Preclinical Evaluation of a Dual Sstr2 and Integrin αβ-targeted Heterodimer [Ga]-NOTA-3PEG-TATE-RGD

Purpose: Multiple receptors are co-expressed in many types of cancers. Octreotate (TATE) and Arg-Gly-Asp (RGD) peptides target somatostatin receptor 2 (sstr2) and integrin αβ, respectively. We developed and synthesized a heterodimer NOTA-3PEG-TATE-RGD (3PTATE-RGD) and aimed to investigate its characteristics for dual-targeting sstr2 and integrin αβ.

Methods: TATE and RGD peptides and 1,4,7-triazacylononane-N',N'',N'''-triacetic acid (NOTA) were linked through a glutamate and polyethylene glycol (PEG) linker, then 3PTATE-RGD was labeled with Ga ion. Receptor-binding characteristics and tumor-targeting efficacy were tested in vitro and in vivo using H69 and A549 lung cancer cell lines and tumor-bearing mice models.

Results: [Ga]-3PTATE-RGD had comparable sstr2 and integrin αβ-binding affinity with monomeric TATE and RGD in cell uptake and PET imaging study, respectively. In the competition study, H69 and A549 tumor uptake of [Ga]-3PTATE-RGD was completed inhibited in the presence of an excess amount of unlabeled TATE or RGD, respectively. The blocked level didn't grow when both of TATE and RGD mixture was co-injected with [Ga]-3PTATE-RGD. The pharmacokinetics of [Ga]-3PTATE-RGD is comparable with [Ga]-TATE and [Ga]-RGD, resulting in a larger application.

Conclusion: [Ga]-3PTATE-RGD showed improved and wider tumor-targeting efficacy compared with monomeric TATE and RGD peptides, which warrants its further investigation in detection both of sstr2 and integrin αβ-related carcinomas.