Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.
Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
Mol Imaging Biol. 2023 Feb;25(1):110-121. doi: 10.1007/s11307-021-01656-3. Epub 2021 Oct 14.
The goal of fluorescence-guided surgery (FGS) in oncology is to improve the surgical therapeutic index by enhancing contrast between cancerous and healthy tissues. However, optimal discrimination between these tissues is complicated by the nonspecific uptake and retention of molecular targeted agents and the variance of fluorescence signal. Paired-agent imaging (PAI) employs co-administration of an untargeted imaging agent with a molecular targeted agent, providing a normalization factor to minimize nonspecific and varied signals. The resulting measured binding potential is quantitative and equivalent to in vivo immunohistochemistry of the target protein. This study demonstrates that PAI improves the accuracy of tumor-to-healthy tissue discrimination compared to single-agent imaging for in vivo FGS.
PAI using a fluorescent anti-epidermal growth factor receptor (EGFR) affibody molecule (ABY-029, eIND 122,681) with untargeted IRDye 700DX carboxylate was compared to ABY-029 alone in an oral squamous cell carcinoma xenograft mouse model at 3 h after dye administration (n = 30).
PAI significantly enhanced tumor discrimination, as compared to ABY-029 alone in low EGFR-expressing tumors and highly heterogeneous populations including multiple cell lines with varying expression (diagnostic accuracy: 0.908 vs. 0.854 and 0.908 vs. 0.822; and ROC curve AUC: 0.963 vs. 0.909 and 0.957 vs. 0.909, respectively) indicating a potential for universal FGS image thresholds to determine surgical margins. In addition, PAI achieved significantly higher diagnostic ability than ABY-029 alone 0.25-5-h post injection and exhibited a stronger correlation to EGFR expression heterogeneity.
The quantitative receptor delineation of PAI promises to improve the surgical therapeutic index of cancer resection in a clinically relevant timeline.
肿瘤荧光引导手术（FGS）的目标是通过增强癌组织与正常组织之间的对比度来提高手术治疗指数。然而，由于分子靶向剂的非特异性摄取和保留以及荧光信号的变化，使这些组织之间的最佳区分变得复杂。配对剂成像（PAI）采用未靶向成像剂与分子靶向剂共同给药，提供了一个标准化因子，以最小化非特异性和变化的信号。由此产生的测量结合势是定量的，相当于目标蛋白的体内免疫组织化学。这项研究表明，与单剂成像相比，PAI 提高了肿瘤与健康组织区分的准确性，从而提高了体内 FGS 的准确性。
在经染料给药后 3 小时（n = 30），在口腔鳞状细胞癌异种移植小鼠模型中，将使用荧光抗表皮生长因子受体（EGFR）亲和体分子（ABY-029，eIND 122,681）与未靶向的 IRDye 700DX 羧酸的 PAI 与 ABY-029 单独进行比较。
与 ABY-029 单独相比，PAI 显著增强了低 EGFR 表达肿瘤和高度异质性肿瘤的肿瘤区分能力，包括具有不同表达的多种细胞系（诊断准确性：0.908 对 0.854 和 0.908 对 0.822；ROC 曲线 AUC：0.963 对 0.909 和 0.957 对 0.909），表明有可能确定普遍的 FGS 图像阈值来确定手术边缘。此外，PAI 在注射后 0.25-5 小时比 ABY-029 单独具有更高的诊断能力，并且与 EGFR 表达异质性的相关性更强。
PAI 的定量受体描绘有望在临床相关时间范围内提高癌症切除的手术治疗指数。
