To ensure the structural integrity of life-limiting component of aeroengines,Probabilistic Damage Tolerance(PDT)assessment is applied to evaluate the failure risk as required by airworthiness regulations and military ...To ensure the structural integrity of life-limiting component of aeroengines,Probabilistic Damage Tolerance(PDT)assessment is applied to evaluate the failure risk as required by airworthiness regulations and military standards.The PDT method holds the view that there exist defects such as machining scratches and service cracks in the tenon-groove structures of aeroengine disks.However,it is challenging to conduct PDT assessment due to the scarcity of effective Probability of Detection(POD)model and anomaly distribution model.Through a series of Nondestructive Testing(NDT)experiments,the POD model of real cracks in tenon-groove structures is constructed for the first time by employing the Transfer Function Method(TFM).A novel anomaly distribution model is derived through the utilization of the POD model,instead of using the infeasible field data accumulation method.Subsequently,a framework for calculating the Probability of Failure(POF)of the tenon-groove structures is established,and the aforementioned two models exert a significant influence on the results of POF.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
Mitochondria are currently known as novel targets for treating cancer,especially for tumors displaying multidrug resistance(MDR). This present study aimed to develop a mitochondriatargeted delivery system by using tri...Mitochondria are currently known as novel targets for treating cancer,especially for tumors displaying multidrug resistance(MDR). This present study aimed to develop a mitochondriatargeted delivery system by using triphenylphosphonium cation(TPP+)-conjugated Brij 98 as the functional stabilizer to modify paclitaxel(PTX) nanocrystals(NCs) against drugresistant cancer cells. Evaluations were performed on 2 D monolayer and 3 D multicellular spheroids(MCs) of MCF-7 cells and MCF-7/ADR cells. In comparison with free PTX and the non-targeted PTX NCs,the targeted PTX NCs showed the strongest cytotoxicity against both2 D MCF-7 and MCF-7/ADR cells,which was correlated with decreased mitochondrial membrane potential. The targeted PTX NCs exhibited deeper penetration on MCF-7 MCs and more significant growth inhibition on both MCF-7 and MCF-7/ADR MCs. The proposed strategy indicated that the TPP+-modified NCs represent a potentially viable approach for targeted chemotherapeutic molecules to mitochondria. This strategy might provide promising therapeutic outcomes to overcome MDR.展开更多
Although therapeutic potential of neurotrophic factors(NTFs)has been well recognized for over two decades,attempts to translate that potential to the clinic have been disappointing,largely due to significant obstacle...Although therapeutic potential of neurotrophic factors(NTFs)has been well recognized for over two decades,attempts to translate that potential to the clinic have been disappointing,largely due to significant obstacles in delivery,including inadequate protein dose/kinetics released at target sites.Considerable efforts have been made to improve the therapeutic performance of NTFs.This articles reviews recent developments in localized delivery systems of NTFs for the neurological disorders treatments with a main focus on sustained delivery strategies.Different non-covalent binding approaches have been employed to immobilize proteins in hydrogels,microspheres,electrospun nanofibers,and their combined systems,which serve as depots for sustained local release of NTFs.The challenges associated with current NTFs delivery systems and how these systems can be applied to neurological diseases and disorders have been discussed in the review.In conclusion,optimal delivery systems for NTFs will be needed for reliable and meaningful clinical benefits;ideally,delivering a time and dose-controlled release of bioactive multiNTFs at different individual optimal kinetics to achieve multi-functions in target tissues is significant preferred.展开更多
Mitochondrial dysfunction is associated with the emergence of several neurological and cardiovascular diseases. Hence, mitochondria-targeting delivery strategies are highly significant and critically needed. In this s...Mitochondrial dysfunction is associated with the emergence of several neurological and cardiovascular diseases. Hence, mitochondria-targeting delivery strategies are highly significant and critically needed. In this study, we developed a small library of peptides simulating the mitochondria-targeting peptide SS-31, a promising tetra-peptide with antioxidant character, and subsequently evaluated the toxicity, antioxidant ability and mitochondrial delivery of nanoparticles. Among the designed peptides, RF-2 (DArg-Dmt-Arg-Phe-NH2) showed controlled toxicity and excellent protection against gentamicin-induced hair cell damage, as compared with SS-31. More importantly, RF-2-modified PLGA nanoparticles demonstrated high colocalization with mitochondria and comparable specific subcellular accumulation, when compared with SS-31. Taken together, the obtained results supported RF-2 as a mitochondriatargeting peptide with high potential as a targeted carrier.展开更多
