Department of Nuclear Medicine, Peking University First Hospital, Beijing 100034, China.
Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, Beijing 100034, China.
Mol Pharm. 2024 May 6;21(5):2544-2554. doi: 10.1021/acs.molpharmaceut.4c00084. Epub 2024 Apr 8.
Vascular endothelial growth factor (VEGF) targeted therapy serves as an important therapeutic approach for renal cancer, but its clinical effectiveness is unsatisfactory. Moreover, there is a lack of reliable biomarkers for preoperative assessment of tumor VEGF expression. This study aimed to explore the potential for further applications of Lu/Zr-labeled aflibercept (Abe), a VEGF-binding agent, in imaging visualization of VEGF expression and therapy for renal cancer. To determine specificity uptake in renal cancer, BALB/c mice with VEGF-expressing Renca tumor were intravenously injected with [Zr]Zr-Abe, [Lu]Lu-Abe, or Cy5.5-Abe and the blocking group was designed as a control group. PET, SPECT, and fluorescence images were acquired, and the biodistribution of [Zr]Zr-Abe and [Lu]Lu-Abe was performed. Additionally, the [Lu]Lu-Abe, [Lu]Lu-Abe-block, Lu only, Abe only, and PBS groups were compared for evaluation of the therapeutic effect. To assess the safety, we monitored and evaluated the body weight, blood biochemistry analysis, and whole blood analysis and major organs were stained with hematoxylin and eosin after [Lu]Lu-Abe treatment. DOTA-Abe was successfully labeled with Lu and Df-Abe with Zr in our study. The uptake in tumor of [Zr]Zr-Abe was significantly higher than that of [Zr]Zr-Abe-block ( < 0.05) and provided excellent tumor contrast in PET images. [Lu]Lu-Abe demonstrated promising tumor-specific targeting capability with a high and persistent tumor uptake. The standardized tumor volume of [Lu]Lu-Abe was significantly smaller than those of other treatment groups ( < 0.05). [Lu]Lu-Abe also had smaller tumor volumes and reduced expression of VEGF and CD31 compared to those of the control groups. Fluorescence images demonstrate higher tumor uptake in the Cy5.5-Abe group compared to the Cy5.5-Abe-block group ( < 0.05). In conclusion, [Zr]Zr-Abe enables noninvasive analysis of VEGF expression, serving as a valuable tool for assessing the VEGF-targeted therapy effect. Additionally, all of the findings support the enhanced therapeutic efficacy and safety of [Lu]Lu-Abe, making it a viable option for clinical practice in renal cancer.
血管内皮生长因子（VEGF）靶向治疗是治疗肾癌的重要方法，但临床疗效并不理想。此外，术前评估肿瘤 VEGF 表达缺乏可靠的生物标志物。本研究旨在探讨 Lu/Zr 标记的 VEGF 结合剂 aflibercept（Abe）在肾癌 VEGF 表达成像可视化和治疗中的进一步应用潜力。为了确定在肾癌中的特异性摄取，将 VEGF 表达的 Renca 肿瘤的 BALB/c 小鼠静脉注射[Zr]Zr-Abe、[Lu]Lu-Abe 或 Cy5.5-Abe，并设计阻断组作为对照组。获取 PET、SPECT 和荧光图像，并进行[Zr]Zr-Abe 和[Lu]Lu-Abe 的生物分布。此外，还比较了[Lu]Lu-Abe、[Lu]Lu-Abe 阻断剂、Lu 仅、Abe 仅和 PBS 组，以评估治疗效果。为了评估安全性，我们在[Lu]Lu-Abe 治疗后监测和评估了体重、血液生化分析和全血分析，并对主要器官进行了苏木精和伊红染色。本研究成功地用 Lu 标记了 DOTA-Abe，用 Zr 标记了 Df-Abe。[Zr]Zr-Abe 在肿瘤中的摄取明显高于[Zr]Zr-Abe 阻断剂（<0.05），并在 PET 图像中提供了出色的肿瘤对比。[Lu]Lu-Abe 具有良好的肿瘤特异性靶向能力，具有高且持久的肿瘤摄取。[Lu]Lu-Abe 的标准化肿瘤体积明显小于其他治疗组（<0.05）。与对照组相比，[Lu]Lu-Abe 的肿瘤体积更小，VEGF 和 CD31 的表达也降低。荧光图像显示 Cy5.5-Abe 组的肿瘤摄取明显高于 Cy5.5-Abe 阻断剂组（<0.05）。总之，[Zr]Zr-Abe 可实现 VEGF 表达的非侵入性分析，是评估 VEGF 靶向治疗效果的有价值工具。此外，所有发现都支持[Lu]Lu-Abe 增强的治疗效果和安全性，使其成为肾癌临床实践的可行选择。
