Due to the non-targeted release and low solubility of anti-gastric cancer agent,apatinib(Apa),a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side effects...Due to the non-targeted release and low solubility of anti-gastric cancer agent,apatinib(Apa),a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side effects.In order to avoid these drawbacks,lipid-film-coated Prussian blue nanoparticles(PB NPs)with hyaluronan(HA)modification was used for Apa loading to improve its solubility and targeting ability.Furthermore,anti-tumor compound of gamabufotalin(CS-6)was selected as a partner of Apawith reducing dosage for combinational gastric therapy.Thus,HA-Apa-Lip@PB-CS-6 NPs were constructed to synchronously transport the two drugs into tumor tissue.In vitro assay indicated that HA-Apa-Lip@PB-CS-6 NPs can synergistically inhibit proliferation and invasion/metastasis of BGC-823 cells via downregulating vascular endothelial growth factor receptor(VEGFR)and matrix metalloproteinase-9(MMP-9).In vivo assay demonstrated strongest anti-tumor growth and liver metastasis of HA-Apa-Lip@PB-CS-6 NPs administration in BGC-823 cells-bearing mice compared with other groups due to the excellent penetration in tumor tissues and outstanding synergistic effects.In summary,we have successfully developed a new nanocomplexes for synchronous Apa/CS-6 delivery and synergistic gastric cancer(GC)therapy.展开更多
Background:The emergence of antimicrobial resistance has necessitated the development of effective alternatives to antibiotics for livestock and poultry production.This study investigated a possible synergy between bu...Background:The emergence of antimicrobial resistance has necessitated the development of effective alternatives to antibiotics for livestock and poultry production.This study investigated a possible synergy between butyrate and forskolin(a natural labdane diterpene)in enhancing innate host defense,barrier function,disease resistance,growth performance,and meat quality of broilers.Methods:The expressions of representative genes involved in host defense(AvBD9 and AvBD10),barrier function(MUC2,CLDN1,and TJP1),and inflammation(IL-1β)were measured in chicken HD11 macrophages in response to butyrate and forskolin in the presence or absence of bacterial lipopolysaccharides(LPS).Intestinal lesions and the Clostridium perfringens titers were also assessed in C.perfringens-challenged chickens fed butyrate and forskolincontaining Coleus forskohlii(CF)extract individually or in combination.Furthermore,growth performance and carcass characteristics were evaluated in broilers supplemented with butyrate and the CF extract for 42 d.Results:Butyrate and forskolin synergistically induced the expressions of AvBD9,AvBD10,and MUC2 in chicken HD11 cells(P<0.05)and the synergy was maintained in the presence of LPS.Butyrate and forskolin also suppressed LPS-induced IL-1βgene expression in HD11 cells in a synergistic manner(P<0.05).The two compounds significantly reduced the intestinal lesions of C.perfringens-challenged chickens when combined(P<0.05),but not individually.Furthermore,butyrate in combination with forskolin-containing CF extract had no influence on weight gain,but significantly reduced feed intake(P<0.05)with a strong tendency to improve feed efficiency(P=0.07)in a 42-d feeding trial.Desirably,the butyrate/forskolin combination significantly decreased abdominal fat deposition(P=0.01)with no impact on the carcass yield,breast meat color,drip loss,or pH of d-42 broilers.Conclusions:Butyrate and forskolin has potential to be developed as novel antibiotic alternatives to improve disease resistance,feed efficiency,and carcass composition of broilers.展开更多
Photothermal(PTT) and photodynamic(PDT) combined therapy has been hindered to clinical translation, due to the lack of available biomaterials, difficult designs of functions,and complex chemical synthetic or preparati...Photothermal(PTT) and photodynamic(PDT) combined therapy has been hindered to clinical translation, due to the lack of available biomaterials, difficult designs of functions,and complex chemical synthetic or preparation procedures. To actualize a high-efficiency combination therapy for cancer via a feasible approach, three readily available materials are simply associated together in one-pot, namely the single-walled carbon nanohorns(SWCNH), zinc phthalocyanine(ZnPc), and surfactant TPGS. The established nanodispersion is recorded as