Design, radiolabeling, and biological evaluation of a novel 177Lu-AAZTA5-Carfilzomib conjugate as a proteasome-targeted theranostic agent for multiple myeloma.

The development of proteasome-targeted radiopharmaceuticals represents a promising strategy for the treatment of multiple myeloma. In this work, a novel Carfilzomib-based radioconjugate was designed through conjugation with the hybrid chelator AAZTA5 and subsequently radiolabeled with Lutetium-177. The conjugate was labeled efficiently under mild conditions with high radiochemical yield and exhibited excellent in vitro stability in both phosphate-buffered saline and serum. Biological evaluation using myeloma cell lines demonstrated a pronounced cytotoxic effect of the 177Lu-AAZTA5-Carfilzomib conjugate compared with the free drug and radionuclide alone, as confirmed by MTT cell viability assays and β2-microglobulin analysis. Molecular docking studies using the proteasome crystal structure (PDB ID: 4R67) revealed strong binding interactions within the catalytic pocket, with a binding affinity of -8.1 kcal/mol. Biodistribution studies in Ehrlich tumor-bearing mice showed significant tumor uptake (6.8%ID/g at 2 h p.i.) with rapid clearance from blood and normal tissues. These findings highlight the potential of 177Lu-AAZTA5-Carfilzomib as a promising proteasome-targeted theranostic candidate for multiple myeloma.