A FAP‐Targeted SMDC Platform Enables Synergistic Radionuclide–Chemotherapy with PET‐Guided Evaluation

Fibroblast activation protein (FAP) is an attractive stromal target for cancer theranostics; however, developing agents that enable non-invasive pharmacokinetic visualization while achieving effective combined radio-chemotherapy remains challenging. Here we report an imaging-enabled FAP-targeted small molecule-drug conjugate (SMDC) platform that supports PET-based pharmacokinetic visualization and synergistic radionuclide-chemotherapy using matched radiolabeled constructs. In this system, ⁶⁸Ga-labeled SMDCs enable positron emission tomography (PET) imaging to visualize in vivo biodistribution, whereas the corresponding ¹⁷⁷Lu-labeled analogues deliver combined radionuclide and cytotoxic therapy. By systematically comparing VC and GP cleavable linkers in DOTA-containing MMAE conjugates, we establish a linker-dependent structure-stability-efficacy relationship. FAPI-46-based constructs retained nanomolar FAP affinity and enabled efficient enzyme-triggered payload release while maintaining selective tumor accumulation in vivo as visualized by ⁶⁸Ga-PET. Therapeutic studies using ¹⁷⁷Lu-labeled conjugates produced pronounced tumor suppression (92-93% inhibition), outperforming either modality alone. Notably, the VC-linked construct showed improved tolerability relative to the GP analogue. These findings establish an imaging-guided strategy for optimizing FAP-targeted radiochemotherapeutics and identify FAP-O-VC-MMAE as a promising candidate for further translational development.