PCT. The association of SWCNH/ZnPc/TPGS was confirmed by energy dispersive spectrum, Raman spectrum and thermogravimetric analysis. Under lighting, PCT induced a temperature rising up to about 60 ℃ due to the presence of SWCNH, production a 7-folds of singlet oxygen level elevation because of ZnPc, which destroyed almost all4T1 tumor cells in vitro. The photothermal effect of PCT depended on both laser intensity and nanodispersion concentration in a linear and nonlinear manner, respectively. After a single peritumoral injection in mice and laser treatment, PCT exhibited the highest tumor temperature rise(to 65 ℃) among all test groups, completely destroyed primary tumor without obvious toxicity, and inhibited distant site tumor. Generally, this study demonstrated the high potential of PCT nanodispersion in tumor combined therapy.展开更多
Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target(m TOR), inhibition of which could result in autophagic cell death(ACD). Though novel combination chemo...Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target(m TOR), inhibition of which could result in autophagic cell death(ACD). Though novel combination chemotherapy of autophagy inducers with chemotherapeutic agents is extensively investigated, nanomedicine-based combination therapy for ACD remains in infancy. In attempt to actively trigger ACD for synergistic chemotherapy, here we incorporated autophagy inducer rapamycin(RAP) into 7 pep-modified PEG-DSPE polymer micelles(7 pep-M-RAP) to specifically target and efficiently priming ACD of MCF-7 human breast cancer cells with high expression of transferrin receptor(Tf R). Cytotoxic paclitaxel(PTX)-loaded micelle(7 pep-M-PTX) was regarded as chemotherapeutic drug model. We discovered that with superior intracellular uptake in vitro and more tumor accumulation of micelles in vivo, 7 pep-M-RAP exhibited excellent autophagy induction and synergistic antitumor efficacy with 7 pep-M-PTX. Mechanism study further revealed that 7 pep-M-RAP and 7 pep-MPTX used in combination provided enhanced efficacy through induction of both apoptosis-and mitochondria-associated autophagic cell death. Together, our findings suggested that the targeted excess autophagy may provide a rational strategy to improve therapeutic outcome of breast cancer, and simultaneous induction of ACD and apoptosis may be a promising anticancer modality.展开更多
Although high-efficiency targeted delivery is investigated for years, the efficiency of tumor targeting seems still a hard core to smash. To overcome this problem, we design a three-step delivery strategy based on str...Although high-efficiency targeted delivery is investigated for years, the efficiency of tumor targeting seems still a hard core to smash. To overcome this problem, we design a three-step delivery strategy based on streptavidin-biotin interaction with the help of c(RGDfK), magnetic fields and lasers.The ultrasmall superparamagnetic iron oxide nanoparticles(USIONPs) modified with c(RGDfK) and biotin are delivered at step 1, followed by streptavidin and the doxorubicin(Dox) loaded nanosystems conjugated with biotin at steps 2 and 3, respectively. The delivery systems were proved to be efficient on A549 cells. The co-localization of signal for each step revealed the targeting mechanism. The external magnetic field could further amplify the endocytosis of USPIONs based on c(RGDfK), and magnify the uptake distinctions among different test groups. Based on photoacoustic imaging, laser-heating treatment could enhance the permeability of tumor venous blood vessels and change the insufficient blood flow in cancer. Then, it was noticed in vivo that only three-step delivery with laser-heating and magnetic fields realized the highest tumor distribution of nanosystem. Finally, the magnetism/laser-auxiliary cascaded delivery exhibited the best antitumor efficacy. Generally, this study demonstrated the necessity of combining physical, biological and chemical means of targeting.展开更多
基金supported by Changsha Municipal Natural Science Foundation(Grant No.:kq2014265),the Construction Program of Hunan's innovative Province(CN)-High-tech Industry Science and Technology Innovation Leading Project(Project No.:2020SK2002)the Natural Science Foundation of Hunan Province(Grant No.:2023JJ40130)+1 种基金Postgraduate Scientific Research Innovation Project of Hunan Province(Project No.:CX20230317)the Changsha Platform and Talent Plan(kq2203002).
