Ablation-Induced Collagen Exposure Enables Dual-Modal Nuclear Imaging–Guided Local Radionuclide Therapy

Percutaneous ethanol injection (PEI) is a first-line ablation therapy for hepatocellular carcinoma (HCC), while effective postoperative management remains challenging. Type I collagen in HCC stroma , linked to resistance and recurrence, is a promising target for imaging-guided theranostic. We developed a dual-modality tracer, [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTA-COL, designed to integrate noninvasive PET imaging with local radiotherapy by selectively targeting exposed type I collagen post-PEI. [⁶⁸Ga]Ga-DOTA-COL exhibited high radiochemical purity (> 99%), strong collagen affinity (IC₅₀ = 8.44 nM), and favorable in vivo PET imaging specificity. In a murine HCC model undergoing PEI, longitudinal PET/CT with [⁶⁸Ga]Ga-DOTA-COL and [¹⁸F]FDG, along with histology and immunohistochemistry, comprehensively assessed collagen remodeling, recurrence, and therapeutic response. PET/CT revealed pronounced [⁶⁸Ga]Ga-DOTA-COL accumulation during five days post-PEI, suggesting that PEI-induced exposure of type I collagen enabled a therapeutic window. Therapeutic [¹⁷⁷Lu]Lu-DOTA-COL administered within this period effectively suppressed tumor regrowth, as confirmed by SPECT and biodistribution, with selective uptake in collagen-exposed regions. PEI induced CD163⁺ M2-like macrophages infiltration, promoting an immunosuppressive microenvironment and recurrence, whereas [¹⁷⁷Lu]Lu-DOTA-COL reduced M2 macrophages, increased CD8⁺ and CD4⁺ T cell infiltration, and markedly suppressed Ki67 expression. These findings provide a rationale paradigm for improving postoperative management following PEI and other local ablation therapies.