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