文摘Due to the non-targeted release and low solubility of anti-gastric cancer agent,apatinib(Apa),a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side effects.In order to avoid these drawbacks,lipid-film-coated Prussian blue nanoparticles(PB NPs)with hyaluronan(HA)modification was used for Apa loading to improve its solubility and targeting ability.Furthermore,anti-tumor compound of gamabufotalin(CS-6)was selected as a partner of Apawith reducing dosage for combinational gastric therapy.Thus,HA-Apa-Lip@PB-CS-6 NPs were constructed to synchronously transport the two drugs into tumor tissue.In vitro assay indicated that HA-Apa-Lip@PB-CS-6 NPs can synergistically inhibit proliferation and invasion/metastasis of BGC-823 cells via downregulating vascular endothelial growth factor receptor(VEGFR)and matrix metalloproteinase-9(MMP-9).In vivo assay demonstrated strongest anti-tumor growth and liver metastasis of HA-Apa-Lip@PB-CS-6 NPs administration in BGC-823 cells-bearing mice compared with other groups due to the excellent penetration in tumor tissues and outstanding synergistic effects.In summary,we have successfully developed a new nanocomplexes for synchronous Apa/CS-6 delivery and synergistic gastric cancer(GC)therapy.
基金supported by the USDA National Institute of Food and Agriculture (grant no. 2018–68003-27462 and 2020–67016-31619)Oklahoma Center for the Advancement of Science and Technology (grant no. AR19–027)+2 种基金Boulware Endowment FundOklahoma Agricultural Experiment Station Project H-3112supported by the USDA-NIFA Predoctoral Fellowship grant 2018–67011-28041
文摘Background:The emergence of antimicrobial resistance has necessitated the development of effective alternatives to antibiotics for livestock and poultry production.This study investigated a possible synergy between butyrate and forskolin(a natural labdane diterpene)in enhancing innate host defense,barrier function,disease resistance,growth performance,and meat quality of broilers.Methods:The expressions of representative genes involved in host defense(AvBD9 and AvBD10),barrier function(MUC2,CLDN1,and TJP1),and inflammation(IL-1β)were measured in chicken HD11 macrophages in response to butyrate and forskolin in the presence or absence of bacterial lipopolysaccharides(LPS).Intestinal lesions and the Clostridium perfringens titers were also assessed in C.perfringens-challenged chickens fed butyrate and forskolincontaining Coleus forskohlii(CF)extract individually or in combination.Furthermore,growth performance and carcass characteristics were evaluated in broilers supplemented with butyrate and the CF extract for 42 d.Results:Butyrate and forskolin synergistically induced the expressions of AvBD9,AvBD10,and MUC2 in chicken HD11 cells(P<0.05)and the synergy was maintained in the presence of LPS.Butyrate and forskolin also suppressed LPS-induced IL-1βgene expression in HD11 cells in a synergistic manner(P<0.05).The two compounds significantly reduced the intestinal lesions of C.perfringens-challenged chickens when combined(P<0.05),but not individually.Furthermore,butyrate in combination with forskolin-containing CF extract had no influence on weight gain,but significantly reduced feed intake(P<0.05)with a strong tendency to improve feed efficiency(P=0.07)in a 42-d feeding trial.Desirably,the butyrate/forskolin combination significantly decreased abdominal fat deposition(P=0.01)with no impact on the carcass yield,breast meat color,drip loss,or pH of d-42 broilers.Conclusions:Butyrate and forskolin has potential to be developed as novel antibiotic alternatives to improve disease resistance,feed efficiency,and carcass composition of broilers.
