic nanoparticles modified by mitochondriotropic moieties like dequalinium (DQA),triphenylphosphonium (TPP), mitochondrial penetrating peptides (MPPs) and mitochondrial protein import machinery that allow specific targeting.The targeted formulations exhibited enhanced pharmacological effect and better therapeutic effect than their untargeted counterpart both in vitro and in vivo. Nanocarriers may be used for bio-therapeutic delivery into specific mitochondria that possess a great potential treatment of mitochondria related diseases.展开更多
基金Supported by NIH/National Cancer Institute Grant,No.R01CA138441 and No.R01CA269452UW Madison Centene Pancreas Cancer Collaborative Award,No.21-8568.
文摘BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration.Nevertheless,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes.We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell death.Erlotinib has not been tested for this effect.AIM To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell death.METHODSΔψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell lines.The viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive MitoQ.The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0.The preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.RESULTS Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive agents.MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of MitoQ.SynergyFinder suggested that these drugs synergistically induced tumor cell lethality.Consistent with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.
基金We are grateful for the financial support from National Natural Science Foundation of China(51703258,81772449 and 81971081)Guangzhou science technology and innovation commission(201804010309 and 201803010090)Science,Technology&Innovation Commission of Shenzhen Municipality(JCYJ20180307154606793 and JCYJ20180507181654186).
文摘Black phosphorus(BP)nano-materials,especially BP quantum dots(BPQDs),performs outstanding photothermal antitumor effects,excellent biocompatibility and biodegradability.However,there are several challenges to overcome before offering real benefits,such as poor stability,poor dispersibility as well as difficulty in tailoring other functions.Here,a“three-in-one”mitochondria-targeted BP nano-platform,called as BPQD-PEG-TPP,was designed.In this nano-platform,BPQDs were covalently grafted with a heterobifunctional PEG,in which one end was an aryl diazo group capable of reacting with BPQDs to form a covalent bond and the other end was a mitochondria-targeted triphenylphosphine(TPP)group.In addition to its excellent near-infrared photothermal properties,BPQD-PEG-TPP had much enhanced stability and dispersibility under physiological conditions,efficient mitochondria targeting and promoted ROS production through a photothermal effect.Both in vitro and in vivo experiments demonstrated that BPQD-PEG-TPP performed much superior photothermal cytotoxicity than BPQDs and BPQD-PEG as the mitochondria targeted PTT.Thus this“three-in-one”nanoplatform fabricated through polymer grafting,with excellent stability,dispersibility and negligible side effects,might be a promising strategy for mitochondria-targeted photothermal cancer therapy.
基金funded by Eurostars project,grant number E!12764。
文摘Human salivary histatin 1(Hst1)exhibits a series of cell-activating properties,such as promoting cell spreading,migration,and metabolic activity.We recently have shown that fluorescently labeled Hst1(F-Hst1)targets and activates mitochondria,presenting an important molecular mechanism.However,its regulating signaling pathways remain to be elucidated.We investigated the influence of specific inhibitors of G protein-coupled receptors(GPCR),endocytosis pathways,extracellular signal-regulated kinases1/2(ERK1/2)signaling,p38 signaling,mitochondrial respiration and Na+/K+-ATPase activity on the uptake,mitochondria-targeting and-activating properties of F-Hst1.We performed a si RNA knockdown(KD)to assess the effect of Sigma-2 receptor(S2R)/Transmembrane Protein 97(TMEM97)—a recently identified target protein of Hst1.We also adopted live cell imaging to monitor the whole intracellular trafficking process of F-Hst1.Our results showed that the inhibition of cellular respiration hindered the internalization of F-Hst1.The inhibitors of GPCR,ERK1/2,phagocytosis,and clathrin-mediated endocytosis(CME)as well as siRNA KD of S2R/TMEM97 significantly reduced the uptake,which was accompanied by the nullification of the promoting effect of F-Hst1 on cell metabolic activity.Only the inhibitor of CME and KD of S2R/TMEM97 significantly compromised the mitochondria-targeting of Hst1.We further showed the intracellular trafficking and targeting process of F-Hst1,in which early endosome plays an important role.Overall,phagocytosis,CME,GPCR,ERK signaling,and S2R/TMEM97 are involved in the internalization of Hst1,while only CME and S2R/TMEM97 are critical for its subcellular targeting.The inhibition of either internalization or mitochondria-targeting of Hst1 could significantly compromise its mitochondria-activating property.
