Harnessing the Coordination Chemistry of 1,4,7‐Triazacyclononane for Biomimicry and Radiopharmaceutical Applications

Abstract

1,4,7‐Triazacyclononane (TACN)‐based mono‐ and poly‐nuclear metal complexes have found extensive use as biological mimics for understanding the structural and operational aspects of complex natural systems. Their coordination flexibility has also provided researchers access to a vast library of radiometal‐binding motifs that display excellent thermodynamic stability and kinetic inertness upon metal complexation. Synthetic modification of the TACN backbone has yielded ligands that can form metal complexes with coordination geometries well suited for these applications. In particular, Leone Spiccia's research has played a significant role in accelerating the progress in these two fields. With a focus on his contributions to the topics of biomimicry and radiopharmaceuticals, this Minireview uses relevant examples to put in perspective the utility of macrocyclic coordination chemistry for biological inorganic chemistry applications.

Active Targeting of Dendritic Polyglycerols for Diagnostic Cancer Imaging

“…Unlike these previous studies, considerable amounts of radioactivity were this time also found in the liver of the animals, resulting in a kidney‐to‐liver ratio of 1.7 ± 0.2 and 3.0 ± 0.6 for CTRL‐dPG and α‐EGFR‐dPG, respectively. Radiometal release from the chelator and transchelation could be one reason behind the observed liver accumulation, although the used chelator DMPTACN possesses excellent kinetic stability with Cu 2+ ions . Released radiocopper from an i.v.…”

“…[17] Dual-labeled dPGfunctionalized cyanine dyes for fluorescence imaging and sdAbs for targeting, respectively, were prepared in an one-pot reaction following a previously described protocol with some modifications (Scheme 1). [18] Small 2020, 16,1905013 Scheme 1. Synthesis of dual-labeled nanomaterials.…”

“…To differentiate between EGFR-specific and nonspecific cell binding and uptake, the EGFR-specific antibody cetuximab was used as a competitor. [14] The herein used sdAb 7C12 binds to EGFR epitopes overlapping with or in close proximity to cetuximab binding sites so Small 2020, 16,1905013 that an excess of the monoclonal antibody efficiently blocks its interaction the receptor. [28] Although the radiolabeled dPG conjugates show binding to EGFR-overexpressing A431 cells, they differ dramatically in the extent of cell association.…”

“…Radiometal release from the chelator and transchelation could be one reason behind the observed liver accumulation, although the used chelator DMPTACN possesses excellent kinetic stability with Cu 2+ ions. [16,29] Released radiocopper from an i.v. injected radiotracer is immediately taken up by serum proteins such as albumin and α2-macroglobulin that deliver the radiometal efficiently to the liver, a central organ of copper homeostasis.…”

“…[15] Both the dPG conjugates were also functionalized with a copper(II)-chelating ligand based on 1,4-bis-(2-pyridinylmethyl)-1,4,7-triazacyclononane (DMPTACN) to stably complex 64 Cu for positron emission tomography (PET) as well as with fluorescent dyes for confocal microscopy and optical imaging (OI). [16] The effect of multifunctionalization on surface charge, hydrodynamic diameter, and macrophage uptake of the dPGs was assessed. In vitro studies using confocal microscopy of EGFR-overexpressing tumor cells were conducted to assess their specific EGFR-mediated binding or uptake in buffer conditions and in the complex biological milieu.…”