基金supported by the National Natural Science Foundation of China (81690264)the National Basic Research Program of China (2015CB932100)the Innovation Team of the Ministry of Education (BMU20110263)。
文摘Photothermal(PTT) and photodynamic(PDT) combined therapy has been hindered to clinical translation, due to the lack of available biomaterials, difficult designs of functions,and complex chemical synthetic or preparation procedures. To actualize a high-efficiency combination therapy for cancer via a feasible approach, three readily available materials are simply associated together in one-pot, namely the single-walled carbon nanohorns(SWCNH), zinc phthalocyanine(ZnPc), and surfactant TPGS. The established nanodispersion is recorded as PCT. The association of SWCNH/ZnPc/TPGS was confirmed by energy dispersive spectrum, Raman spectrum and thermogravimetric analysis. Under lighting, PCT induced a temperature rising up to about 60 ℃ due to the presence of SWCNH, production a 7-folds of singlet oxygen level elevation because of ZnPc, which destroyed almost all4T1 tumor cells in vitro. The photothermal effect of PCT depended on both laser intensity and nanodispersion concentration in a linear and nonlinear manner, respectively. After a single peritumoral injection in mice and laser treatment, PCT exhibited the highest tumor temperature rise(to 65 ℃) among all test groups, completely destroyed primary tumor without obvious toxicity, and inhibited distant site tumor. Generally, this study demonstrated the high potential of PCT nanodispersion in tumor combined therapy.
基金supported by the National Natural Science Foundation of China(81690264)Key Project from the Ministry of Science and Technology(Grant No.2018ZX09721003)Scientific Research Incubation Fund of Beijing Children’s Hospital,Capital Medical University(Grant No.GPY201711,China)
文摘Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target(m TOR), inhibition of which could result in autophagic cell death(ACD). Though novel combination chemotherapy of autophagy inducers with chemotherapeutic agents is extensively investigated, nanomedicine-based combination therapy for ACD remains in infancy. In attempt to actively trigger ACD for synergistic chemotherapy, here we incorporated autophagy inducer rapamycin(RAP) into 7 pep-modified PEG-DSPE polymer micelles(7 pep-M-RAP) to specifically target and efficiently priming ACD of MCF-7 human breast cancer cells with high expression of transferrin receptor(Tf R). Cytotoxic paclitaxel(PTX)-loaded micelle(7 pep-M-PTX) was regarded as chemotherapeutic drug model. We discovered that with superior intracellular uptake in vitro and more tumor accumulation of micelles in vivo, 7 pep-M-RAP exhibited excellent autophagy induction and synergistic antitumor efficacy with 7 pep-M-PTX. Mechanism study further revealed that 7 pep-M-RAP and 7 pep-MPTX used in combination provided enhanced efficacy through induction of both apoptosis-and mitochondria-associated autophagic cell death. Together, our findings suggested that the targeted excess autophagy may provide a rational strategy to improve therapeutic outcome of breast cancer, and simultaneous induction of ACD and apoptosis may be a promising anticancer modality.
基金financially supported by the National Basic Research Program of China(2015CB932100)the National Natural Science Foundation of China(81690264 and 81821004)the Foundation for the Innovation Team of Ministry of Education(No.BMU2017TD003,China)
文摘Although high-efficiency targeted delivery is investigated for years, the efficiency of tumor targeting seems still a hard core to smash. To overcome this problem, we design a three-step delivery strategy based on streptavidin-biotin interaction with the help of c(RGDfK), magnetic fields and lasers.The ultrasmall superparamagnetic iron oxide nanoparticles(USIONPs) modified with c(RGDfK) and biotin are delivered at step 1, followed by streptavidin and the doxorubicin(Dox) loaded nanosystems conjugated with biotin at steps 2 and 3, respectively. The delivery systems were proved to be efficient on A549 cells. The co-localization of signal for each step revealed the targeting mechanism. The external magnetic field could further amplify the endocytosis of USPIONs based on c(RGDfK), and magnify the uptake distinctions among different test groups. Based on photoacoustic imaging, laser-heating treatment could enhance the permeability of tumor venous blood vessels and change the insufficient blood flow in cancer. Then, it was noticed in vivo that only three-step delivery with laser-heating and magnetic fields realized the highest tumor distribution of nanosystem. Finally, the magnetism/laser-auxiliary cascaded delivery exhibited the best antitumor efficacy. Generally, this study demonstrated the necessity of combining physical, biological and chemical means of targeting.
