Albumin,owing to its high abundance and excellent biocompatibility,is widely used as a drug carrier to enhance delivery efficiency and reduce systemic toxicity.The Michael addition between albumin thiols and maleimide...Albumin,owing to its high abundance and excellent biocompatibility,is widely used as a drug carrier to enhance delivery efficiency and reduce systemic toxicity.The Michael addition between albumin thiols and maleimide-functionalized prodrugs is a common in situ macromolecular prodrug strategy.However,the resulting reversible adducts are susceptible to retro-Michael reactions in vivo,leading to premature drug release and off-target effects.To address this limitation,a gemcitabine prodrug(GAB)bearing a chloroacetamide group was designed to form irreversible covalent bonds with albumin via nucleophilic substitution.A maleimide-based prodrug(GAM)was synthesized as a control.Compared to GAM,GAB showed faster and stronger albumin binding in plasma,enhanced blood circulation time,improved tumor accumulation,and superior in vivo antitumor efficacy.Moreover,GAB exhibited a better safety profile,with reduced cytotoxicity in normal tissues and no observable systemic toxicity.These advantages are attributed to the stable albumin-drug conjugate formed by GAB,which improves drug retention and targeted delivery.This study presents an effective and generalizable albumin-hitchhiking strategy for constructing irreversible prodrugs,offering a promising approach to enhance the therapeutic index of chemotherapeutic agents.展开更多
The effects of drawing strain during intermediate annealing on the microstructure and properties of Cu-20 wt%Fe alloy wires while maintaining constant total deformation were investigated.Intermediate annealing effecti...The effects of drawing strain during intermediate annealing on the microstructure and properties of Cu-20 wt%Fe alloy wires while maintaining constant total deformation were investigated.Intermediate annealing effectively removes work hardening in both the Cu matrix and Fe fibers,restoring their plastic deformation capacity and preserving fiber continuity during subsequent redrawing.The process also refines the Fe phase,leading to a more uniform size distribution and straighter,better-aligned Cu/Fe phase interfaces,thereby enhancing the comprehensive properties of the alloy.The magnitude of drawing strain during intermediate annealing plays a critical role in balancing the mechanical strength and electrical conductivity of redrawn wires.A lower initial drawing strain requires greater redrawing strain,leading to excessive hardening of the Fe fibers,which negatively impacts the electrical conductivity and tensile plasticity.Conversely,a higher initial drawing strain can result in insufficient work hardening during the redrawing deformation process,yielding minimal strength improvements.Among the tested alloys,H/3.5 wires show a slight reduction in strength and hardness compared to W and H/4.5 wires but exhibit a significant increase in tensile elongation and electrical conductivity.The tensile strength was 755 MPa,and the electrical conductivity was 47%international-annealed copper standard(IACS).The optimal performance is attributed to the formation of a high-density,ultrafine Fe fiber structure-aligned parallel to the drawing direction,which is achieved through a suitable combination of the drawing process and intermediate annealing.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82372115,52073139 and 82404553)the Postdoctoral Fellowship Program of Chinese Postdoctoral Science Foundation(No.GZC20231085).
文摘Albumin,owing to its high abundance and excellent biocompatibility,is widely used as a drug carrier to enhance delivery efficiency and reduce systemic toxicity.The Michael addition between albumin thiols and maleimide-functionalized prodrugs is a common in situ macromolecular prodrug strategy.However,the resulting reversible adducts are susceptible to retro-Michael reactions in vivo,leading to premature drug release and off-target effects.To address this limitation,a gemcitabine prodrug(GAB)bearing a chloroacetamide group was designed to form irreversible covalent bonds with albumin via nucleophilic substitution.A maleimide-based prodrug(GAM)was synthesized as a control.Compared to GAM,GAB showed faster and stronger albumin binding in plasma,enhanced blood circulation time,improved tumor accumulation,and superior in vivo antitumor efficacy.Moreover,GAB exhibited a better safety profile,with reduced cytotoxicity in normal tissues and no observable systemic toxicity.These advantages are attributed to the stable albumin-drug conjugate formed by GAB,which improves drug retention and targeted delivery.This study presents an effective and generalizable albumin-hitchhiking strategy for constructing irreversible prodrugs,offering a promising approach to enhance the therapeutic index of chemotherapeutic agents.
基金support provided by the National Natural Science Foundation of China(Nos.52405364,and 52171110)the Jiangsu Funding Program for Excellent Postdoctoral Talent.W.Huo acknowledges the support from the European Union Horizon 2020 Research and Innovation Program(No.857470)+1 种基金from the European Regional Development Fund via the Foundation for Polish Science International Research Agenda PLUS Program(No.MAB PLUS/2018/8)The publication was partly created within the framework of the project of the Minister of Science and Higher Education"Support for the activities of Centers of Excellence established in Poland under Horizon 2020"(No.MEiN/2023/DIR/3795).
文摘The effects of drawing strain during intermediate annealing on the microstructure and properties of Cu-20 wt%Fe alloy wires while maintaining constant total deformation were investigated.Intermediate annealing effectively removes work hardening in both the Cu matrix and Fe fibers,restoring their plastic deformation capacity and preserving fiber continuity during subsequent redrawing.The process also refines the Fe phase,leading to a more uniform size distribution and straighter,better-aligned Cu/Fe phase interfaces,thereby enhancing the comprehensive properties of the alloy.The magnitude of drawing strain during intermediate annealing plays a critical role in balancing the mechanical strength and electrical conductivity of redrawn wires.A lower initial drawing strain requires greater redrawing strain,leading to excessive hardening of the Fe fibers,which negatively impacts the electrical conductivity and tensile plasticity.Conversely,a higher initial drawing strain can result in insufficient work hardening during the redrawing deformation process,yielding minimal strength improvements.Among the tested alloys,H/3.5 wires show a slight reduction in strength and hardness compared to W and H/4.5 wires but exhibit a significant increase in tensile elongation and electrical conductivity.The tensile strength was 755 MPa,and the electrical conductivity was 47%international-annealed copper standard(IACS).The optimal performance is attributed to the formation of a high-density,ultrafine Fe fiber structure-aligned parallel to the drawing direction,which is achieved through a suitable combination of the drawing process and intermediate annealing.
