[64Cu]Cu(DDC)2 NPs: A Novel PET Probe for Noninvasive Visualization of NPL4 Expression in Tumors In Vivo

体内 可视化 化学 纳米技术 癌症研究 放射化学 材料科学 计算机科学 医学 生物 遗传学 数据挖掘
作者
Shun Huang,Liang Xiang,Dazhi Shi,Xiaohui Chen,Shimin Ye,Xinran Liu,Yali Yang,Yijin Zou,Huiran Hu,Hubing Wu
出处
期刊:Molecular Pharmaceutics [American Chemical Society]
标识
DOI:10.1021/acs.molpharmaceut.4c01002
摘要

Nuclear protein localization 4 (NPL4) plays a key role in the ubiquitination pathway and has emerged as a promising target for cancer therapy. The ditiocarb-copper complex, Cu(DDC)2, an anticancer metabolite derived from the antialcoholism drug disulfiram (DSF), exhibits a high affinity for NPL4. Thus, quantifying NPL4 expression in tumors is crucial for ubiquitination research and for developing NPL4-targeted diagnostic and therapeutic strategies. In this study, we replaced the cold copper ion in Cu(DDC)2 with the positron-emitting isotope copper-64 and developed three methods for visualizing NPL4 in tumors in vivo using positron emission tomography/computed tomography (PET/CT): (1) an in vivo "synthesis-free" method for preparing [64Cu]Cu(DDC)2, (2) an in vitro synthesis method, and (3) a stabilization method using PEG5000-PLA5000 (PP) to enhance [64Cu]Cu(DDC)2's hydrophilicity by preparing [64Cu]Cu(DDC)2 NPs. Micro-PET/CT imaging showed minimal uptake of [64Cu]Cu(DDC)2 in NPL4-positive tumors with the in vivo "synthesis-free" method, resulting in poor lesion visualization. However, in vitro synthesized [64Cu]Cu(DDC)2 and [64Cu]Cu(DDC)2 NPs successfully visualized NPL4-positive U87MG tumors. Compared to [64Cu]Cu(DDC)2, [64Cu]Cu(DDC)2NPs demonstrated significantly higher tumor uptake (7.2 ± 0.7% ID/g vs 3.8 ± 0.6% ID/g at 12 h postinjection, P = 0.001) and tumor-to-muscle (T/M) ratio (7.8 ± 1.2 vs. 3.2 ± 0.7, P = 0.001). Tumor uptake of [64Cu] Cu (DDC)2NPs was consistent with NPL4 expression levels and was inhibited by an excess of Cu(DDC)2. The optimal PP stabilizer concentration was determined to be 0.0005%. This study successfully developed a PET probe, [64Cu]Cu(DDC)2NPs, and established a novel imaging modality for in vivo visualization of NPL4 expression, potentially guiding future NPL4-targeted therapies.
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