Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α_vβ₃-Targeted Radionuclide Therapy

Peptide receptor radionuclide therapy (PRRT) is an emerging approach for patients with unresectable or metastatic tumors. Our previously optimized RGD peptide (3PRGD₂) has excellent targeting specificity for a variety of integrin α_vβ₃/α_vβ₅-positive tumors and has been labeled with the therapeutic radionuclide [¹⁷⁷Lu]LuCl₃ for targeted radiotherapy of tumors. However, the rapid clearance of [¹⁷⁷Lu]Lu-DOTA-3PRGD₂ (¹⁷⁷Lu-3PRGD₂) in vivo requires two doses of 111 MBq/3 mCi to achieve effective tumor suppression, limiting its further clinical application. Albumin binders have been attached to drugs to facilitate binding to albumin in vivo to prolong the drug half-life in plasma and obtain long-term effects. In this study, we modified 3PRGD₂ with albumin-binding palmitic acid (Palm-3PRGD₂) and then radiolabeled Palm-3PRGD₂ with ¹⁷⁷Lu. [¹⁷⁷Lu]Lu-DOTA-Palm-3PRGD₂ (¹⁷⁷Lu-Palm-3PRGD₂) retained a specific binding affinity for integrin α_vβ₃/α_vβ₅, with an IC₅₀ value of 5.13 ± 1.16 nM. Compared with ¹⁷⁷Lu-3PRGD₂, the ¹⁷⁷Lu-Palm-3PRGD₂ circulation time in blood was more than 6 times longer (slow half-life: 73.42 min versus 11.81 min), and the tumor uptake increased more than fivefold (21.34 ± 4.65 %IA/g and 4.11 ± 0.70 %IA/g at 12 h post-injection). Thus, the significant increase in tumor uptake and tumor retention resulted in enhanced efficacy of targeted radiotherapy, and tumor growth was completely inhibited by a single and relatively lowdose of 18.5 MBq/0.5 mCi. Thus, ¹⁷⁷Lu-Palm-3PRGD₂ shows great potential for clinical application.