Although several artificial nanotherapeutics have been approved for practical treatment of metastatic breast cancer,their inefficient therapeutic outcomes,serious adverse effects,and high cost of mass production remai...Although several artificial nanotherapeutics have been approved for practical treatment of metastatic breast cancer,their inefficient therapeutic outcomes,serious adverse effects,and high cost of mass production remain crucial challenges.Herein,we developed an alternative strategy to specifically trigger apoptosis of breast tumors and inhibit their lung metastasis by using natural nanovehicles from tea flowers(TFENs).These nanovehicles had desirable particle sizes(131 nm),exosome-like morphology,and negative zeta potentials.Furthermore,TFENs were found to contain large amounts of polyphenols,flavonoids,functional proteins,and lipids.Cell experiments revealed that TFENs showed strong cytotoxicities against cancer cells due to the stimulation of reactive oxygen species(ROS)amplification.The increased intracellular ROS amounts could not only trigger mitochondrial damage,but also arrest cell cycle,resulting in the in vitro anti-proliferation,anti-migration,and anti-invasion activities against breast cancer cells.Further mice investigations demonstrated that TFENs after intravenous(i.v.)injection or oral administration could accumulate in breast tumors and lung metastatic sites,inhibit the growth and metastasis of breast cancer,and modulate gut microbiota.This study brings new insights to the green production of natural exosome-like nanoplatform for the inhibition of breast cancer and its lung metastasis via i.v.and oral routes.展开更多
The clomiphene citrate (CC), a nonsteroidal triphenylethylene compound, is a first line of medicine used for the induction of ovulation in anovulatory women worldwide. In spite of high ovulation induction with the use...The clomiphene citrate (CC), a nonsteroidal triphenylethylene compound, is a first line of medicine used for the induction of ovulation in anovulatory women worldwide. In spite of high ovulation induction with the use of CC, the pregnancy rate is much lower. Such a discrepancy could be due to the peripheral anti-estrogenic effect of CC, particularly at the level of ovary, endometrium and cervical mucus. CC induces ovulation by binding to the estrogen receptors and generates hypoestrogrnic state in hypothalamus leading to release of pituitary gonadotropins. CC may have a direct effect at the level of ovary but the molecular mechanism remains unclear. Animal studies suggest that the CC induces apoptosis in granulosa cells and results hypoestrogenic state in the ovary. Reduced estradiol 17β level in the ovary affects development and maturation of oocyte leading to oocyte apoptosis. Further, CC increases hydrogen peroxide (H2O2) level and thereby bax protein expression and DNA fragmentation in cumulus-granulosa cells as well as in oocytes. The exogenous supplementation of either estradiol 17β or melatonin reduces H2O2 level in ovary, delays meiotic cell cycle progression in oocyte and protects oocyte apoptosis. Hence, supplementation of estradiol 17β or melatonin along with CC could be beneficial to protect granulosa cell as well as oocyte apoptosis and inhibit deterioration of oocyte quality. Thus, maintenance of oocyte quality may overcome the adverse effect caused due to CC treatment during infertility management.展开更多
Plastic products widespread in natural water can be broken into smaller-sized microplastics(MPs,<5 mm)under light irradiation,thermal degradation and biodegradation,posing a serious threat to aquatic ecosystems and...Plastic products widespread in natural water can be broken into smaller-sized microplastics(MPs,<5 mm)under light irradiation,thermal degradation and biodegradation,posing a serious threat to aquatic ecosystems and human health.This perspective concludes that MPs can generate reactive oxygen species(ROS)through initiation,propagation and termination steps,which can attack the polymer resulting in the photoaging and breakdown of C–C and C–H bonds under ultraviolet(UV)irradiation.Free radical generation and weathering degree of MPs depend on their physicochemical properties and environmental conditions.In general,UV irradiation and co-existed MPs can significantly accelerate MP photoaging.With plentiful chromophores carbonyl,carboxyl and benzene rings,Dissolved organic matter(DOM)mainly absorbs photons(300–500 nm)and generates hydrated electrons,^(3)DOM^(*) and ROS,which may affect MP photoaging.However,whether DOM may transfer the electron and energy to MPs under UV irradiation,affect ROS generation of MPs and their photoaging pathway are inadequately studied.More studies are needed to elucidate MP photoaging pathways and mechanisms,consider the influence of stabilization capacity,photosensitization and photoionization of DOM as well as their competitive light absorption with MPs,which provides valuable insights into the environmental behavior and ecological risk of MPs in natural water.展开更多
