Development of an orally-administrable tumor vasculature-targeting therapeutic using annexin A1-binding D-peptides

Abstract

We previously reported that IF7 peptide, which binds to the annexin A1 (ANXA1) N-terminus, functions as a tumor vasculature-targeted drug delivery vehicle after intravenous injection. To enhance IF7 stability in vivo, we undertook mirror-image peptide phage display using a synthetic D-peptide representing the ANXA1 N-terminus as target. We then identified peptide sequences, synthesized them as D-amino acids, and designated the resulting peptide dTIT7, which we showed bound to the ANXA1 N-terminus. Whole body imaging of mouse brain tumor models injected with near infrared fluorescent IRDye-conjugated dTIT7 showed fluorescent signals in brain and kidney. Furthermore, orally-administered dTIT7/geldanamycin (GA) conjugates suppressed brain tumor growth. Ours is a proof-of-concept experiment showing that ANXA1-binding D-peptide can be developed as an orally-administrable tumor vasculature-targeted therapeutic.

Annexin A1-Binding Carbohydrate Mimetic Peptide Targets Drugs to Brain Tumors

“…IF7-SN38 is, however, susceptible to esterases and proteases. To circumvent stability issues, we have developed an ANXA1-binding D-peptide, designated dTIT7 [39]. We have found that GA-dTIT7, in which geldanamycin is conjugated to dTIT7 through an esterase-resistant linker, is orally administrable and suppresses brain tumor growth in the mouse.…”