PO.ET08.02 · 实验与分子治疗
一种新型NTSR1靶向诊断放射性配体SKL35502用于无创实体瘤成像
A novel NTSR1-targeting diagnostic radioligand SKL35502 for noninvasive solid tumor imaging
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：神经降压素受体1（NTSR1）在多种侵袭性恶性肿瘤中高表达，包括胰腺导管腺癌、结直肠癌、食管癌、胃癌、胆道癌和头颈部鳞状细胞癌。鉴于其在肿瘤进展中的作用，NTSR1代表了分子成像以及为NTSR1导向放射性核素治疗筛选患者的一个引人注目的靶点。SKL35502是一种111In标记的小分子NTSR1配体，开发用于实现对NTSR1阳性肿瘤的敏感和选择性可视化。本研究评估了SKL35502的临床前药理学、生物分布和成像性能。
方法：使用基于细胞的饱和结合实验测定SKL35502的结合亲和力。在HCT116人结直肠癌细胞中评估时间依赖性摄取和内化。在荷HCT116或AsPC-1异种移植瘤的雌性小鼠中，通过SPECT/CT成像评估体内生物分布长达注射后168小时，并在HCT116异种移植模型中确认离体生物分布和排泄长达48小时。在给药后8、24、48、72和96小时收集尿液和粪便。
结果：SKL35502对HCT116细胞表现出高结合亲和力（KD = 0.37 nM）。细胞摄取呈时间依赖性且NTSR1特异性，在90分钟时达到31.5%，在240分钟时保持在30.5%。在两个时间点，内化均约占总摄取的56%。体内SPECT/CT成像显示初始广泛分布，随后从非靶器官（心脏、肝脏、肾脏）快速清除。肿瘤摄取在注射后4小时达到峰值，并持续至168小时。离体生物分布证实了强烈的肿瘤富集（8小时时44 %ID/g），肿瘤暴露（AUC）约为血液的22倍。到给药后96小时（4天），排泄的总放射活性为给药剂量的84.12%。
结论：SKL35502在表达NTSR1的肿瘤细胞中表现出高亲和力和特异性摄取，同时具有快速的全身清除，最大限度地减少了对健康组织的非特异性辐射暴露。这些特性支持其作为一种高度敏感和选择性的成像剂的潜力，用于检测NTSR1阳性肿瘤并指导NTSR1靶向诊疗一体化方法中的患者筛选。
查看英文原文 English abstract
Background: Neurotensin receptor 1 (NTSR1) is highly expressed in several aggressive malignancies, including pancreatic ductal adenocarcinoma, colorectal cancer, esophageal cancer, gastric cancer, biliary tract cancer, and head and neck squamous cell carcinoma. Given its role in tumor progression, NTSR1 represents a compelling target for molecular imaging and for selecting patients for NTSR1-directed radionuclide therapy. SKL35502, an 111 In-labeled small-molecule NTSR1 ligand, was developed to enable sensitive and selective visualization of NTSR1-positive tumors. This study evaluates the preclinical pharmacology, biodistribution, and imaging performance of SKL35502.
Methods: The binding affinity of SKL35502 was determined using a cell-based saturation binding assay. Time-dependent uptake and internalization were assessed in HCT116 human colorectal carcinoma cells. In vivo biodistribution was evaluated in female mice bearing HCT116 or AsPC-1 xenografts by SPECT/CT imaging up to 168 hours post-injection, and ex vivo biodistribution and excretion were confirmed in HCT116 xenograft models up to 48 hours. Urine and feces were collected at 8, 24, 48, 72 and 96 hours post-dose.
Results: SKL35502 exhibited high binding affinity to HCT116 cells (KD = 0.37 nM). Cellular uptake was time-dependent and NTSR1-specific, reaching 31.5% at 90 minutes and remaining at 30.5% at 240 minutes. Internalization accounted for approximately 56% of total uptake at both time points.
In vivo SPECT/CT imaging revealed an initial widespread distribution followed by rapid clearance from non-target organs (heart, liver, kidney). Tumor uptake peaked at 4 hours post-injection and persisted through 168 hours. Ex vivo biodistribution confirmed strong tumor enrichment (44 %ID/g at 8 hours), with tumor exposure (AUC) approximately 22-fold higher than blood. By 96 hours (4 days) post-dose, the total excreted radioactivity was 84.12% of the administered dose
Conclusions: SKL35502 demonstrates high affinity and specific uptake in NTSR1-expressing tumor cells, together with rapid systemic clearance that minimizes nonspecific radiation exposure to healthy tissues. These properties support its potential as a highly sensitive and selective imaging agent for detecting NTSR1-positive tumors and guiding patient selection in NTSR1-targeted theranostic approaches.
利益披露 Disclosure
J. Na, None..
T. Lee, None..
S. Jeon, None..
H. Lee, None..
S. Lee, None..
S. Hwang, None..
J. Park, None.