Imageological/Structural Study regarding the Improved Pharmacokinetics by Ga-68-Labeled PEGylated PSMA Multimer in Prostate Cancer

作者全名："Zhang, Huihui; Rao, Maohua; Zhao, Huayi; Ren, Jianli; Hao, Lan; Zhong, Meng; Chen, Yue; Yang, Xia; Feng, Yue; Yuan, Gengbiao"

作者地址："[Zhang, Huihui; Rao, Maohua; Zhao, Huayi; Yuan, Gengbiao] Chongqing Med Univ, Dept Nucl Med, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Ren, Jianli; Hao, Lan] Chongqing Med Univ, Chongqing Key Lab Ultrasound Mol Imaging, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Zhong, Meng] Southwest Med Univ, Dept Pharm, Affiliated Hosp, Luzhou 646600, Peoples R China; [Chen, Yue; Feng, Yue] Nucl Med & Mol Imaging Key Lab Sichuan Prov, Luzhou 646600, Peoples R China; [Yang, Xia] Acad Engn Phys, Inst Nucl Phys & Chem, Mianyang 621900, Peoples R China"

通信作者："Yuan, GB (通讯作者)，Chongqing Med Univ, Dept Nucl Med, Affiliated Hosp 2, Chongqing 400010, Peoples R China.; Feng, Y (通讯作者)，Nucl Med & Mol Imaging Key Lab Sichuan Prov, Luzhou 646600, Peoples R China."

来源：PHARMACEUTICALS

ESI学科分类：　

WOS号：WOS:000978659000001

JCR分区：Q1

影响因子：4.3

年份：2023

卷号：16

期号：4

开始页：　

结束页：　

文献类型：Article

关键词：PSMA; prostate cancer; PSMA dimer; molecular probe; PET imaging

摘要："PMSA (prostate-specific membrane antigen) is currently the most significant target for diagnosing and treating PCa (prostate cancer). Herein, we reported a series Ga-68/Lu-177-labeled multimer PSMA tracer conjugating with PEG chain, including [Ga-68]Ga-DOTA-(1P-PEG(4)), [Ga-68]Ga-DOTA-(2P-PEG(0)), [Ga-68]Ga-DOTA-(2P-PEG(4)), and [Ga-68]Ga/[Lu-177]Lu-DOTA-(2P-PEG(4))(2), which showed an advantage of a multivalent effect and PEGylation to achieve higher tumor accumulation and faster kidney clearance. To figure out how structural optimizations based on a PSMA multimer and PEGylation influence the probe's tumor-targeting ability, biodistribution, and metabolism, we examined PSMA molecular probes' affinities to PC-3 PIP (PSMA-highly-expressed PC-3 cell line), and conducted pharmacokinetics analysis, biodistribution detection, small animal PET/CT, and SPECT/CT imaging. The results showed that PEG(4) and PSMA dimer optimizations enhanced the probes' tumor-targeting ability in PC-3 PIP tumor-bearing mice models. Compared with the PSMA monomer, the PEGylated PSMA dimer reduced the elimination half-life in the blood and increased uptake in the tumor, and the biodistribution results were consistent with PET/CT imaging results. [Ga-68]Ga-DOTA-(2P-PEG(4))(2) exhibited higher tumor-to-organ ratios. When labeled by lutetium-177, relatively high accumulation of DOTA-(2P-PEG(4))(2) was still detected in PC-3 PIP tumor-bearing mice models after 48 h, indicating its prolonged tumor retention time. Given the superiority in imaging, simple synthetic processes, and structural stability, DOTA-(2P-PEG(4))(2) is expected to be a promising tumor-targeting diagnostic molecular probe in future clinical practice."

基金机构："Department of Nuclear Medicine at The Second Affiliated Hospital of Chongqing Medical University; National Natural Science Foundation of China (NSFC) [31630026, 81630047, 81873901]; Basic Research and Frontier Exploration of Chongqing Science and Technology Commission [cstc2018jcyjAX0747]; Open Project Program of Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province [HYX20001]"

基金资助正文："This research received no external funding. This work was supported by the Department of Nuclear Medicine at The Second Affiliated Hospital of Chongqing Medical University, The National Natural Science Foundation of China (NSFC) [Grant No. 31630026, 81630047 and 81873901], the Basic Research and Frontier Exploration of Chongqing Science and Technology Commission [Grant No. cstc2018jcyjAX0747], and an Open Project Program of Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province (HYX20001)."