The objective of this study was to understand the impact of active pharmaceutical ingredients(API) particle size on a re-developed generic product of glipizide and to improve its formulation so that it exhibits bioequ...The objective of this study was to understand the impact of active pharmaceutical ingredients(API) particle size on a re-developed generic product of glipizide and to improve its formulation so that it exhibits bioequivalent to that of the reference listed drug(RLD). Two commercial batches of APIs(API-1 and API-2) with the same polymorphism and one batch of home-made APIs(API-3) with super-small particle size were used in the present study.The in vitro dissolution profiles of the tested formulations were compared with the RLD in a series of dissolution media. Then, the impact of particle size on in vivo absorption was evaluated in Beagle dogs. Compared with the RLD, formulation A with larger API size showed slower dissolution in p H 6.0 and 7.4 medium, resulting bioinequivalent with the RLD. Conversely, formulation B with smaller API size demonstrated similar in vitro dissolution profiles with the RLD and thus exhibited bioequivalent in the present study. Furthermore, formulation C with super small particle size still exhibited identical oral absorption although rapid dissolution was observed in the tested condition. Herein, it indicated that 2–5 μm might be defined as the "inert size range" of glipizide for ensuring the bioequivalence with the RLD. The results in the present study might help to obtain a better understanding of the variability in raw materials for oral absorption, develop a bioequivalent product and thus post-market quality control.展开更多
Diabetic foot ulcer is a serious complication of diabetes.Excessive accumulation of advanced glycation end products(AGEs)is one of the critical pathogenic factors in postponing diabetic wound healing.The main pathogen...Diabetic foot ulcer is a serious complication of diabetes.Excessive accumulation of advanced glycation end products(AGEs)is one of the critical pathogenic factors in postponing diabetic wound healing.The main pathogenic mechanisms of AGEs include inducing cellular dysfunction,prolonging inflammatory response,increasing oxidative stress and reducing endogenous nitric oxide(NO)production.Combination therapy of blocking the deleterious effects of AGEs and supplementing exogenous NO is hypothesized to promote diabetic wound healing.Here,we presented nanoparticles/hydrogel composite dressings to co-delivery rosiglitazone and S-nitroso glutathione into the wound bed.The designed co-delivery system augmented the survival of fibroblasts,reduced oxidative stress levels,reversed the change of mitochondrial membrane potential and decreased the proinflammatory cytokine expression.Local sustained release of therapeutic agents significantly improved the wound healing of diabetic rats including increasing the wound closure rate,alleviating inflammation,promoting collagen fiber production and angiogenesis.Our finding indicated this local deliver strategy aimed at inhibiting the toxic effects of AGEs has great clinical potential for diabetic wound treatment.展开更多
For many years,drug delivery to the inner ear has been a challenge to physicians in the treatment of inner ear disorders.In the past decade,the field of inner ear drug delivery has emerged with the development of new ...For many years,drug delivery to the inner ear has been a challenge to physicians in the treatment of inner ear disorders.In the past decade,the field of inner ear drug delivery has emerged with the development of new biomaterials and drug delivery technologies to improve the effectiveness of inner ear drug therapy.This paper reviews a number of inner ear drug delivery strategies including systemic,intratympanic,and intracochlear delivery.A focus of this review is the recent advances in intratympanic delivery of medications;approaches utilizing novel biomaterials as well as other recent developments are also discussed.Biotechnology-based approaches,such as gene and stem cell therapy methods are also reviewed.Among the various strategies,local drug delivery approaches including intratympanic and intracochlear drug delivery methods that limit systemic exposure are particularly promising.These inner ear drug delivery systems provide a new opportunity to improve the treatment of inner ear disorders.展开更多
Liposomes have made remarkable achievements as drug delivery vehicles in the clinic.Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs,but seem...Liposomes have made remarkable achievements as drug delivery vehicles in the clinic.Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs,but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents,thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy.In this study,a series of weak acid drug derivatives were designed by a simplistic one step synthesis,which could be remotely loaded into liposomes by p H gradient method.Cabazitaxel(CTX)weak acid derivatives were selected to evaluate regarding its safety profiles,pharmacodynamics,and pharmacokinetics.CTX weak acid derivative liposomes were superior to Jevtanaa in terms of safety profiles,including systemic toxicity,hematological toxicity,and potential central nerve toxicity.Specifically,it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons.Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.展开更多
