The reactive oxygen species(ROS) generation efficiency is always limited by the extreme tumor microenvironment(TME), leading to unsatisfactory antitumor effects in photodynamic therapy(PDT). As a promising gas therapy...The reactive oxygen species(ROS) generation efficiency is always limited by the extreme tumor microenvironment(TME), leading to unsatisfactory antitumor effects in photodynamic therapy(PDT). As a promising gas therapy molecule, nitric oxide(NO) is independent of oxygen and could even synergize ROS to enhance the therapeutic effect. However, the short half-life, instability, and uncontrollable release of exogenous NO limited the application of tumor synergistic therapy. Herein, we reported a novel kind of red-emissive carbon dots(CDs) that was capable of lysosome-targeted and light-controlled NO delivery. The CDs were synthesized by using metformin and methylene blue(MB) via a hydrothermal method.The obtained metformin-MB CDs(MMCDs) exhibited a higher1O2quantum yield and NO generation efficiency under light emitting diode(LED) light irradiation. Noteworthily, the1O2could further in situ oxidize NO into peroxynitrite anions(ONOO-), which own the higher cytotoxicity against cancer cells.Cell experiments indicate that MMCDs could destruct lysosome membrane integrity and kill almost 80%of Hep G2 cells under light irradiation while very low cytotoxicity in the dark. Moreover, MMCDs significantly decreased tumor volume and weight after phototherapy in hepatoma Hep G2-bearing mice. Our study provides a new strategy for light-controlled NO generation as well as precise lysosome-targeting for enhancement of PDT efficiency.展开更多
AIM To evaluate the safety and efficacy of inhaled milrinone in acute respiratory distress syndrome(ARDS).METHODS Open-label prospective cross-over pilot study where fifteen adult patients with hypoxemic failure meeti...AIM To evaluate the safety and efficacy of inhaled milrinone in acute respiratory distress syndrome(ARDS).METHODS Open-label prospective cross-over pilot study where fifteen adult patients with hypoxemic failure meeting standard ARDS criteria and monitored with a pulmonary artery catheter were recruited in an academic 24-bed medico-surgical intensive care unit. Random sequential administration of i NO(20 ppm) or nebulized epoprostenol(10 μg/mL) was done in all patients. Thereafter, inhaled milrinone(1 mg/mL) alone followed by inhaled milrinone in association with inhaled nitric oxide(iN O) was administered. A jet nebulization device synchronized with the mechanical ventilation was use to administrate the epoprostenol and the milrinone. Hemodynamic measurements and partial pressure of arterial oxygen(PaO_2) were recorded before and after each inhaled therapyadministration.RESULTS The majority of ARDS were of pulmonary cause(n = 13) and pneumonia(n = 7) was the leading underlying initial disease. Other pulmonary causes of ARDS were: Post cardiopulmonary bypass(n = 2), smoke inhalation injury(n = 1), thoracic trauma and pulmonary contusions(n = 2) and aspiration(n = 1). Two patients had an extra pulmonary cause of ARDS: A polytrauma patient and an intra-abdominal abscess Inhaled nitric oxide, epoprostenol, inhaled milrinone and the combination of inhaled milrinone and i NO had no impact on systemic hemodynamics. No significant adverse events related to study medications were observed. The median increase of PaO 2 from baseline was 8.8 mmH g [interquartile range(IQR) = 16.3], 6.0 mm Hg(IQR = 18.4), 6 mm Hg(IQR = 15.8) and 9.2 mm Hg(IQR = 20.2) respectively with i NO, epoprostenol, inhaled milrinone, and i NO added to milrinone. Only i NO and the combination of inhaled milrinone and i NO had a statistically significant effect on PaO 2. CONCLUSION When comparing the effects of inhaled NO, milrinone and epoprostenol, only NO significantly improved oxygenation. Inhaled milrinone appeared safe but failed to improve oxygenation in ARDS.展开更多