Ferroptosis is a form of regulated cell death characterized by iron-dependent accumulation of lipid peroxidation and lethal reactive oxygen species(ROS).To date,misregulated ferroptosis has been implicated in several ...Ferroptosis is a form of regulated cell death characterized by iron-dependent accumulation of lipid peroxidation and lethal reactive oxygen species(ROS).To date,misregulated ferroptosis has been implicated in several types of cancers,and ferroptosis inducers can be used to promote ferroptosis in tumor cells and play an anti-tumor role.However,the specificity and efficacy of ferroptosis inducers remain unsatisfactory.Here,a new mitochondria-targeted photosensitizer(PS)with aggregation-induced emission(AIE)characteristic named TCSVP was designed,which efficiently generates ROS in mitochondria after light exposure.TCSVP administration significantly sensitizes tumor cells to ferroptosis inducer(RSL3)-mediated cell death by specifically and light-dependently triggering a moderate ROS generation in vitro and in vivo.Mechanically,the expression levels of ferroptosis related proteins Acyl-CoA synthetase long-chain family member 4(FACL4/ACSL4)and cyclooxygenase-2(COX2)were increased in TCSVP/RSL3-treated cells after light exposure,coupled with decreased Glutathione peroxidase 4(GPX4)activity and excessive malondialdehyde(MDA)accumulation.This study declared that light-induced moderate ROS generation within mitochondria in cancer cells by AIE-PS can be used to enhance the specificity and efficacy of ferroptosis inducers,bringing a new synergistic strategy for tumor intervention.展开更多
Vanadium compounds show potential in diabetes and cancer treatment, although the toxicity remains a great concern. Previous studies have shown that vanadium-induced oxidative stress affecting mitochondrial function is...Vanadium compounds show potential in diabetes and cancer treatment, although the toxicity remains a great concern. Previous studies have shown that vanadium-induced oxidative stress affecting mitochondrial function is intensively responsible for the toxicity. In this work, we investigated the effects of the vanadium compounds sodium metavanadate （NaVO3） and vanadyl acetylacetonate （VO（acac）2） on mitochondrial ROS generation and respiratory complex activities. The experimental results showed that vanadium compounds affected the ROS generation and complex activities in different patterns depending on the chemical species. NaVO3 inhibited mitochondrial complexes Ⅰ and Ⅱ activities and stimulated ROS generation at low concentration range; while VO（acac）2 promoted complex Ⅱ activity but resulted in electron leakage from the complex Ⅰ-involved pathway. The present results provide new evidence for understanding the toxicity of antidiabetic vanadium compounds.展开更多
Objectives:Pesticide toxicity has become one of the major environmental menaces affecting all types of life forms of the ecosystem.Pesticides get washed off from agricultural fields into nearby water bodies and enter ...Objectives:Pesticide toxicity has become one of the major environmental menaces affecting all types of life forms of the ecosystem.Pesticides get washed off from agricultural fields into nearby water bodies and enter the aquatic organisms.Their bio-accumulated form finally reaches the human race,through consumption of pesticide infested aquatic animals,causing several physiological dysfunctions.Hence it becomes necessary to find a therapeutic cure/a preventive measure to stop the health hazard issues of pesticide.With this projection a search for a phyto-based-product was made whose primary objective would be to lower the pesticidal toxicity in fish and simultaneously in the human race.Methods:In this study we tried to check whether the phyto-chemical,Chlorophyllin(CHL),known for its anti-genotoxic,anti-oxidant activities,could render any kind of protection against Cypermethrin(CM)induced-toxicity in fish model and mammalian cell line L6.Both the model L6 and fish were pre-treated with CHL prior to exposure of CM.Different scientific parameters like%cellular cytotoxicity,reactive oxygen species(ROS)generation,nuclear condensation,etc were checked to validate the possibility of CHL in protecting CM-induced toxicity.Results:The overall results revealed that pre-treatment with CHL could restrict the ROS generation leading to modulation in associated cytokine proteins expression NFkβand IFNγ.Further,CHL lowered nuclear condensation and elevated expression of DNA repair proteins p53 and PARP,showing a kind of pre-activation of signalling cascades for overall protection against the severity of pesticidal toxicity.Conclusion:Thus,this phyto-based preventive approach would possibly solve many areas of human health issues related to pesticide toxicity in future.展开更多