基金financially supported by the National Natural Science Foundation of China(Nos.22077101,22004099)the Joint Research Funds of Department of Science&Technology of Shaanxi Province and Northwestern Polytechnical University(Nos.2020GXLH-Z-008,2020GXLH-Z-021,2020GXLH-Z-023)+4 种基金Natural Science Foundation of Shaanxi Province(No.2022JM-130)The Natural Science Foundation of Ningbo(Nos.202003N4049,202003N4065)the Open Project Program of Wuhan National Laboratory for Optoelectronics(Nos.2020WNLOKF023,2022WNLOKF009)Innovation Foundation for Doctor Dissertation of Northwestern Polytechnical University(No.CX2022034)Innovation Capability Support Program of Shaanxi(No.2023-CX-PT-23)。
文摘Hepatic ischemia-reperfusion injury(HIRI)is the cause of postoperative hepatic dysfunction and failure,and even death.As an important biological effector molecule,hydrogen sulfide(H_(2)S)of mitochondria as a gasotransmitter that is usually used to protect against acute HIRI injury.However,the exact relationship between HIRI and mitochondrial H_(2)S remains tangled due to the lack of an effective analytical method.Herein,we have fabricated a mitochondria-targeted H_(2)S-activatable fluorogenic probe(Mito-GW)to explore the stability of mitochondrial H_(2)S and track the changes of mitochondrial H_(2)S during the HIRI.By virtue of pyridinium electropositivity and its amphiphilicity,Mito-GW could accumulate in mitochondria.It goes through an analyte-prompted immolation when reacts with H_(2)S,resulting in the releasing of the fluorophore(GW).Therefore,the extent of Mito-GW conversion to GW can be used to evaluate the changes of mitochondrial H_(2)S level in living cells and tissues.As proof-of-principle,we have used MitoGW to demonstrate the mitochondria H_(2)S-levels increase and then decrease during HIRI in vitro and in vivo.Our research highlights the tremendous potential of Mito-GW as a mitochondrial H_(2)S fluorogenic probe in elucidating the pathogenesis of HIRI,providing a powerful tool for promoting future research on hepatology.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)[(NRF-2022R1A2C1007207,Korea)Basic Research Laboratory Program(NRF-2020R1A4A2002894,Korea)+3 种基金Basic Science Research Program(NRF-2020R1A2B5B01001719,Korea)Engineering Research Center of Excellence Program(NRF-2016R1A5A1010148,Korea)]supported by Basic Science Research Program through the NRF funded by the Ministry of Education(NRF-2021R1I1A1A01042149,Korea)support by the Brigham Research Institute,USA。
文摘Glioblastoma(GBM)is the most aggressive malignant brain tumor and has a high mortality rate.Photodynamic therapy(PDT)has emerged as a promising approach for the treatment of malignant brain tumors.However,the use of PDT for the treatment of GBM has been limited by its low blood-brain barrier(BBB)permeability and lack of cancer-targeting ability.Herein,brain endothelial cell-derived extracellular vesicles(bEVs)were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the BBB.To enhance PDT efficacy,the photosensitizer chlorin e6(Ce6)was linked to mitochondria-targeting triphenylphosphonium(TPP)and entrapped into bEVs.TPPconjugated Ce6(TPP-Ce6)selectively accumulated in the mitochondria,which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light irradiation.Moreover,the encapsulation of TPP-Ce6 into b EVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6,leading to significantly enhanced PDT efficacy in U87MG GBM cells.An in vivo biodistribution study using orthotopic GBM-xenografted mice showed that b EVs containing TPP-Ce6[b EV(TPP-Ce6)]substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated transcytosis.As such,b EV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity,suggesting that mitochondria are an effective target for photodynamic GBM therapy.
