Targeting HER2-receptors with ¹⁷⁷Lu-labeled triazole stapled cyclic peptidomimetic

In this study on-resin Cu(I)-catalyzed click reaction was performed to synthesize triazole-stapled cyclic peptidomimetic, DOTA-c[TZ]A9 targeting HER2 receptor expression in breast cancers. Spectroscopic (circular dichroism) and docking analysis provided evidence of enhanced helicity and secondary structure stabilization along with improved HER2 affinity in comparison to the corresponding linear peptide, DOTA-[Pra¹, Aza⁷]A9. ¹⁷⁷Lu-labeled cyclic peptide, ¹⁷⁷Lu-DOTA-c[TZ]A9 displayed higher in vitro serum stability and in vivo metabolic stability and better HER2 binding affinity {K_d of 16.93 ± 3.02 nM} than the linear counterpart, [¹⁷⁷Lu]DOTA-[Pra¹, Aza⁷]A9 {K_d of 26.28 ± 2.87 nM}. Biodistribution profile in SKBR3 tumor bearing SCID mice demonstrated elevated radioactivity levels and prolonged retention of cyclic peptide in the tumor compared to the linear peptide. Thus, solid phase click cyclization technique can be extended towards preparation of triazole-stapled peptides targeting different receptors with improved stability and efficacy.