Background: Glucose is the main substrate for the generation of NADPH, the cofactor of the oxidative burst enzyme NADPH-oxidase of blood neutrophils. Changes in blood glucose are thus expected to modify the generation...Background: Glucose is the main substrate for the generation of NADPH, the cofactor of the oxidative burst enzyme NADPH-oxidase of blood neutrophils. Changes in blood glucose are thus expected to modify the generation of reactive oxygen species (ROS). The new blood ROS generation assay (BRGA) quantifies ROS changes induced by blood glucose concentrations as they are found in diabetes mellitus. Material and Methods: Citrated or EDTA blood of 6 healthy donors were analyzed in the BRGA: 10 μl sample in black polystyrene F-microwells (Brand 781608) were incubated in triplicate with 125 μl Hanks’ balanced salt solution, 40 μl 0 - 200 mM glucose in 0.9% NaCl (final added conc.: 0 - 41 mM;final basal glucose conc.: about4 mM), 10 μl5 mMluminol, and 10 μl zymosan A (final conc.: 1.9 μg/ml) in 0.9% NaCl. The plates were measured within 0 - 250 min (37℃) in a photons-multiplyer microtiter plate luminometer (LUmo) with an integration time of 1 s. Results: Up to about 30 min reaction time the mean ROS generation was 50% inhibited by about1 mMadded glucose (= approx. IC50). At ≥80 min reaction time (possibly necessary for full phosphorylation of glucose to glucose-6-phosphate (G6P), the substrate metabolized by G6P-dehydrogenase to generate NADPH, the cofactor of the NADPH-oxidase) the mean ROS generation approximately doubled at about1 mMadded glucose (= approx. SC200) in citrated blood. Discussion: Elevated glucose concentrations not only increase systemic thrombin generation, they can also diminish cellular fibrinolysis and increase systemic inflammation, resulting in a chronic pro-thrombotic state. The fascinating importance of NADPH-oxidases not only in phagocytes but also in the beta cells of pancreas points towards a new pathogenesis explication of diabetes mellitus type 1: whatever stimulus (e.g. a pancreas-tropic virus) could activate the beta cell’s autodestructive NADPH-oxidase.展开更多
Construction of multifunctional stimuli-responsive nanotherapeutics enabling improved intratumoral penetration of therapeutics and reversal of multiple-drug resistance(MDR)is potent to achieve effective cancer treatme...Construction of multifunctional stimuli-responsive nanotherapeutics enabling improved intratumoral penetration of therapeutics and reversal of multiple-drug resistance(MDR)is potent to achieve effective cancer treatment.Herein,we report a general method to synthesize pH-dissociable calcium carbonate(CaCO_(3))hollow nanoparticles with amorphous CaCO_(3)as the template,gallic acid(GA)as the organic ligand,and ferrous ions as the metallic center via a one-pot coordination reaction.The obtained GA–Fe@CaCO_(3)exhibits high loading efficiencies to both oxidized cisplatin prodrug and doxorubicin,yielding drug loaded GA-Fe@CaCO_(3)nanotherapeutics featured in pH-responsive size shrinkage,drug release,and Fenton catalytic activity.Compared to nonresponsive GA-Fe@silica nanoparticles prepared with silica nanoparticles as the template,such GA-Fe@CaCO_(3)confers significantly improved intratumoral penetration capacity.Moreover,both types of drug-loaded GA–Fe@CaCO_(3)nanotherapeutics exhibit synergistic therapeutic efficacies to corresponding MDR cancer cells because of the GA–Fe mediated intracellular oxidative stress amplification that could reduce the efflux of engulfed drugs by impairing the mitochondrial-mediated production of adenosine triphosphate(ATP).As a result,it is found that the doxorubicin loaded GA-Fe@CaCO_(3)exhibits superior therapeutic effect towards doxorubicin-resistant 4T1 breast tumors via combined chemodynamic and chemo-therapies.This work highlights the preparation of pH-dissociable CaCO_(3)-based nanotherapeutics to enable effective tumor penetration for enhanced treatment of drug-resistant tumors.展开更多
基金supported by the National Natural Science Foundation of China(82072060 and 81571807,China)the Fundamental Research Funds for the Central Universities(XDJK2019TY002 and 2020CDJQY-A041,China)+1 种基金the Natural Science Foundation Project of Chongqing(cstc2020jcyjmsxm X0292,China)the Venture&Innovation Support Program for Chongqing Overseas Returnees(cx2018029,China)。