BACKGROUND:Acupuncture-induced oxygen therapy combines acupoint theory in traditional Chinese medicine and modern oxygen therapy. Clinical studies have shown that acupuncture-induced oxygen therapy results in favorabl...BACKGROUND:Acupuncture-induced oxygen therapy combines acupoint theory in traditional Chinese medicine and modern oxygen therapy. Clinical studies have shown that acupuncture-induced oxygen therapy results in favorable outcomes for brain injury. However,the mechanisms of action remain poorly understood. OBJECTIVE:To determine pathological changes and malondialdehyde (MDA) content,superoxide dismutase (SOD) and nitric oxide synthase (NOS) activity,as well as hemorheological brain alterations following acupuncture-induced oxygen therapy,and to explore possible mechanisms of acupuncture-induced oxygen therapy on brain injury. DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment was performed at the Animal Experimental Center of Xi'an Medical University from January 2006 to April 2009. MATERIALS:An oxygen delivery device,through the use of acupuncture (oxygen delivery machine + silver hollowed needle,0.5 mm inner diameter),was purchased from Research Center of Machine,Shaanxi University of Science and Technology in China. METHODS:A total of 180 Sprague Dawley rats were randomly assigned to six groups (n = 30):normal,sham-surgery (dura mater exposure),model (brain injury induced by free-falling of heavy object to head),Xiantai mixture (0.417 mL/100 g following brain injury),electroacupuncture [acupuncture at Baihui (DU 20),Housanli (ST 36),Yanglingquan (GB 34),and Sanyinjiao (SP 6) following brain injury],and acupuncture-induced oxygen therapy (oxygen delivery through hollowed needle to Baihui (DU 20),Housanli (ST 36),Yanglingquan (GB 34),and Sanyinjiao (SP 6) following brain injury,0.01 mL/minute). Group intervention was performed once a day for 14 consecutive days. MAIN OUTCOME MEASURES:Pathological changes,MDA content,SOD and NOS activity,and hemorheological alterations in the brain. RESULTS:Obvious pathological changes were observed,such as hemorrhage,edema,and cell necrosis,following brain injury. These alterations were significantly improved following 14 days of treatment with Xiantai mixture,electroacupuncture,and acupuncture-induced oxygen therapy. In particular,acupuncture-induced oxygen therapy resulted in recovery to normal conditions. In the Xiantai mixture,electroacupuncture,and acupuncture-induced oxygen therapy groups,MDA content was significantly reduced (P < 0.01),SOD activity was significantly increased (P < 0.01),NOS activity was significantly decreased (P < 0.01),and hemorheological indices were reduced,compared with the model group. In particular,acupunture-induced oxygen therapy resulted in the most obvious changes (P < 0.01). CONCLUSION:Acupuncture-induced oxygen therapy improved pathological changes following brain injury by possibly improving blood supply,ameliorating ischemia/hypoxia,and inhibiting peroxidation and free radicals.展开更多
There are growing evidences on the role of adaptive mechanisms of all cell types in pathological processes: atherosclerosis, ischemic attack, bacterial infections, etc. All kinds of these processes involve as main mec...There are growing evidences on the role of adaptive mechanisms of all cell types in pathological processes: atherosclerosis, ischemic attack, bacterial infections, etc. All kinds of these processes involve as main mechanism oxidative stress. Aerobic organisms use oxygen in processes that accidentally or deliberately generate aggressive species for the biologic components in the form of radicals. Radicals were looked initially as “harmful” molecules and this is true for large quantities but in small or even moderate amounts these molecules prove to have a physiological role. Reactive species are highly reactive and as a consequence are short living species. Their impact is supposed to be limited in the proximity area of their formation. Instead recent evidences indicate their implications in cellular signaling suggesting that individual chemical properties of reactive species make a difference in their biological role. This paper presents superoxide, nitric oxide and peroxide radical generation under cellular changing conditions, the adapting behavior of the enzymes that synthesize and remove them as well as some therapeutic target in superoxide related pathology.展开更多
Objective:To investigate the effects of long-term low-dose hormone replacement therapy(HRT)on blood pressure,the plasma renin activity(PRA),plasma angiotensin Ⅱ(AngⅡ)leveland serum nitric oxide(NO)concentration in p...Objective:To investigate the effects of long-term low-dose hormone replacement therapy(HRT)on blood pressure,the plasma renin activity(PRA),plasma angiotensin Ⅱ(AngⅡ)leveland serum nitric oxide(NO)concentration in postmenopausal women.Methods:A total of 140 postmenopausal women were selected from the medical staff of thePeking Union Medical College Hospital.Of these,63 subjects who had been treated with low-dose sex hormone for over 5(5-32)years were set up as HRT group,and 77 age-matched sub-jects who had never received HRT were designed as control group.The levels of serum estradiol(E_2),follicle stimulating hormone(FSH)and nitric oxide(NO),the concentration of plasma an-giotensin Ⅱ(AngⅡ),plasma rennin activity(PRA)and the blood pressure were evaluated inthese two groups.Results:The serum level of estradiol in HRT group was significantly higher than that in con-trol group(median,interquartile range;124.0 pmol/L,113.4 vs.78.2 pmol/L,121.8)(P<0.05)and systolic blood pressure in HRT groups was significantly lower than that in control group[(126.7±14.4)mmHg vs.