基金supported by the National Research Foundation of Korea (NRF)funded by the Korean government (MSIT) (NRF2017R1A4A1015036 and NRF-2015R1A1A05001459)the study was supported by BK21PLUS grant of NRF funded by the Korean government (ME) (22A20130012250)
文摘mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium(TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides,dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively,compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated in vitro and in vivo, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors.
文摘Subcellular organelle-specific nanoparticles for simultaneous tumor targeting, imaging, and drug delivery are of enormous interest in cancer therapy. Herein, we report a selective mitochondria-targeting probe 1, which was synthesized by incorporating a triphenyl phosphine with a cyanostilbene and a long alkyl chain moiety. Probe 1 was found to display fluorescence via aggregation-induced emission （AIE）. The low molecular-weight cyanostilbene-based probe 1, with and without an anticancer drug, formed a narrow homogeneous nanorod with ca. 110 nm of length or nanopartides with ca. 20 nm diameter in aqueous media. The self-assembled cyanostilbene nanoparticles （N1） selectively accumulated in the mitochondria of cancer cells and emitted fluorescence. N1 was also able to deliver an anticancer drug, doxorubicin （DOX）, to the mitochondria with high efficiency. More importantl~ N1 exhibited highly selective cytotoxicity for cancer cells over normal cells. The great potential applications of this self-assembled nanoparticle to biological systems result from its ability to aggregate in the mitochondria. This aggregation led to a significant increase in the generation of intraceUular reactive oxygen species and to a decrease in the mitochondrial membrane potential in cancer cells. Furthermore, tumor tissue uptake experiments in mice proposed that the self-assembled N1 had the ability to internalize and deliver the anticancer drug into tumor tissues effectively. Moreover, both N1 and Nl-encapsulated doxorubicin （N1-DOX） effectively suppressed tumor growth in a xenograft model in vivo. Taken together, our findings indicate that applications of N1 as a mitochondrial targeting probe, drug delivery platform, and chemotherapeutic agent provide a unique strategy for potential image-guided therapy as well as a site-specific delivery system to cancer cells.
基金supported by the National Natural Science Foundation of China(Nos.21376117,21406109 and 31401588)the Jiangsu Natural Science Funds for Distinguished Young Scholars(No.BK20140043)+1 种基金the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(No.14KJA150005)the Qing Lan Project and the Project of Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)
文摘Hypochlorous acid（HOCl） plays a vital role in many physiological and pathological processes as one of reactive oxygen species（ROS）. Developing highly sensitive and selective methods for HOCl detection is of significant interest. In this work, we developed a benzothiazole based probe 1 for ratiometric fluorescence detection of hypochlorite in living cells. The probe can detect HOCl with high selectivity, fast response（within 30 s） as well as low detection limit（0.18 mmol/L）. Fluorescence co-localization studies demonstrated that probe 1 was a mitochondria-targeted fluorescent probe. Furthermore, confocal fluorescence images of He La cell indicated that probe 1 could be used for monitoring intracellular HOCl in living cells. Finally, test strips experiment suggests that the probe 1 can detect the hypochlorous acid in tap water accompanied by remarkable color change.