文摘Although several artificial nanotherapeutics have been approved for practical treatment of metastatic breast cancer,their inefficient therapeutic outcomes,serious adverse effects,and high cost of mass production remain crucial challenges.Herein,we developed an alternative strategy to specifically trigger apoptosis of breast tumors and inhibit their lung metastasis by using natural nanovehicles from tea flowers(TFENs).These nanovehicles had desirable particle sizes(131 nm),exosome-like morphology,and negative zeta potentials.Furthermore,TFENs were found to contain large amounts of polyphenols,flavonoids,functional proteins,and lipids.Cell experiments revealed that TFENs showed strong cytotoxicities against cancer cells due to the stimulation of reactive oxygen species(ROS)amplification.The increased intracellular ROS amounts could not only trigger mitochondrial damage,but also arrest cell cycle,resulting in the in vitro anti-proliferation,anti-migration,and anti-invasion activities against breast cancer cells.Further mice investigations demonstrated that TFENs after intravenous(i.v.)injection or oral administration could accumulate in breast tumors and lung metastatic sites,inhibit the growth and metastasis of breast cancer,and modulate gut microbiota.This study brings new insights to the green production of natural exosome-like nanoplatform for the inhibition of breast cancer and its lung metastasis via i.v.and oral routes.
文摘The clomiphene citrate (CC), a nonsteroidal triphenylethylene compound, is a first line of medicine used for the induction of ovulation in anovulatory women worldwide. In spite of high ovulation induction with the use of CC, the pregnancy rate is much lower. Such a discrepancy could be due to the peripheral anti-estrogenic effect of CC, particularly at the level of ovary, endometrium and cervical mucus. CC induces ovulation by binding to the estrogen receptors and generates hypoestrogrnic state in hypothalamus leading to release of pituitary gonadotropins. CC may have a direct effect at the level of ovary but the molecular mechanism remains unclear. Animal studies suggest that the CC induces apoptosis in granulosa cells and results hypoestrogenic state in the ovary. Reduced estradiol 17β level in the ovary affects development and maturation of oocyte leading to oocyte apoptosis. Further, CC increases hydrogen peroxide (H2O2) level and thereby bax protein expression and DNA fragmentation in cumulus-granulosa cells as well as in oocytes. The exogenous supplementation of either estradiol 17β or melatonin reduces H2O2 level in ovary, delays meiotic cell cycle progression in oocyte and protects oocyte apoptosis. Hence, supplementation of estradiol 17β or melatonin along with CC could be beneficial to protect granulosa cell as well as oocyte apoptosis and inhibit deterioration of oocyte quality. Thus, maintenance of oocyte quality may overcome the adverse effect caused due to CC treatment during infertility management.
基金supported by the Fund for National Key R&D Program of China(No.2021YFC3200401)the National Natural Science Foundation of China(Nos.52170024,21677015,22006031).
文摘Plastic products widespread in natural water can be broken into smaller-sized microplastics(MPs,<5 mm)under light irradiation,thermal degradation and biodegradation,posing a serious threat to aquatic ecosystems and human health.This perspective concludes that MPs can generate reactive oxygen species(ROS)through initiation,propagation and termination steps,which can attack the polymer resulting in the photoaging and breakdown of C–C and C–H bonds under ultraviolet(UV)irradiation.Free radical generation and weathering degree of MPs depend on their physicochemical properties and environmental conditions.In general,UV irradiation and co-existed MPs can significantly accelerate MP photoaging.With plentiful chromophores carbonyl,carboxyl and benzene rings,Dissolved organic matter(DOM)mainly absorbs photons(300–500 nm)and generates hydrated electrons,^(3)DOM^(*) and ROS,which may affect MP photoaging.However,whether DOM may transfer the electron and energy to MPs under UV irradiation,affect ROS generation of MPs and their photoaging pathway are inadequately studied.More studies are needed to elucidate MP photoaging pathways and mechanisms,consider the influence of stabilization capacity,photosensitization and photoionization of DOM as well as their competitive light absorption with MPs,which provides valuable insights into the environmental behavior and ecological risk of MPs in natural water.
