Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α(v)β(3)-Targeted Radionuclide Therapy

Peptide receptor radionuclide therapy (PRRT) is an emerging approach for patients with unresectable or metastatic tumors. Our previously optimized RGD peptide (3PRGD(2)) has excellent targeting specificity for a variety of integrin α(v)β(3)/α(v)β(5)-positive tumors and has been labeled with the therapeutic radionuclide [(177)Lu]LuCl(3) for targeted radiotherapy of tumors. However, the rapid clearance of [(177)Lu]Lu-DOTA-3PRGD(2) ((177)Lu-3PRGD(2)) 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 3PRGD(2) with albumin-binding palmitic acid (Palm-3PRGD(2)) and then radiolabeled Palm-3PRGD(2) with (177)Lu. [(177)Lu]Lu-DOTA-Palm-3PRGD(2) ((177)Lu-Palm-3PRGD(2)) retained a specific binding affinity for integrin α(v)β(3)/α(v)β(5), with an IC(50) value of 5.13 ± 1.16 nM. Compared with (177)Lu-3PRGD(2), the (177)Lu-Palm-3PRGD(2) 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, (177)Lu-Palm-3PRGD(2) shows great potential for clinical application.