Translational Potential of a Contrast Agent for FGS Applications in pNETs.
Translational Potential of a Contrast Agent for FGS Applications in pNETs.
复制标题
对比剂在 pNET 中 FGS 应用的转化潜力。
DOI：
10.1007/s11307-024-01894-1
复制
发表时间：
2024
影响因子：
3.1
通讯作者：
Ikoma,Naruhiko
中科院分区：
文献类型：
--
作者：
AghaAmiri,Solmaz;Estrella,JeannelynS;Vargas,ServandoHernandez;Hurd,MarkW;Ghosh,SukhenC;Azhdarinia,Ali;Ikoma,Naruhiko
肿瘤手术期间对准确肿瘤检测的迫切需求导致了针对癌组织的荧光造影剂的开发。这种技术被称为荧光引导手术 (FGS)，通常涉及全身施用含有肿瘤靶向部分的荧光化合物，并在近红外光谱范围内成像，以最大限度地提高图像对比度和诊断准确性 [1]。 2021 年，叶酸类似物 OTL-38 (CYTALUX®) 成为第一个临床批准的 FGS 药物，通过主动的受体介导过程靶向肿瘤。正如一项随机 3 期研究所示，与标准护理方法相比，FGS 可以更有效地识别接受细胞减灭术的卵巢癌患者的病变[2]。这项具有里程碑意义的研究结果不仅证明了 FGS 在卵巢癌患者中的价值，而且为将新兴 FGS 药物应用于其他癌症奠定了重要的转化先例。胰腺神经内分泌肿瘤 (pNET) 是一种癌症，分子驱动的 FGS 可以显着改善手术结果。术中准确定位原发性和转移性 pNET 具有挑战性，特别是对于小型多灶性病变，并导致 15-45% 的病例切除不完全 [3]。此外，不必要的扩大切除可能导致随后的胰腺功能不全：约 40% 接受 pNET 切除的患者会出现新发糖尿病形式的内分泌功能不全 [4, 5]，20-30% 会出现外分泌功能不全和消化受损 [5, 6]。鉴于pNET患者的预期寿命较长，保留胰腺功能和完全切除病灶至关重要[7]，因此，术中准确的肿瘤定位至关重要。鉴于绝大多数pNET中生长抑素受体亚型2（SSTR2）的过表达，我们选择了临床批准的SSTR2靶向放射性药物68Ga-DOTA-TOC作为开发荧光对应物的基础，并生产了第一代药物，该药物显示出SSTR2 介导的癌细胞和多种体内肿瘤模型中的靶向[8]。为了进一步提高图像对比度，我们开发了优化的第二代试剂 MMC (FNIR-Tag)-TOC，其中包含电荷平衡荧光团（FNIR-Tag，λabs= 772 和 λem= 788 nm）。对翻译相关肿瘤模型的评估表明，与我们的初始药物相比，MMC (FNIR-Tag)-TOC 具有优异的靶向特异性和药代动力学，这导致肿瘤和正常组织之间的对比度明显更高[9]。因此，我们确定 MMC (FNIR-Tag)-TOC 作为临床开发的先导化合物。
The critical need for accurate tumor detection during oncologic surgery has led to the development of fluorescent contrast agents that target cancerous tissues. This technique, known as fluorescence-guided surgery (FGS), typically involves systemic administration of a fluorescent compound that contains a tumor-targeting moiety and is imaged in the near-infrared spectral range in order to maximize image contrast and diagnostic accuracy [1]. In 2021, the folic acid analog OTL-38 (CYTALUX®) became the first clinically approved FGS agent to target tumors via an active, receptor-mediated process. As shown in a randomized phase 3 study, lesions in ovarian cancer patients undergoing cytoreductive surgery were more effectively identified with FGS than with standardof-care methods [2]. Findings from this landmark study not only demonstrated the value of FGS in ovarian cancer patients but also set an important translational precedent for applying emerging FGS agents to other cancers. Pancreatic neuroendocrine tumors (pNETs) are a type of cancer where molecularly driven FGS could significantly improve surgical outcomes. Accurate intraoperative localization of primary and metastatic pNETs is challenging, particularly for small, multifocal lesions, and leads to incomplete resection in 15–45% of cases [3]. Also, unnecessarily extended resections can cause subsequent pancreatic insufficiency: about 40% of patients who undergo pNET resection experience endocrine insufficiency in the form of de novo diabetes [4, 5], and 20–30% develop exocrine insufficiency and impaired digestion [5, 6]. Given the long life expectancy of pNET patients, preservation of pancreatic function and complete resection of lesions are of paramount importance [7], thus, accurate intraoperative tumor localization is critical.Given the overexpression of somatostatin receptor subtype-2 (SSTR2) in the vast majority of pNETs, we selected the clinically approved SSTR2-targeted radiopharmaceutical 68Ga-DOTA-TOC as a foundation for developing a fluorescent counterpart and produced a first-generation agent that showed SSTR2-mediated targeting in cancer cells and multiple in vivo tumor models [8]. To further increase image contrast, we developed an optimized second-generation agent, MMC (FNIR-Tag)-TOC, that contains a charge-balanced fluorophore (FNIR-Tag, λabs= 772 and λem= 788 nm). Evaluation in translationally relevant tumor models revealed that MMC (FNIR-Tag)-TOC has superior targeting specificity and pharmacokinetics compared to our initial agent, which resulted in markedly higher contrast between tumor and normal tissue [9]. Accordingly, we identified MMC (FNIR-Tag)-TOC as the lead compound for clinical development.