(132.4+19.8)mmHg](P<0.05).Diastolic blood pressure[(79.7±7.9)mmHg vs.(79.6±10.4)mmHg],the serum level of FSH[(54.4±18.9)IU/L vs.(60.4±24.4)IU/L],the plasma level of PRA(median,interquartile range;0.14 pg/L/hr,0.11vs.0.12 pg/L/hr,0.10),AngⅡ(median,interquartile range;46.0,31.1 pg/ml vs.44.4,33.0pg/ml)and serum level of NO(median,interquartile range;63.8 μmol/L,58.9 vs.56.0 μmol/L,94.8)showed no significant difference between HRT and control groups(P>0.05).Conclusions:Long-term low-dose HRT decreased the systolic blood pressure,but showed noeffects on the diastolic blood pressure,plasma level of AngⅡ,PRA,and serum level of NO inpostmenopausal women.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
Nitric oxide(NO)gas therapy,especially,L-arginine(L-Arg)-based NO treatment strategies have attracted extensive attention in the field of oncotherapy.However,current strategies are unable to differentiate well between...Nitric oxide(NO)gas therapy,especially,L-arginine(L-Arg)-based NO treatment strategies have attracted extensive attention in the field of oncotherapy.However,current strategies are unable to differentiate well between normal cells and cancer cells,which may lead to unpredictable toxicity.Motivated by the fact that mitochondria of cancer cells can express excessive nitric oxide synthetase(NOS),herein,a nanozyme-based NO generator,cerium oxide(CeO_(2))-AT,is fabricated to specifically catalyze the production of NO in cancer cells for selective tumor treatment.In this system,after being endocytosed into cancer cells,the generator can produce a number of NO under the catalysis of NOS in mitochondria of cancer cells,which can disrupt the mitochondrial respiratory chain of tumor cells and further induce cell apoptosis.In addition,the generator with catalase(CAT)-like activity can catalyze H_(2)O_(2)to produce O_(2),which can promote the generation of NO and improve the performance of NO gas therapy.What is more,our system has no obvious impact on the viability of normal cells owing to the less production of NO.Our work paves a new way for the development of highly selective NO-based treatment particularly useful for the safe and specific cancer therapy.展开更多
基金financially supported by the National Natural Science Foundation of China (Nos. 52172033 and 22005280)the support from the support of the Key Laboratory of Structure and Functional Regulation of Hybrid Materials of the Ministry of Education, Anhui University, China+1 种基金the support from the Key Laboratory of Environment Friendly Polymer Materials of Anhui Province, ChinaKey Laboratory of Functional Inorganic Material Chemistry of Anhui Province, Anhui University, China。
文摘The reactive oxygen species(ROS) generation efficiency is always limited by the extreme tumor microenvironment(TME), leading to unsatisfactory antitumor effects in photodynamic therapy(PDT). As a promising gas therapy molecule, nitric oxide(NO) is independent of oxygen and could even synergize ROS to enhance the therapeutic effect. However, the short half-life, instability, and uncontrollable release of exogenous NO limited the application of tumor synergistic therapy. Herein, we reported a novel kind of red-emissive carbon dots(CDs) that was capable of lysosome-targeted and light-controlled NO delivery. The CDs were synthesized by using metformin and methylene blue(MB) via a hydrothermal method.The obtained metformin-MB CDs(MMCDs) exhibited a higher1O2quantum yield and NO generation efficiency under light emitting diode(LED) light irradiation. Noteworthily, the1O2could further in situ oxidize NO into peroxynitrite anions(ONOO-), which own the higher cytotoxicity against cancer cells.Cell experiments indicate that MMCDs could destruct lysosome membrane integrity and kill almost 80%of Hep G2 cells under light irradiation while very low cytotoxicity in the dark. Moreover, MMCDs significantly decreased tumor volume and weight after phototherapy in hepatoma Hep G2-bearing mice. Our study provides a new strategy for light-controlled NO generation as well as precise lysosome-targeting for enhancement of PDT efficiency.
