Peptide-based radiopharmaceuticals targeting integrinα5β1 show promise for precise tumor diagnosis and treatment.However,current peptide-based radioligands that targetα5β1 demonstrate inadequate in vivo performanc...Peptide-based radiopharmaceuticals targeting integrinα5β1 show promise for precise tumor diagnosis and treatment.However,current peptide-based radioligands that targetα5β1 demonstrate inadequate in vivo performance owing to limited tumor retention.The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity.Therefore,a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed.Here,we developed a PEGylation-enabled peptide multidisplay platform(PEGibody)for PR_b,anα5β1 targeting peptide.PEGibody generation involved PEGylation and self-assembly.[^(64)Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter.Compared with non-PEGylated radioligands,[^(64)Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability.Importantly,the biodistribution analysis confirmed rapid clearance of[^(64)Cu]QM-2303 from the bloodstream.Administration of a single dose of[^(177)Lu]QM-2303 led to robust antitumor efficacy.Furthermore,[^(64)Cu]/[^(177)Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice.Therefore,this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime.The PEGibody-based radiopharmaceutical[^(64)Cu]/[^(177)Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy forα5β1-overexpressing tumors.展开更多
Astragalus membranaceus var.mongholicus(AMM),a member of the Leguminosae,is one of the most important medicinal plants worldwide.The dried roots of AMM have a wide range of pharmacological effects and are a traditiona...Astragalus membranaceus var.mongholicus(AMM),a member of the Leguminosae,is one of the most important medicinal plants worldwide.The dried roots of AMM have a wide range of pharmacological effects and are a traditional Chinese medicine.Here,we report the first chromosome-level reference genome of AMM,comprising nine pseudochromosomes with a total size of 1.47 Gb and 27868 protein-encoding genes.Comparative genomic analysis reveals that AMM has not experienced an independent wholegenome duplication(WGD)event after the WGD event shared by the Papilionoideae species.Analysis of long terminal repeat retrotransposons suggests a recent burst of these elements at approximately 0.13 million years ago,which may explain the large size of the AMM genome.Multiple gene families involved in the biosynthesis of triterpenoids and flavonoids were expanded,and our data indicate that tandemduplication has been the main driver for expansion of these families.Among the expanded families,the phenylalanine ammonia-lyase gene family was primarily expressed in the roots of AMM,suggesting their roles in the biosynthesis of phenylpropanoid compounds.The functional versatility of 2,3-oxidosqualene cyclase genes in cluster Ⅲ may play a critical role in the diversification of triterpenoids in AMM.Our findings provide novel insights into triterpenoid and flavonoid biosynthesis and can facilitate future research on the genetics and medical applications of AMM.展开更多
基金supported by the National Natural Science Foundation of China(No.82372002)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2022-RC350-04,China)+6 种基金the CAMS Innovation Fund for Medical Sciences(Nos.2021-I2M-1-026(2023),2022-I2M-2-002-2,and 2021-I2M-3-001(2023),China)the National Key Research and Development Program of China(No.2022YFE0111700)the Beijing Nova Program to Kuan Hu(No.0104002,China)supported by the Beijing Natural Science Foundation(No.L234044,China)the Fundamental Research Funds for the Central Universities(Nos.3332023044 and 3332023151,China)the CIRP Open Fund of Radiation Protection Laboratories(No.ZHYLYB2021005,China)the China National Nuclear Corporation Young Talent Program.
文摘Peptide-based radiopharmaceuticals targeting integrinα5β1 show promise for precise tumor diagnosis and treatment.However,current peptide-based radioligands that targetα5β1 demonstrate inadequate in vivo performance owing to limited tumor retention.The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity.Therefore,a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed.Here,we developed a PEGylation-enabled peptide multidisplay platform(PEGibody)for PR_b,anα5β1 targeting peptide.PEGibody generation involved PEGylation and self-assembly.[^(64)Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter.Compared with non-PEGylated radioligands,[^(64)Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability.Importantly,the biodistribution analysis confirmed rapid clearance of[^(64)Cu]QM-2303 from the bloodstream.Administration of a single dose of[^(177)Lu]QM-2303 led to robust antitumor efficacy.Furthermore,[^(64)Cu]/[^(177)Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice.Therefore,this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime.The PEGibody-based radiopharmaceutical[^(64)Cu]/[^(177)Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy forα5β1-overexpressing tumors.
基金supported by grants from the City-University Cooperation Project of China(201904710111639).
文摘Astragalus membranaceus var.mongholicus(AMM),a member of the Leguminosae,is one of the most important medicinal plants worldwide.The dried roots of AMM have a wide range of pharmacological effects and are a traditional Chinese medicine.Here,we report the first chromosome-level reference genome of AMM,comprising nine pseudochromosomes with a total size of 1.47 Gb and 27868 protein-encoding genes.Comparative genomic analysis reveals that AMM has not experienced an independent wholegenome duplication(WGD)event after the WGD event shared by the Papilionoideae species.Analysis of long terminal repeat retrotransposons suggests a recent burst of these elements at approximately 0.13 million years ago,which may explain the large size of the AMM genome.Multiple gene families involved in the biosynthesis of triterpenoids and flavonoids were expanded,and our data indicate that tandemduplication has been the main driver for expansion of these families.Among the expanded families,the phenylalanine ammonia-lyase gene family was primarily expressed in the roots of AMM,suggesting their roles in the biosynthesis of phenylpropanoid compounds.The functional versatility of 2,3-oxidosqualene cyclase genes in cluster Ⅲ may play a critical role in the diversification of triterpenoids in AMM.Our findings provide novel insights into triterpenoid and flavonoid biosynthesis and can facilitate future research on the genetics and medical applications of AMM.
