Radiopharmaceuticals for Melanoma Theranostics.

Abstract

Malignant melanoma (MM) remains a formidable clinical challenge due to its high metastatic potential and the eventual emergence of resistance to current BRAF/MEK and immune checkpoint inhibitors. To address these limitations, the theranostic strategy integrating diagnostic imaging with targeted radionuclide therapy to enable personalized treatment has gained significant traction. Current research primarily exploits the overexpression of the melanocortin 1 receptor (MC1R), very late antigen-4 (VLA-4), and melanin as primary molecular targets for radiopharmaceutical development. For MC1R, α-MSH peptide analogs have been engineered with β-emitters such as ¹⁷⁷Lu and ⁹⁰Y for peptide receptor radionuclide therapy (PRRT), as well as α-emitters like ²²⁵Ac and ²¹²Pb (β- decay to ²¹²Bi and then emit α particles) for targeted alpha therapy (TAT), showing high specificity and rapid clearance. Concurrently, VLA-4-targeted platforms utilizing high-affinity LLP2A ligands have been optimized through PEGylation and albumin-binding strategies to enhance bioavailability and tumor retention. Beyond these primary receptors, this review evaluates alternative strategies, including copper transporter (CTR1) targeting with ⁶⁴CuCl₂ and the use of gold nanocages for multimodal applications. Together, these advancements represent a critical shift toward image-guided, dosimetry-driven radionuclide therapies that may work synergistically with existing immunotherapies to improve survival in metastatic melanoma.