文摘AIM To evaluate the safety and efficacy of inhaled milrinone in acute respiratory distress syndrome(ARDS).METHODS Open-label prospective cross-over pilot study where fifteen adult patients with hypoxemic failure meeting standard ARDS criteria and monitored with a pulmonary artery catheter were recruited in an academic 24-bed medico-surgical intensive care unit. Random sequential administration of i NO(20 ppm) or nebulized epoprostenol(10 μg/mL) was done in all patients. Thereafter, inhaled milrinone(1 mg/mL) alone followed by inhaled milrinone in association with inhaled nitric oxide(iN O) was administered. A jet nebulization device synchronized with the mechanical ventilation was use to administrate the epoprostenol and the milrinone. Hemodynamic measurements and partial pressure of arterial oxygen(PaO_2) were recorded before and after each inhaled therapyadministration.RESULTS The majority of ARDS were of pulmonary cause(n = 13) and pneumonia(n = 7) was the leading underlying initial disease. Other pulmonary causes of ARDS were: Post cardiopulmonary bypass(n = 2), smoke inhalation injury(n = 1), thoracic trauma and pulmonary contusions(n = 2) and aspiration(n = 1). Two patients had an extra pulmonary cause of ARDS: A polytrauma patient and an intra-abdominal abscess Inhaled nitric oxide, epoprostenol, inhaled milrinone and the combination of inhaled milrinone and i NO had no impact on systemic hemodynamics. No significant adverse events related to study medications were observed. The median increase of PaO 2 from baseline was 8.8 mmH g [interquartile range(IQR) = 16.3], 6.0 mm Hg(IQR = 18.4), 6 mm Hg(IQR = 15.8) and 9.2 mm Hg(IQR = 20.2) respectively with i NO, epoprostenol, inhaled milrinone, and i NO added to milrinone. Only i NO and the combination of inhaled milrinone and i NO had a statistically significant effect on PaO 2. CONCLUSION When comparing the effects of inhaled NO, milrinone and epoprostenol, only NO significantly improved oxygenation. Inhaled milrinone appeared safe but failed to improve oxygenation in ARDS.
基金This work was supported by grants from the National Natural Science Foundation of China （30872801）, the Excellence in Doctorate Research Program by Ministry of Education （20090071110061）, and Shanghai Rising-Star Program （09QA1400700）.
