Development and Characterization of Novel FAP-Targeted Theranostic Pairs: A Bench-to-Bedside Study

Area of Science:

• Nuclear Medicine
• Oncology
• Radiopharmaceutical Chemistry

Background:

• Fibroblast activation protein (FAP) is a key target in cancer theranostics, but existing small-molecule inhibitors have short circulation times, leading to poor tumor uptake and efficacy.
• Rapid renal clearance of FAP inhibitors limits their diagnostic and therapeutic potential in nuclear medicine.

Purpose of the Study:

• To engineer novel peptides with improved pharmacokinetic properties for enhanced FAP-targeted cancer theranostics.
• To evaluate the diagnostic and therapeutic efficacy of new FAP-targeting peptides in preclinical cancer models.

Main Methods:

• Solid-phase peptide synthesis was used to create three peptides: FD1, FD2, and FD3, designed for differential circulation times.
• Peptide binding affinity to human and murine FAP was quantified using surface plasmon resonance.
• Radiolabeling with Gallium-68 (⁶⁸Ga) for PET imaging and Lutetium-177 (¹⁷⁷Lu) for therapy was performed.
• Diagnostic and therapeutic evaluations were conducted in tumor models with varying FAP expression levels.

Main Results:

• FD1, FD2, and FD3 peptides demonstrated high binding affinity to FAP.
• Radiolabeled FD2 and FD3 exhibited prolonged circulation, increased tumor uptake, and reduced kidney accumulation compared to FD1.
• [⁶⁸Ga]Ga-DOTA-FD1 enabled effective PET imaging of FAP dynamics, identifying primary and metastatic tumors.
• [¹⁷⁷Lu]Lu-DOTA-FD2 and [¹⁷⁷Lu]Lu-DOTA-FD3 showed significant therapeutic efficacy in FAP-overexpressing tumors, including pancreatic cancer models.

Conclusions:

• Engineered peptides FD2 and FD3 overcome the limitations of short circulation time associated with previous FAP inhibitors.
• [⁶⁸Ga]Ga-DOTA-FD1 serves as a valuable diagnostic agent for FAP imaging, while [¹⁷⁷Lu]Lu-DOTA-FD2 and [¹⁷⁷Lu]Lu-DOTA-FD3 are promising therapeutic agents for FAP-targeted radioligand therapy.