Enhanced radiotheranostic targeting of integrinα5β1 with PEGylation-enabled peptide multidisplay platform(PEGibody):A strategy for prolonged tumor retention with fast blood clearance  

作　　者：Siqi Zhang Xiaohui Ma Jiang Wu Jieting Shen Yuntao Shi Xingkai Wang Lin Xie Xiaona Sun Yuxuan Wu Hao Tian Xin Gao Xueyao Chen Hongyi Huang Lu Chen Xuekai Song Qichen Hu Hailong Zhang Feng Wang Zhao-Hui Jin Ming-Rong Zhang Rui Wang Kuan Hu 

机构地区：[1]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China [2]Department of Advanced Nuclear Medicine Sciences,Institute for Quantum Medical Science,National Institutes for Quantum Science and Technology(QST),Chiba 263-8555,Japan [3]Department of Molecular Imaging and Theranostics,Institute for Quantum Medical Science,National Institutes for Quantum Science and Technology(QST),Chiba 263-8555,Japan [4]Department of Vascular and Endovascular Surgery,the First Medical Center of Chinese PLA General Hospital,Beijing 100853,China [5]Department of Nuclear Medicine,Nanjing First Hospital,Nanjing Medical University,Nanjing 211166,China [6]Key Laboratory of Preclinical Study for New Drugs of Gansu Province,School of Basic Medical Sciences&Research Unit of Peptide Science,Chinese Academy of Medical Sciences,Lanzhou University,Lanzhou 730000,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第2期692-706,共15页药学学报(英文版)

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);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.

摘　　要：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.

关 键 词：Integrinα5β1 PEPTIDE PET imaging Targeted radionuclide therapy PEGYLATION TUMOR Multidisplay PEGibody 

分 类 号：R730.5[医药卫生—肿瘤]