Kondo Naoya, Kato Marika, Oshima Aoi, Hirano Fuko, Miyazaki Anna, Temma Takashi
Department of Biofunctional Analysis, Graduate School of Pharmaceutical Sciences, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan.
Division of Fundamental Technology Development, Near InfraRed Photo-ImmunoTherapy Institute, Kansai Medical University, 2-5-1 Shin-machi, Hirakata 573-1010, Osaka, Japan.
Pharmaceuticals (Basel). 2025 Apr 8;18(4):549. doi: 10.3390/ph18040549.
: Integrin αβ plays a crucial role in tumor angiogenesis and cancer progression, making it a key target for radiolabeled probes used in imaging and therapy. A previously developed probe, [I]bcRGD, exhibited high selectivity for αβ but limited tumor accumulation due to rapid blood clearance. This study aimed to address this issue through two strategies: (1) conjugating albumin-binding molecules to enhance systemic circulation and (2) dimerizing RGD peptides to improve binding affinity via multivalency effects. : Three [I]bcRGD derivatives were synthesized: [I]bcRGD (with palmitic acid), [I]bcRGD (with 4-(-iodophenyl)butyric acid), and [I]bcRGD (a dimeric bicyclic RGD peptide). Their physicochemical properties, αβ-selectivity, albumin-binding capacity, and biodistribution were assessed in vitro and in vivo using tumor-bearing mice. Tumor models included αβ-high U-87 MG and αβ-low A549 xenografts. : [I]bcRGD and [I]bcRGD exhibited prolonged blood retention (30-fold and 55-fold vs. [I]bcRGD, respectively) and increased tumor accumulation (3.9% ID/g and 3.6% ID/g at 2 h, respectively). Despite improved systemic circulation, tumor-to-blood ratios remained low (<1), indicating limited tumor retention. [I]bcRGD achieved significantly greater tumor accumulation (4.2% ID/g at 2 h) and favorable tumor-to-blood (22) and tumor-to-muscle (14) ratios, with a 5.4-fold higher uptake in U-87 MG tumors compared to A549 tumors. : Dimerization was more effective than albumin binding in enhancing bcRGD's tumor-targeting potential. The dimeric probe demonstrated improved tumor accumulation, favorable pharmacokinetics, and preserved integrin selectivity. These findings provide a foundation for further structural optimization of bicyclic RGD peptides for integrin αβ-targeted imaging and therapy applications.
整合素αβ在肿瘤血管生成和癌症进展中起着关键作用，使其成为用于成像和治疗的放射性标记探针的关键靶点。先前开发的探针[I]bcRGD对αβ具有高选择性，但由于血液清除迅速，肿瘤蓄积有限。本研究旨在通过两种策略解决这一问题：（1）结合白蛋白结合分子以增强全身循环；（2）使RGD肽二聚化以通过多价效应提高结合亲和力。：合成了三种[I]bcRGD衍生物：[I]bcRGD（含棕榈酸）、[I]bcRGD（含4-（-碘苯基）丁酸）和[I]bcRGD（一种二聚体双环RGD肽）。使用荷瘤小鼠在体外和体内评估了它们的物理化学性质、αβ选择性、白蛋白结合能力和生物分布。肿瘤模型包括αβ高表达的U-87 MG和αβ低表达的A549异种移植物。：[I]bcRGD和[I]bcRGD表现出延长的血液滞留时间（分别比[I]bcRGD长30倍和55倍）和增加的肿瘤蓄积（2小时时分别为3.9%ID/g和3.6%ID/g）。尽管全身循环有所改善，但肿瘤与血液的比率仍然很低（<1），表明肿瘤滞留有限。[I]bcRGD实现了显著更高的肿瘤蓄积（2小时时为4.2%ID/g）以及良好的肿瘤与血液（22）和肿瘤与肌肉（14）比率，在U-87 MG肿瘤中的摄取比A549肿瘤高5.4倍。：二聚化在增强bcRGD的肿瘤靶向潜力方面比白蛋白结合更有效。二聚体探针表现出改善的肿瘤蓄积、良好的药代动力学和保留的整合素选择性。这些发现为进一步对双环RGD肽进行结构优化以用于整合素αβ靶向成像和治疗应用奠定了基础。
