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

Area of Science:

• Oncology
• Radiochemistry
• Molecular Imaging

Background:

• Fibroblast activation protein (FAP) is a key target in cancer stroma for theranostics.
• Developing agents for simultaneous pharmacokinetic visualization and combined radio-chemotherapy is challenging.

Purpose of the Study:

• To develop an imaging-enabled FAP-targeted small molecule-drug conjugate (SMDC) platform.
• To enable PET-based pharmacokinetic visualization and synergistic radionuclide-chemotherapy.

Main Methods:

• Utilized matched ⁶⁸Ga-labeled SMDCs for PET imaging and ¹⁷⁷Lu-labeled analogues for therapy.
• Systematically compared VC and GP cleavable linkers in DOTA-containing MMAE conjugates.
• Assessed FAPI-46-based constructs for FAP affinity, enzyme-triggered release, tumor accumulation, and therapeutic efficacy.

Main Results:

• FAPI-46 constructs demonstrated nanomolar FAP affinity and selective tumor accumulation via ⁶⁸Ga-PET.
• ¹⁷⁷Lu-labeled conjugates achieved significant tumor suppression (92-93% inhibition), exceeding single modalities.
• The VC-linked construct exhibited improved tolerability compared to the GP analogue.

Conclusions:

• Established a linker-dependent structure-stability-efficacy relationship for FAP-targeted SMDCs.
• Identified FAP-O-VC-MMAE as a promising candidate for further translational development.
• Demonstrated an effective imaging-guided strategy for optimizing FAP-targeted radiochemotherapeutics.