基金supported by the National Natrual Science Foundation of China(NSFC,Nos.21771197,21720102007,21821003)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(No.2017BT01C161)FRF for the central universities。
文摘An Ir8 Pd4-heteronuclear metal-organic cage(MOC-51)was assembled from bipodal metalloligand[Ir(ppy)2(qpy)(BF4)](qpy=4,4′:2′,2″:4″,4′′′-quaterpyridine;ppy-2-phenylpridine)with Pd(Ⅱ)salt.The cubic barrel shaped MOC shows one-photon and two-photon excited deep-red emission,as well as large singlet oxygen quantum yields under visible light irradiation,therefore exhibiting great potentials in organelles-targeted cell imaging and photodynamic therapy(PDT).Compared with the Ir(Ⅲ)metalloligand,the Ir8 Pd4-MOC showed less dark toxicity and higher mitochondria-targeting efficiency.The localization in mitochondria overco mes the limitation of short lifetime and diffusion distance of ROS in cell,thus improved PDT effect can be obtained in low light dose usage of the MOC.This study presents the first case of Ir-based metal-organic cages for bio-applications in successful integration of imaging diagnosis and photodynamic therapy.
基金supported by the Medico-Engineering Cooperation Funds from the University of Electronic Science and Technology of China(ZYGX2021YGCX018)Sichuan Provincial Science Fund for applied basic research of China(2020YJ0108)Sichuan Provincial Science Fund for applied basic research of China(2020YFS0424).
文摘Targetingmitochondria via nano platform emerged as an attractive anti-tumor pathway due to the central regulation role in cellar apoptosis and drug resistance.Here,a mitochondria-targeting nanoparticle(TOS-PDA-PEG-TPP)was designed to precisely deliver polydopamine(PDA)as the photothermal agent and alphatocopherol succinate(α-TOS)as the chemotherapeutic drug to the mitochondria of the tumor cells,which inhibits the tumor growth through chemo-and photothermal-synergistic therapies.TOSPDA-PEG-TPP was constructed by coating PDA on the surface of TOS NPs self-assembled byα-TOS,followed by grafting PEGand triphenylphosphonium(TPP)on their surface to prolong the blood circulation time and target delivery of TOS and PDA to the mitochondria of tumor cells.In vitro studies showed that TOS-PDA-PEGTPP could be efficiently internalized by tumor cells and accumulated atmitochondria,resulting in cellular apoptosis and synergistic inhibition of tumor cell proliferation.In vivo studies demonstrated that TOS-PDA-PEG-TPP could be efficiently localized at tumor sites and significantly restrain the tumor growth under NIR irradiation without apparent toxicity or deleterious effects.Conclusively,the combination strategy adopted for functional nanodrugs construction aimed at target-delivering therapeutic agents with different action mechanisms to the same intracellular organelles can be extended to other nanodrugs-dependent therapeutic systems.
基金supported by the National Natural Science Foundation of China(21663005,21871060,21672220,81501591)the Natural Science Foundation of Jiangxi Province(2018ACB21009,20181BAB213007)+1 种基金the Science and Technology Plan of Shenzhen(JCYJ20170818113851132)the Research Grants Council of Hong Kong(16301614,16305015,AoE/P-03/08,Ao E/P-02/12,A-HKUST 605/16,N_HKUST604/14)
文摘Nitroxyl(HNO)has been reported to possess unique biological and pharmacological performances,and emerged as a novel therapy for congestive heart failure.Recent studies also suggest that HNO may be produced and involved in important metabolisms in mitochondria.However,due to its high reactivity and short life properties,fast,sensitive and selective observation and monitoring of HNO related dynamic changes in mitochondria still remains a great challenge.Herein,we synthesized a mitochondria-targeting near-infrared(NIR)fluorescent probe(DCMHNO)for rapid detection of HNO with remarkably high sensitivity,selectivity and photostability.DCMHNO shows fast response(about 4 min)towards HNO via 2-(diphenylphosphino)benzoyl group through the Staudinger reaction to boost the bright NIR emission(700 nm)with excellent sensitivity(detection limit of 13 nM),high p H stability and very low interference from other species.DCMHNO can selectively locate in mitochondria and visualize exogenous and endogenous HNO in live He La cells with high biocompatibility and photostability.The probe could also monitor the interaction between NO and H2 S that gives rise to the generation of HNO in live He La cells.In addition,DCMHNO was further utilized in ex vivo NIR imaging of HNO in live mouse liver tissues at the depth of about 50μm.In vivo imaging of HNO with high signal-to-noise ratio in live mice was also realized by using DCMHNO.These remarkable imaging performances could render NIR DCMNHNO as a useful tool to reveal HNO related dynamic changes in live samples.
