Dear Editor,Urogenital tuberculosis(UGTB)is the second most common type of extra-pulmonary tuberculosis(TB)and is defined as tuberculous infectious inflammation of urogenital system organs.Currently,the modern therape...Dear Editor,Urogenital tuberculosis(UGTB)is the second most common type of extra-pulmonary tuberculosis(TB)and is defined as tuberculous infectious inflammation of urogenital system organs.Currently,the modern therapeutic approach to UGTB has shifted focus from saving lives to saving functional kidney units,which implies that surgical intervention should be considered for kidneys with structural damage.展开更多
Although the discovery of insulin 100 years ago revolutionized the treatment of diabetes,its therapeutic potential is compromised by its short half-life and narrow therapeutic index.Current long-acting insulin analogs...Although the discovery of insulin 100 years ago revolutionized the treatment of diabetes,its therapeutic potential is compromised by its short half-life and narrow therapeutic index.Current long-acting insulin analogs,such as insulin-polymer conjugates,are mainly used to improve pharmacokinetics by reducing renal clearance.However,these conjugates are synthesized without sacrificing the bioactivity of insulin,thus retaining the narrow therapeutic index of native insulin,and exceeding the efficacious dose still leads to hypoglycemia.Here,we report a kind of di-PEGylated insulin that can simultaneously reduce renal clearance and receptor-mediated clearance.By impairing the binding affinity to the receptor and the activation of the receptor,di-PEGylated insulin not only further prolongs the half-life of insulin compared to classical mono-PEGylated insulin but most importantly,increases its maximum tolerated dose 10-fold.The target of long-term glycemic management in vivo has been achieved through improved pharmacokinetics and a high dose.This work represents an essential step towards long-acting insulin medication with superior safety in reducing hypoglycemic events.展开更多
Biologics play an essential role in treating various indications from cancers to the metabolic diseases,while the current development of new classes of intracellular-acting protein drugs is still hindered because of h...Biologics play an essential role in treating various indications from cancers to the metabolic diseases,while the current development of new classes of intracellular-acting protein drugs is still hindered because of high molecular mass and overall hydrophilicity of proteins creating extremely poor permeability across cell membrane.Hence,there remains an unmet need to develop safe,potent approaches to augment intracellular protein delivery efficiency.Here,we described a facile multicomponent reaction system for generating a small library of redox-responsive cationic polypeptoids with high biocompatibility.The co-assembly of optimized polymer with protein leads to the formation of compacted nanocomplexes with smaller size and high encapsulation efficiency,thus improving cellular internalization via the macropinocytosis and/or caveolae-mediated endocytosis mainly.After endo-lysosomal escape,the nanocomplexes can be disassociated to efficiently release cargo proteins into the cytosol,owing to the intracellular glutathione(GSH)-triggered rapid cleavage of disulfide bonds in polymers backbone.As a result,we screened a promising platform reagent for efficient cytosolic protein delivery application.展开更多
文摘Dear Editor,Urogenital tuberculosis(UGTB)is the second most common type of extra-pulmonary tuberculosis(TB)and is defined as tuberculous infectious inflammation of urogenital system organs.Currently,the modern therapeutic approach to UGTB has shifted focus from saving lives to saving functional kidney units,which implies that surgical intervention should be considered for kidneys with structural damage.
基金supported by the National Natural Science Foundation of China(No.51820105004,China)the Key Areas Research and Development Program of Guangzhou(No.202007020006,China).
文摘Although the discovery of insulin 100 years ago revolutionized the treatment of diabetes,its therapeutic potential is compromised by its short half-life and narrow therapeutic index.Current long-acting insulin analogs,such as insulin-polymer conjugates,are mainly used to improve pharmacokinetics by reducing renal clearance.However,these conjugates are synthesized without sacrificing the bioactivity of insulin,thus retaining the narrow therapeutic index of native insulin,and exceeding the efficacious dose still leads to hypoglycemia.Here,we report a kind of di-PEGylated insulin that can simultaneously reduce renal clearance and receptor-mediated clearance.By impairing the binding affinity to the receptor and the activation of the receptor,di-PEGylated insulin not only further prolongs the half-life of insulin compared to classical mono-PEGylated insulin but most importantly,increases its maximum tolerated dose 10-fold.The target of long-term glycemic management in vivo has been achieved through improved pharmacokinetics and a high dose.This work represents an essential step towards long-acting insulin medication with superior safety in reducing hypoglycemic events.
基金This work was supported by the National Natural Science Foundation of China(51803243,51820105004)the Guangdong Basic and Applied Basic Research Foundation(2020A1515011285)the Guangdong Innovative and Entrepreneurial Research Team Program(2013S086).
文摘Biologics play an essential role in treating various indications from cancers to the metabolic diseases,while the current development of new classes of intracellular-acting protein drugs is still hindered because of high molecular mass and overall hydrophilicity of proteins creating extremely poor permeability across cell membrane.Hence,there remains an unmet need to develop safe,potent approaches to augment intracellular protein delivery efficiency.Here,we described a facile multicomponent reaction system for generating a small library of redox-responsive cationic polypeptoids with high biocompatibility.The co-assembly of optimized polymer with protein leads to the formation of compacted nanocomplexes with smaller size and high encapsulation efficiency,thus improving cellular internalization via the macropinocytosis and/or caveolae-mediated endocytosis mainly.After endo-lysosomal escape,the nanocomplexes can be disassociated to efficiently release cargo proteins into the cytosol,owing to the intracellular glutathione(GSH)-triggered rapid cleavage of disulfide bonds in polymers backbone.As a result,we screened a promising platform reagent for efficient cytosolic protein delivery application.
