Design and development of nanoprobes radiolabelled with 99mTc for the diagnosis and monitoring of therapeutic interventions in oncology preclinical research

IF 4.4 Q1 CHEMISTRY, INORGANIC & NUCLEAR EJNMMI Radiopharmacy and Chemistry Pub Date : 2024-10-29 DOI:10.1186/s41181-024-00300-z
María Jimena Salgueiro, Mariano Portillo, Fiorella Tesán, Melisa Nicoud, Vanina Medina, Marcela Moretton, Diego Chiappetta, Marcela Zubillaga
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Abstract

Background

Previous studies employing polymeric micelles and molecular imaging for in vivo nanosystem characterization have led to the development of radionanoprobes (RNPs) designed for diagnosing and monitoring therapeutic interventions in preclinical oncology research, specifically within breast and colon cancer models. These models exhibit high GLUT1 expression on tumor cells and VEGFR expression on the tumor vasculature. We aimed to enhance the tumor-targeting specificity of these RNPs by functionalizing micelles with glucose and bevacizumab. The choice of 99mTc to label the nanoprobes is based on its availability and that direct labeling method is a widespread strategy to prepare radiopharmaceuticals using cold reagents and a 99Mo/99mTc generator. Soluplus® is an attractive polymer for synthesizing micelles that also allows their functionalization. With all the above, the objective of this work was to design, develop and characterize nanoprobes based on polymeric micelles and radiolabeled with 99mTc for the characterization of biological processes associated to the diagnosis, prognosis and monitoring of animal models of breast and colon cancer in preclinical research using molecular images.

Results

Four RNPs ([99mTc]Tc-Soluplus®, [99mTc]Tc-Soluplus®+TPGS, [99mTc]Tc-Soluplus®+glucose and [99mTc]Tc-Soluplus®+bevacizumab) were produced with high radiochemical purity (> 95% in all cases) and stability in murine serum for up to 3 h. The RNPs maintained the 100 nm size of the Soluplus® polymeric micelles even when they were functionalized and labeled with 99mTc. The image acquisition protocol enabled the visualization of tumor uptake in two cancer experimental models using the assigned RNPs. In vivo biological characterization showed signal-to-background ratios of 1.7 ± 0.03 for [99mTc]Tc-Soluplus®+TPGS, 1.8 ± 0.02 for [99mTc]Tc-Soluplus®, and 2.3 ± 0.02 for [99mTc]Tc-Soluplus®+glucose in the breast cancer model, and 1.8 ± 0.04 for [99mTc]Tc-Soluplus® and 3.7 ± 0.07 for [99mTc]Tc-Soluplus®+bevacizumab in the colon cancer model. Ex vivo biodistribution, showed that the uptake of the tumors, regardless of the model, is < 2% IA/g while the blood activity concentration is higher, suggesting that the enhanced permeability and retention effect (EPR) would be one of the mechanisms involved in imaging tumors in addition to the active targeting of RNPs.

Conclusions

Soluplus®-based polymeric micelles provide a promising nanotechnological platform for the development of RNPs. The functionalization with glucose and bevacizumab enhances tumor specificity enabling effective imaging and monitoring of cancer in animal models.

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设计和开发使用 99mTc 放射性标记的纳米探针,用于诊断和监测肿瘤临床前研究中的治疗干预措施
背景以前的研究采用了聚合物胶束和分子成像技术进行体内纳米系统表征,从而开发出了放射性核素探针 (RNPs),专门用于诊断和监测临床前肿瘤学研究中的治疗干预措施,特别是在乳腺癌和结肠癌模型中。这些模型的肿瘤细胞中 GLUT1 高表达,肿瘤血管中 VEGFR 高表达。我们的目标是通过用葡萄糖和贝伐珠单抗对胶束进行功能化,增强这些 RNPs 的肿瘤靶向特异性。选择 99mTc 标记纳米探针是基于其可用性,而且直接标记法是使用冷试剂和 99Mo/99mTc 发生器制备放射性药物的广泛策略。Soluplus® 是一种极具吸引力的聚合物,可用于合成胶束,也可对胶束进行功能化。综上所述,这项工作的目的是设计、开发和鉴定基于聚合物胶束并用 99mTc 放射性标记的纳米探针,以便在临床前研究中利用分子图像鉴定与乳腺癌和结肠癌动物模型的诊断、预后和监测有关的生物过程。结果制备出四种 RNPs([99mTc]Tc-Soluplus®、[99mTc]Tc-Soluplus®+TPGS、[99mTc]Tc-Soluplus®+葡萄糖和[99mTc]Tc-Soluplus®+贝伐珠单抗),其放射化学纯度高(所有情况下均为 95%),在小鼠血清中的稳定性长达 3 小时。即使在用 99mTc 进行功能化和标记后,RNPs 仍能保持 Soluplus® 聚合物胶束 100 nm 的大小。通过图像采集协议,可在两种癌症实验模型中使用指定的 RNPs 观察肿瘤摄取情况。体内生物学特征显示,[99mTc]Tc-Soluplus®+TPGS 的信噪比为 1.7 ± 0.03,[99mTc]Tc-Soluplus® 为 1.8 ± 0.02,[99mTc]Tc-Soluplus® 为 2.3 ± 0.02。在乳腺癌模型中,[99mTc]Tc-Soluplus®+葡萄糖为1.8 ± 0.04,[99mTc]Tc-Soluplus®+贝伐单抗为3.7 ± 0.07。体内外生物分布显示,无论哪种模型,肿瘤的吸收率都是2% IA/g,而血液中的活性浓度更高,这表明除了RNPs的主动靶向作用外,增强的渗透性和滞留效应(EPR)也是肿瘤成像的机制之一。葡萄糖和贝伐珠单抗的功能化增强了肿瘤的特异性,可在动物模型中对癌症进行有效成像和监测。
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来源期刊
CiteScore
7.20
自引率
8.70%
发文量
30
审稿时长
5 weeks
期刊最新文献
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