基金supported by the National Major Science and Technology Project,China(No.J2019-Ⅳ-0007-0075)the Fundamental Research Funds for the Central Universities,China(No.JKF-20240036)。
文摘To ensure the structural integrity of life-limiting component of aeroengines,Probabilistic Damage Tolerance(PDT)assessment is applied to evaluate the failure risk as required by airworthiness regulations and military standards.The PDT method holds the view that there exist defects such as machining scratches and service cracks in the tenon-groove structures of aeroengine disks.However,it is challenging to conduct PDT assessment due to the scarcity of effective Probability of Detection(POD)model and anomaly distribution model.Through a series of Nondestructive Testing(NDT)experiments,the POD model of real cracks in tenon-groove structures is constructed for the first time by employing the Transfer Function Method(TFM).A novel anomaly distribution model is derived through the utilization of the POD model,instead of using the infeasible field data accumulation method.Subsequently,a framework for calculating the Probability of Failure(POF)of the tenon-groove structures is established,and the aforementioned two models exert a significant influence on the results of POF.
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.
文摘Mitochondria are currently known as novel targets for treating cancer,especially for tumors displaying multidrug resistance(MDR). This present study aimed to develop a mitochondriatargeted delivery system by using triphenylphosphonium cation(TPP+)-conjugated Brij 98 as the functional stabilizer to modify paclitaxel(PTX) nanocrystals(NCs) against drugresistant cancer cells. Evaluations were performed on 2 D monolayer and 3 D multicellular spheroids(MCs) of MCF-7 cells and MCF-7/ADR cells. In comparison with free PTX and the non-targeted PTX NCs,the targeted PTX NCs showed the strongest cytotoxicity against both2 D MCF-7 and MCF-7/ADR cells,which was correlated with decreased mitochondrial membrane potential. The targeted PTX NCs exhibited deeper penetration on MCF-7 MCs and more significant growth inhibition on both MCF-7 and MCF-7/ADR MCs. The proposed strategy indicated that the TPP+-modified NCs represent a potentially viable approach for targeted chemotherapeutic molecules to mitochondria. This strategy might provide promising therapeutic outcomes to overcome MDR.
基金the National Natural Science Foundation of China(Grant No.81102401).
文摘Although therapeutic potential of neurotrophic factors(NTFs)has been well recognized for over two decades,attempts to translate that potential to the clinic have been disappointing,largely due to significant obstacles in delivery,including inadequate protein dose/kinetics released at target sites.Considerable efforts have been made to improve the therapeutic performance of NTFs.This articles reviews recent developments in localized delivery systems of NTFs for the neurological disorders treatments with a main focus on sustained delivery strategies.Different non-covalent binding approaches have been employed to immobilize proteins in hydrogels,microspheres,electrospun nanofibers,and their combined systems,which serve as depots for sustained local release of NTFs.The challenges associated with current NTFs delivery systems and how these systems can be applied to neurological diseases and disorders have been discussed in the review.In conclusion,optimal delivery systems for NTFs will be needed for reliable and meaningful clinical benefits;ideally,delivering a time and dose-controlled release of bioactive multiNTFs at different individual optimal kinetics to achieve multi-functions in target tissues is significant preferred.
基金financially supported by the National Natural Science Foundation of China (No. 81473162)the Program for Liaoning Excellent Talents in Universitythe Young and Middleaged Career Development Planning of Shenyang Pharmaceutical University
文摘Mitochondrial dysfunction is associated with the emergence of several neurological and cardiovascular diseases. Hence, mitochondria-targeting delivery strategies are highly significant and critically needed. In this study, we developed a small library of peptides simulating the mitochondria-targeting peptide SS-31, a promising tetra-peptide with antioxidant character, and subsequently evaluated the toxicity, antioxidant ability and mitochondrial delivery of nanoparticles. Among the designed peptides, RF-2 (DArg-Dmt-Arg-Phe-NH2) showed controlled toxicity and excellent protection against gentamicin-induced hair cell damage, as compared with SS-31. More importantly, RF-2-modified PLGA nanoparticles demonstrated high colocalization with mitochondria and comparable specific subcellular accumulation, when compared with SS-31. Taken together, the obtained results supported RF-2 as a mitochondriatargeting peptide with high potential as a targeted carrier.