文摘目的探讨新生儿持续肺动脉高压(persistent pulmonary hypertension of newborn,PPHN)患儿血清人CXC型趋化因子配体8(C-X-C motif chemokine ligand 8,CXCL8)、CXCL12与一氧化氮吸入治疗临床转归的关系。方法选择2021-08/2023-05月作者医院收治并给予一氧化氮吸入治疗的PPHN患儿135例为研究对象。根据患儿出院时临床转归结局分为死亡组(n=32)和存活组(n=103)。比较两组PPHN患儿血清CXCL8、CXCL12水平。单因素及多因素Logistic回归模型分析接受一氧化氮吸入治疗PPHN患儿临床转归的影响因素。受试者工作特征(receiver operating characteristic,ROC)曲线分析血清CXCL8、CXCL12对接受一氧化氮吸入治疗PPHN患儿临床转归的预测价值。结果死亡组患儿血清CXCL8、CXCL12水平显著高于存活组(P均<0.05)。多因素Logsitic回归分析结果显示,血清CXCL8水平升高、血清CXCL12水平升高、早产、出生时Apgar评分0~3分、合并并发症是接受一氧化氮吸入治疗的PPHN患儿死亡的危险因素,肺表面活性物质应用、吸入一氧化氮早期反应则是保护因素(P<0.05)。ROC曲线分析结果显示,血清CXCL8、CXCL12联合检测对接受一氧化氮吸入治疗的PPHN患儿死亡预测的曲线下面积(area under the curve,AUC)为0.828,大于血清CXCL8、CXCL12单独检测(AUC分别为0.762、0.714)。结论PPHN患儿血清CXCL8、CXCL12水平升高与接受一氧化氮治疗的不良临床转归有关,且CXCL8、CXCL12水平升高是PPHN患儿死亡的危险因素。CXCL8、CXCL12联合检测对接受一氧化氮治疗PPHN患儿死亡具有较高的预测价值。
基金the Medical Scientific Research and Development Program of Lanzhou Military Area Com-mand,No.LXH-20-06
文摘BACKGROUND:Acupuncture-induced oxygen therapy combines acupoint theory in traditional Chinese medicine and modern oxygen therapy. Clinical studies have shown that acupuncture-induced oxygen therapy results in favorable outcomes for brain injury. However,the mechanisms of action remain poorly understood. OBJECTIVE:To determine pathological changes and malondialdehyde (MDA) content,superoxide dismutase (SOD) and nitric oxide synthase (NOS) activity,as well as hemorheological brain alterations following acupuncture-induced oxygen therapy,and to explore possible mechanisms of acupuncture-induced oxygen therapy on brain injury. DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment was performed at the Animal Experimental Center of Xi'an Medical University from January 2006 to April 2009. MATERIALS:An oxygen delivery device,through the use of acupuncture (oxygen delivery machine + silver hollowed needle,0.5 mm inner diameter),was purchased from Research Center of Machine,Shaanxi University of Science and Technology in China. METHODS:A total of 180 Sprague Dawley rats were randomly assigned to six groups (n = 30):normal,sham-surgery (dura mater exposure),model (brain injury induced by free-falling of heavy object to head),Xiantai mixture (0.417 mL/100 g following brain injury),electroacupuncture [acupuncture at Baihui (DU 20),Housanli (ST 36),Yanglingquan (GB 34),and Sanyinjiao (SP 6) following brain injury],and acupuncture-induced oxygen therapy (oxygen delivery through hollowed needle to Baihui (DU 20),Housanli (ST 36),Yanglingquan (GB 34),and Sanyinjiao (SP 6) following brain injury,0.01 mL/minute). Group intervention was performed once a day for 14 consecutive days. MAIN OUTCOME MEASURES:Pathological changes,MDA content,SOD and NOS activity,and hemorheological alterations in the brain. RESULTS:Obvious pathological changes were observed,such as hemorrhage,edema,and cell necrosis,following brain injury. These alterations were significantly improved following 14 days of treatment with Xiantai mixture,electroacupuncture,and acupuncture-induced oxygen therapy. In particular,acupuncture-induced oxygen therapy resulted in recovery to normal conditions. In the Xiantai mixture,electroacupuncture,and acupuncture-induced oxygen therapy groups,MDA content was significantly reduced (P < 0.01),SOD activity was significantly increased (P < 0.01),NOS activity was significantly decreased (P < 0.01),and hemorheological indices were reduced,compared with the model group. In particular,acupunture-induced oxygen therapy resulted in the most obvious changes (P < 0.01). CONCLUSION:Acupuncture-induced oxygen therapy improved pathological changes following brain injury by possibly improving blood supply,ameliorating ischemia/hypoxia,and inhibiting peroxidation and free radicals.
