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

IF 4.5 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Pharmaceutics Pub Date : 2025-02-10 DOI:10.1021/acs.molpharmaceut.4c01002

Shun Huang, Xiang Liang, Dazhi Shi, Xiaohui Chen, Shimin Ye, Xinran Liu, Yali Yang, Yijin Zou, Huiran Hu, Hubing Wu

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引用次数: 0

Abstract

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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来源期刊

Molecular Pharmaceutics 医学-药学

CiteScore

8.00

自引率

6.10%

发文量

391

审稿时长

2 months

期刊介绍： Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.