基金supported by National Science and Technology Major Projects for "Major New Drugs Innovation and Development"(No.2017ZX09101-001-005,Beijing,China)
文摘The objective of this study was to understand the impact of active pharmaceutical ingredients(API) particle size on a re-developed generic product of glipizide and to improve its formulation so that it exhibits bioequivalent to that of the reference listed drug(RLD). Two commercial batches of APIs(API-1 and API-2) with the same polymorphism and one batch of home-made APIs(API-3) with super-small particle size were used in the present study.The in vitro dissolution profiles of the tested formulations were compared with the RLD in a series of dissolution media. Then, the impact of particle size on in vivo absorption was evaluated in Beagle dogs. Compared with the RLD, formulation A with larger API size showed slower dissolution in p H 6.0 and 7.4 medium, resulting bioinequivalent with the RLD. Conversely, formulation B with smaller API size demonstrated similar in vitro dissolution profiles with the RLD and thus exhibited bioequivalent in the present study. Furthermore, formulation C with super small particle size still exhibited identical oral absorption although rapid dissolution was observed in the tested condition. Herein, it indicated that 2–5 μm might be defined as the "inert size range" of glipizide for ensuring the bioequivalence with the RLD. The results in the present study might help to obtain a better understanding of the variability in raw materials for oral absorption, develop a bioequivalent product and thus post-market quality control.
基金financially supported by the National Natural Science Foundation of China(no.82273878).
文摘Diabetic foot ulcer is a serious complication of diabetes.Excessive accumulation of advanced glycation end products(AGEs)is one of the critical pathogenic factors in postponing diabetic wound healing.The main pathogenic mechanisms of AGEs include inducing cellular dysfunction,prolonging inflammatory response,increasing oxidative stress and reducing endogenous nitric oxide(NO)production.Combination therapy of blocking the deleterious effects of AGEs and supplementing exogenous NO is hypothesized to promote diabetic wound healing.Here,we presented nanoparticles/hydrogel composite dressings to co-delivery rosiglitazone and S-nitroso glutathione into the wound bed.The designed co-delivery system augmented the survival of fibroblasts,reduced oxidative stress levels,reversed the change of mitochondrial membrane potential and decreased the proinflammatory cytokine expression.Local sustained release of therapeutic agents significantly improved the wound healing of diabetic rats including increasing the wound closure rate,alleviating inflammation,promoting collagen fiber production and angiogenesis.Our finding indicated this local deliver strategy aimed at inhibiting the toxic effects of AGEs has great clinical potential for diabetic wound treatment.
文摘For many years,drug delivery to the inner ear has been a challenge to physicians in the treatment of inner ear disorders.In the past decade,the field of inner ear drug delivery has emerged with the development of new biomaterials and drug delivery technologies to improve the effectiveness of inner ear drug therapy.This paper reviews a number of inner ear drug delivery strategies including systemic,intratympanic,and intracochlear delivery.A focus of this review is the recent advances in intratympanic delivery of medications;approaches utilizing novel biomaterials as well as other recent developments are also discussed.Biotechnology-based approaches,such as gene and stem cell therapy methods are also reviewed.Among the various strategies,local drug delivery approaches including intratympanic and intracochlear drug delivery methods that limit systemic exposure are particularly promising.These inner ear drug delivery systems provide a new opportunity to improve the treatment of inner ear disorders.
基金financially supported by the National Nature Science Foundation of China(U1608283)the Career Development Program for Young and Middle-aged Teachers in Shenyang Pharmaceutical University
文摘Liposomes have made remarkable achievements as drug delivery vehicles in the clinic.Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs,but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents,thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy.In this study,a series of weak acid drug derivatives were designed by a simplistic one step synthesis,which could be remotely loaded into liposomes by p H gradient method.Cabazitaxel(CTX)weak acid derivatives were selected to evaluate regarding its safety profiles,pharmacodynamics,and pharmacokinetics.CTX weak acid derivative liposomes were superior to Jevtanaa in terms of safety profiles,including systemic toxicity,hematological toxicity,and potential central nerve toxicity.Specifically,it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons.Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.