文摘There are growing evidences on the role of adaptive mechanisms of all cell types in pathological processes: atherosclerosis, ischemic attack, bacterial infections, etc. All kinds of these processes involve as main mechanism oxidative stress. Aerobic organisms use oxygen in processes that accidentally or deliberately generate aggressive species for the biologic components in the form of radicals. Radicals were looked initially as “harmful” molecules and this is true for large quantities but in small or even moderate amounts these molecules prove to have a physiological role. Reactive species are highly reactive and as a consequence are short living species. Their impact is supposed to be limited in the proximity area of their formation. Instead recent evidences indicate their implications in cellular signaling suggesting that individual chemical properties of reactive species make a difference in their biological role. This paper presents superoxide, nitric oxide and peroxide radical generation under cellular changing conditions, the adapting behavior of the enzymes that synthesize and remove them as well as some therapeutic target in superoxide related pathology.
基金This study was supported by the"Climbing"Program from the Ministry of Science and Technology of China(Grant No.[1999]045)
文摘Objective:To investigate the effects of long-term low-dose hormone replacement therapy(HRT)on blood pressure,the plasma renin activity(PRA),plasma angiotensin Ⅱ(AngⅡ)leveland serum nitric oxide(NO)concentration in postmenopausal women.Methods:A total of 140 postmenopausal women were selected from the medical staff of thePeking Union Medical College Hospital.Of these,63 subjects who had been treated with low-dose sex hormone for over 5(5-32)years were set up as HRT group,and 77 age-matched sub-jects who had never received HRT were designed as control group.The levels of serum estradiol(E_2),follicle stimulating hormone(FSH)and nitric oxide(NO),the concentration of plasma an-giotensin Ⅱ(AngⅡ),plasma rennin activity(PRA)and the blood pressure were evaluated inthese two groups.Results:The serum level of estradiol in HRT group was significantly higher than that in con-trol group(median,interquartile range;124.0 pmol/L,113.4 vs.78.2 pmol/L,121.8)(P<0.05)and systolic blood pressure in HRT groups was significantly lower than that in control group[(126.7±14.4)mmHg vs.(132.4+19.8)mmHg](P<0.05).Diastolic blood pressure[(79.7±7.9)mmHg vs.(79.6±10.4)mmHg],the serum level of FSH[(54.4±18.9)IU/L vs.(60.4±24.4)IU/L],the plasma level of PRA(median,interquartile range;0.14 pg/L/hr,0.11vs.0.12 pg/L/hr,0.10),AngⅡ(median,interquartile range;46.0,31.1 pg/ml vs.44.4,33.0pg/ml)and serum level of NO(median,interquartile range;63.8 μmol/L,58.9 vs.56.0 μmol/L,94.8)showed no significant difference between HRT and control groups(P>0.05).Conclusions:Long-term low-dose HRT decreased the systolic blood pressure,but showed noeffects on the diastolic blood pressure,plasma level of AngⅡ,PRA,and serum level of NO inpostmenopausal women.
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supported by the National Key R&D Program of China(No.2021YFF1200701)the National Natural Science Foundation of China(Nos.91856205,21820102009,and 21871249)the Key Program of Frontier of Sciences(No.CAS QYZDJ-SSW-SLH052)。
文摘Nitric oxide(NO)gas therapy,especially,L-arginine(L-Arg)-based NO treatment strategies have attracted extensive attention in the field of oncotherapy.However,current strategies are unable to differentiate well between normal cells and cancer cells,which may lead to unpredictable toxicity.Motivated by the fact that mitochondria of cancer cells can express excessive nitric oxide synthetase(NOS),herein,a nanozyme-based NO generator,cerium oxide(CeO_(2))-AT,is fabricated to specifically catalyze the production of NO in cancer cells for selective tumor treatment.In this system,after being endocytosed into cancer cells,the generator can produce a number of NO under the catalysis of NOS in mitochondria of cancer cells,which can disrupt the mitochondrial respiratory chain of tumor cells and further induce cell apoptosis.In addition,the generator with catalase(CAT)-like activity can catalyze H_(2)O_(2)to produce O_(2),which can promote the generation of NO and improve the performance of NO gas therapy.What is more,our system has no obvious impact on the viability of normal cells owing to the less production of NO.Our work paves a new way for the development of highly selective NO-based treatment particularly useful for the safe and specific cancer therapy.
