Biodistribution-Driven Discovery Identifies a Glycosidase-Cleavable Linker to Reprogram Radiotheranostics

Area of Science:

• Oncology
• Radiopharmaceutical Chemistry
• Molecular Imaging

Background:

• Radiopharmaceutical therapy (RPT) is standard for advanced prostate cancer and neuroendocrine tumors (NETs), but cures are limited by normal tissue toxicity.
• Enzyme-cleavable linkers offer a strategy to improve RPT's therapeutic index by targeting tumor-specific enzymes.

Purpose of the Study:

• To design, synthesize, and evaluate novel cleavable linkers for DOTA-TATE, an RPT agent.
• To assess the impact of cleavable linkers on tumor uptake, kidney retention, and therapeutic efficacy in preclinical models.

Main Methods:

• Synthesized a series of DOTA-TATE analogs with diverse cleavable linkers.
• Utilized 86Y-labeled agents for positron emission tomography (PET) imaging in murine neuroendocrine tumor models.
• Conducted in vitro and in vivo enzyme cleavage studies.
• Performed therapeutic efficacy studies using 225Ac-labeled agents.

Main Results:

• Two cleavable linkers, DOTA-MVK(ε)-TATE and DOTA-β-Gal-TATE, reduced kidney retention compared to DOTA-TATE.
• 86Y-DOTA-β-Gal-TATE showed enhanced tumor uptake and up to 10-fold improved tumor-to-kidney ratios.
• Both 225Ac-labeled cleavable agents demonstrated therapeutic efficacy with improved survival and reduced toxicity.
• 225Ac-DOTA-β-Gal-TATE exhibited notably lower nephrotoxicity.

Conclusions:

• Cleavable linker chemistry is a viable strategy to enhance RPT agent pharmacokinetics and reduce toxicity.
• DOTA-β-Gal-TATE represents a promising next-generation RPT agent with improved tumor targeting and safety profile.
• This approach holds potential for broader application in developing improved radiopharmaceutical therapies.