177Lu-Labeled Heterodimeric Agent with High Stability Targeting Neovascularization for Tumor Radioligand Therapy

Radiopharmaceutical theranostics holds significant promise in tumor diagnosis and treatment, but suboptimal tumor uptake and retention remain a persistent limitation. We have conjugated a unique albumin binder to our previously developed heterodimeric precursor HX01 and achieved a novel precursor L6, aiming to prolong circulation time and enhance tumor accumulation and retention. However, we observed that the NGR sequence of L6 was gradually rearranged to iso-DGR under alkaline conditions, resulting in decreased stability. In this study, we further modified the L6 to synthesize XH02, subsequently assessing their in vitro and in vivo properties following radiolabeling. Utilizing positron emission tomography (PET)/computed tomography (CT) imaging, single-photon emission computed tomography (SPECT)/CT imaging, and biodistribution study in BxPC-3 xenograft mice, we observed striking accumulation and retention of radiopharmaceutical within tumors. Two cycles of administration of 177Lu-XH02 displayed exceptional tumor growth inhibition in BxPC-3 tumors while causing minimal side effects. This promising result underscores the immense potential of this agent for further clinical translation and investigation.