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

[Display omitted] •Triazole staple introduced in HER2 targeting A9 peptide by ‘click’ reaction.•Molecular docking & circular dichroism studies performed for linear and c[Tz] peptide.•177Lu-labeled c[Tz] peptide demonstrated higher in vitro and in vivo stability.•Cellular experiments established higher HER2-affinity of 177Lu-c[Tz] peptide.•High tumor activity and retention displayed by 177Lu-c[Tz] peptide. 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 {Kd of 16.93 ± 3.02 nM} than the linear counterpart, [177Lu]DOTA-[Pra1, Aza7]A9 {Kd 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.