基金supported by the National Natural Science Foundation of China(81790633,61922047,81830054,81902412,81903184,81988101,91859205,21788102,51620105009)the Innovation Program of Shanghai Municipal Education Commission(2019-01-07-0007-E00065,21XD1404600)+4 种基金the Research Grants Council of Hong Kong(16306620,N_HKUST609/19 and C6014-20W)the Innovation and Technology Commission(ITC-CNERC14SC01,ITCPD/17-9,MHP/047/19 and ITS/301/18FX)the support of Shanghai Key Laboratory of Hepato-biliary Tumor BiologyMilitary Key Laboratory on Signal Transductionsupported by the Innovation Program of Shanghai Municipal Education Commission。
文摘Ferroptosis is a form of regulated cell death characterized by iron-dependent accumulation of lipid peroxidation and lethal reactive oxygen species(ROS).To date,misregulated ferroptosis has been implicated in several types of cancers,and ferroptosis inducers can be used to promote ferroptosis in tumor cells and play an anti-tumor role.However,the specificity and efficacy of ferroptosis inducers remain unsatisfactory.Here,a new mitochondria-targeted photosensitizer(PS)with aggregation-induced emission(AIE)characteristic named TCSVP was designed,which efficiently generates ROS in mitochondria after light exposure.TCSVP administration significantly sensitizes tumor cells to ferroptosis inducer(RSL3)-mediated cell death by specifically and light-dependently triggering a moderate ROS generation in vitro and in vivo.Mechanically,the expression levels of ferroptosis related proteins Acyl-CoA synthetase long-chain family member 4(FACL4/ACSL4)and cyclooxygenase-2(COX2)were increased in TCSVP/RSL3-treated cells after light exposure,coupled with decreased Glutathione peroxidase 4(GPX4)activity and excessive malondialdehyde(MDA)accumulation.This study declared that light-induced moderate ROS generation within mitochondria in cancer cells by AIE-PS can be used to enhance the specificity and efficacy of ferroptosis inducers,bringing a new synergistic strategy for tumor intervention.
基金National Natural Science Foundation of China (Grant No.20671008/20971008)
文摘Vanadium compounds show potential in diabetes and cancer treatment, although the toxicity remains a great concern. Previous studies have shown that vanadium-induced oxidative stress affecting mitochondrial function is intensively responsible for the toxicity. In this work, we investigated the effects of the vanadium compounds sodium metavanadate （NaVO3） and vanadyl acetylacetonate （VO（acac）2） on mitochondrial ROS generation and respiratory complex activities. The experimental results showed that vanadium compounds affected the ROS generation and complex activities in different patterns depending on the chemical species. NaVO3 inhibited mitochondrial complexes Ⅰ and Ⅱ activities and stimulated ROS generation at low concentration range; while VO（acac）2 promoted complex Ⅱ activity but resulted in electron leakage from the complex Ⅰ-involved pathway. The present results provide new evidence for understanding the toxicity of antidiabetic vanadium compounds.
基金Grateful acknowledgements are extended to SERB(DST)(ECR/2017/000355),UGC-BSR Start-up grant for providing nesearch funds which was used partly to accomplish this piece of workAuthors thank University of Kalyani(PRG and DST-PURSE)for their minor research funding which was used for the pupose of this work.
文摘Objectives:Pesticide toxicity has become one of the major environmental menaces affecting all types of life forms of the ecosystem.Pesticides get washed off from agricultural fields into nearby water bodies and enter the aquatic organisms.Their bio-accumulated form finally reaches the human race,through consumption of pesticide infested aquatic animals,causing several physiological dysfunctions.Hence it becomes necessary to find a therapeutic cure/a preventive measure to stop the health hazard issues of pesticide.With this projection a search for a phyto-based-product was made whose primary objective would be to lower the pesticidal toxicity in fish and simultaneously in the human race.Methods:In this study we tried to check whether the phyto-chemical,Chlorophyllin(CHL),known for its anti-genotoxic,anti-oxidant activities,could render any kind of protection against Cypermethrin(CM)induced-toxicity in fish model and mammalian cell line L6.Both the model L6 and fish were pre-treated with CHL prior to exposure of CM.Different scientific parameters like%cellular cytotoxicity,reactive oxygen species(ROS)generation,nuclear condensation,etc were checked to validate the possibility of CHL in protecting CM-induced toxicity.Results:The overall results revealed that pre-treatment with CHL could restrict the ROS generation leading to modulation in associated cytokine proteins expression NFkβand IFNγ.Further,CHL lowered nuclear condensation and elevated expression of DNA repair proteins p53 and PARP,showing a kind of pre-activation of signalling cascades for overall protection against the severity of pesticidal toxicity.Conclusion:Thus,this phyto-based preventive approach would possibly solve many areas of human health issues related to pesticide toxicity in future.
