Radioiodinated Bicyclic RGD Peptide Derivatives for Enhanced Tumor Accumulation
<b>Background/Objectives</b>: Integrin α<sub>V</sub>β<sub>3</sub> 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, [<sup>125</sup&g...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-04-01
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| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/18/4/549 |
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| Summary: | <b>Background/Objectives</b>: Integrin α<sub>V</sub>β<sub>3</sub> 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, [<sup>125</sup>I]bcRGD, exhibited high selectivity for α<sub>V</sub>β<sub>3</sub> 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. <b>Methods</b>: Three [<sup>125</sup>I]bcRGD derivatives were synthesized: [<sup>125</sup>I]bcRGD<sub>pal</sub> (with palmitic acid), [<sup>125</sup>I]bcRGD<sub>iba</sub> (with 4-(<i>p</i>-iodophenyl)butyric acid), and [<sup>125</sup>I]bcRGD<sub>dimer</sub> (a dimeric bicyclic RGD peptide). Their physicochemical properties, α<sub>V</sub>β<sub>3</sub>-selectivity, albumin-binding capacity, and biodistribution were assessed in vitro and in vivo using tumor-bearing mice. Tumor models included α<sub>V</sub>β<sub>3</sub>-high U-87 MG and α<sub>V</sub>β<sub>3</sub>-low A549 xenografts. <b>Results</b>: [<sup>125</sup>I]bcRGD<sub>pal</sub> and [<sup>125</sup>I]bcRGD<sub>iba</sub> exhibited prolonged blood retention (30-fold and 55-fold vs. [<sup>125</sup>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. [<sup>125</sup>I]bcRGD<sub>dimer</sub> 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. <b>Conclusions</b>: 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 α<sub>V</sub>β<sub>3</sub>-targeted imaging and therapy applications. |
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| ISSN: | 1424-8247 |