A Pretargeted Imaging Strategy for EGFR-Positive Colorectal Carcinoma via Modulation of Tz-Radioligand Pharmacokinetics
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RESEARCH ARTICLE
A Pretargeted Imaging Strategy for EGFR-Positive Colorectal Carcinoma via Modulation of Tz-Radioligand Pharmacokinetics Lin Qiu,1,2,3 Qingyu Lin,1 Zhan Si,1 Hui Tan,1 Guobing Liu,1 Jun Zhou,1 Tingting Wang,1 Yue Chen,2,3 Yingzhao Huang,4 Tao Yu,4 Mingzhi Jin,5 Dengfeng Cheng,1 Hongcheng Shi 1 1
Department of Nuclear Medicine, Zhongshan Hospital Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, China Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China 3 Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, China 4 WuXi AppTec, Shanghai, China 5 WuXi Biologics (Shanghai) Co., Ltd, Shanghai, China 2
Abstract Purpose: Previously, we successfully developed a pretargeted imaging strategy (atezolizumabTCO/[99mTc]HYNIC-PEG11-Tz) for evaluating programmed cell death ligand-1 (PD-L1) expression in xenograft mice. However, the surplus unclicked [99mTc]HYNIC-PEG11-Tz is cleared somewhat sluggishly through the intestines, which is not ideal for colorectal cancer (CRC) imaging. To shift the excretion of the Tz-radioligand to the renal system, we developed a novel Tz-radioligand by adding a polypeptide linker between HYNIC and PEG11. Procedures: Pretargeted molecular probes [ 99m Tc]HYNIC-polypeptide-PEG 11 -Tz and cetuximab-TCO were synthesized. [99mTc]HYNIC-polypeptide-PEG11-Tz was evaluated for in vitro stability and in vivo blood pharmacokinetics. In vitro ligation reactivity of [99mTc]HYNICpolypeptide-PEG11-Tz towards cetuximab-TCO was also tested. Biodistribution assay and imaging of [99mTc]HYNIC-polypeptide-PEG11-Tz were performed to observe its excretion pathway. Pretargeted biodistribution was measured at three different accumulation intervals to determine the optimal pretargeted interval time. Pretargeted (cetuximab-TCO 48 h/ [99mTc]HYNIC-PEG11-Tz 6 h) and (cetuximab-TCO 48 h/[99mTc]HYNIC-Polypeptide-PEG11-Tz 6 h) imagings were compared to examine the effect of the excretion pathway on tumor imaging. Results: [99mTc]HYNIC-polypeptide-PEG11-Tz showed favorable in vitro stability and rapid blood clearance in mice. SEC-HPLC revealed almost complete reaction between cetuximab-TCO and [99mTc]HYNIC-polypeptide-PEG11-Tz in vitro, with the 8:1 Tz-to-mAb reaction providing a conversion yield of 87.83 ± 3.27 %. Biodistribution and imaging analyses showed that the Tzradioligand was cleared through the kidneys. After 24, 48, and 72 h of accumulation in HCT116 tumor, the tumor-to-blood ratio of cetuximab-TCO was 0.83 ± 0.13, 1.40 ± 0.31, and 1.15 ± 0.21, respectively. Both pretargeted (cetuximab-TCO 48 h/[99mTc]HYNIC-PEG11-Tz 6 h) and
Electronic supplementary material The online version of this article (https:// doi.org/10.1007/s11307-020-01539-z) contains supplementary material, which is available to authorized users. Correspondence to: Dengfeng Cheng; e-mail: [email protected], Hongcheng Shi; e-mail: [email protected]
Qiu L. et al.: Pretargeted Imaging for EGFR-Posit
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