基金This work was supported by the National Key Research and Development Program of China(Nos.2017YFC1309100 and 2017YFA0205200)National Natural Science Foundation of China(Nos.81671753,91959124,81227901,and 21804104)+4 种基金Natural Science Foundation of Shaanxi Province of China(No.2020PT-020)Key Research and Development Program of Shaanxi Province(2019NY-085)Natural Science Basic Research Program of Shaanxi Province of China(Nos.2019JQ-139,2019JQ-662,2018JM2041)the Fundamental Research Funds for the Central Universities(Nos.JB191211,JB191207,JB191208)the Open Project Program of the State Key Laboratory of Cancer Biology(Fourth Military Medical University)(No.CBSKL2019ZDKF06).
文摘Cancer phototheranostics involving optical imaging-guided photodynamic therapy(PDT)and photothermal therapy(PTT)is a localized noninvasive approach in treating cancer.Mitochondria-targeted near-infrared(NIR)cyanines are excellent therapeutic photosensitizers of cancer.However,most mitochondria-targeted cyanines exist in the form of hydrophobic structures,which in vivo may cause cyanine aggregation during blood circulation,resulting in poor biocompatibility and limited therapeutic efficacy.Therefore,we developed a trade-off strategy by encapsulating mitochondria-targeted cyanines into liposomal bilayers(CyBI7-LPs),which balanced hydrophilicity that favored blood circulation and hydrophobicity that enhanced mitochondria tumor targeting.Moreover,CyBI7-LPs greatly minimized photobleaching of cyanine as self-generated reactive oxygen species(ROS)could rapidly escape from the liposomal bilayer,affording enhanced PTT/PDT efficacy.Bioorthogonal-mediated targeting strategy was further employed to improve uptake of tumor cells by modifying the liposomal surface to generate CyBI7-LPB.The CyBI7-LPB probe produced a tumor-to-background ratio(TBR)of approximately 6.4 at 24 HPI.Guiding by highly sensitive imaging resulted in excellent anti-tumor therapy outcomes using CyBI7-LPB due to the enhanced photothermal and photodynamic effects.This proposed liposomal nanoplatform exhibited a simple and robust approach as an imaging-guided synergistic anti-tumor therapeutic strategy.
基金financially supported by the National Natural Science Foundation of China (Grant No.81473162)the Program for Liaoning Excellent Talents in Universitythe Young and middle-aged career development planning of Shenyang Pharmaceutical University
文摘Mitochondria are a novel and promising therapeutic target for diagnosis, treatment and prevention of a lot of human diseases such as cancer, metabolic diseases and neurodegenerative disease. Owing to the mitochondrial special bilayer structure and highly negative potential nature, therapeutic molecules have multiple difficulties in reaching mitochondria. To overcome multiple barriers for targeting mitochondria, the researchers developed various pharmaceutical preparations such as liposomes, polymeric nanoparticles and inorganic nanoparticles modified by mitochondriotropic moieties like dequalinium (DQA),triphenylphosphonium (TPP), mitochondrial penetrating peptides (MPPs) and mitochondrial protein import machinery that allow specific targeting.The targeted formulations exhibited enhanced pharmacological effect and better therapeutic effect than their untargeted counterpart both in vitro and in vivo. Nanocarriers may be used for bio-therapeutic delivery into specific mitochondria that possess a great potential treatment of mitochondria related diseases.