文摘Background: Glucose is the main substrate for the generation of NADPH, the cofactor of the oxidative burst enzyme NADPH-oxidase of blood neutrophils. Changes in blood glucose are thus expected to modify the generation of reactive oxygen species (ROS). The new blood ROS generation assay (BRGA) quantifies ROS changes induced by blood glucose concentrations as they are found in diabetes mellitus. Material and Methods: Citrated or EDTA blood of 6 healthy donors were analyzed in the BRGA: 10 μl sample in black polystyrene F-microwells (Brand 781608) were incubated in triplicate with 125 μl Hanks’ balanced salt solution, 40 μl 0 - 200 mM glucose in 0.9% NaCl (final added conc.: 0 - 41 mM;final basal glucose conc.: about4 mM), 10 μl5 mMluminol, and 10 μl zymosan A (final conc.: 1.9 μg/ml) in 0.9% NaCl. The plates were measured within 0 - 250 min (37℃) in a photons-multiplyer microtiter plate luminometer (LUmo) with an integration time of 1 s. Results: Up to about 30 min reaction time the mean ROS generation was 50% inhibited by about1 mMadded glucose (= approx. IC50). At ≥80 min reaction time (possibly necessary for full phosphorylation of glucose to glucose-6-phosphate (G6P), the substrate metabolized by G6P-dehydrogenase to generate NADPH, the cofactor of the NADPH-oxidase) the mean ROS generation approximately doubled at about1 mMadded glucose (= approx. SC200) in citrated blood. Discussion: Elevated glucose concentrations not only increase systemic thrombin generation, they can also diminish cellular fibrinolysis and increase systemic inflammation, resulting in a chronic pro-thrombotic state. The fascinating importance of NADPH-oxidases not only in phagocytes but also in the beta cells of pancreas points towards a new pathogenesis explication of diabetes mellitus type 1: whatever stimulus (e.g. a pancreas-tropic virus) could activate the beta cell’s autodestructive NADPH-oxidase.
基金supported by the National Natural Science Foundation of China(No.51802209),the National Research Programs from Ministry of Science and Technology(MOST)of China(No.2016YFA0201200)the Natural Science Foundation of Jiangsu Province(No.BK20180848)+1 种基金the China Postdoctoral Science Foundation(No.2018T110545)the Collaborative Innovation Center of Suzhou Nano Science and Technology,and the 111 Program from the Ministry of Education of China.
文摘Construction of multifunctional stimuli-responsive nanotherapeutics enabling improved intratumoral penetration of therapeutics and reversal of multiple-drug resistance(MDR)is potent to achieve effective cancer treatment.Herein,we report a general method to synthesize pH-dissociable calcium carbonate(CaCO_(3))hollow nanoparticles with amorphous CaCO_(3)as the template,gallic acid(GA)as the organic ligand,and ferrous ions as the metallic center via a one-pot coordination reaction.The obtained GA–Fe@CaCO_(3)exhibits high loading efficiencies to both oxidized cisplatin prodrug and doxorubicin,yielding drug loaded GA-Fe@CaCO_(3)nanotherapeutics featured in pH-responsive size shrinkage,drug release,and Fenton catalytic activity.Compared to nonresponsive GA-Fe@silica nanoparticles prepared with silica nanoparticles as the template,such GA-Fe@CaCO_(3)confers significantly improved intratumoral penetration capacity.Moreover,both types of drug-loaded GA–Fe@CaCO_(3)nanotherapeutics exhibit synergistic therapeutic efficacies to corresponding MDR cancer cells because of the GA–Fe mediated intracellular oxidative stress amplification that could reduce the efflux of engulfed drugs by impairing the mitochondrial-mediated production of adenosine triphosphate(ATP).As a result,it is found that the doxorubicin loaded GA-Fe@CaCO_(3)exhibits superior therapeutic effect towards doxorubicin-resistant 4T1 breast tumors via combined chemodynamic and chemo-therapies.This work highlights the preparation of pH-dissociable CaCO_(3)-based nanotherapeutics to enable effective tumor penetration for enhanced treatment of drug-resistant tumors.
