Inorganic Chemistry Frontiers Blog

Advances in the coordination chemistry of multinuclear compounds have been exploited to drive the self-assembly of many new discrete metallo-supramolecular motifs. Due to the nature of the metal-ligand interactions, many of these systems have a dynamic character with reversible association and dissociation able to generate complex mixtures. Unveil such dynamic behaviours, it is a priority to fully understand, control and design their functional properties. Among metallo-supramolecular systems, lanthanide (Ln) based architectures attracts much attention due to their remarkable optical and magnetic properties. However, design and control of the final supramolecule is very challenging due to the inner nature of the 4f orbitals and consequent small ligand-field effects. There is, however, a steady variation of the effective ionic radius (EIR) across the series, the so called “lanthanide contraction”. Although the radii difference (ΔEIR) is quite small (ca. 0.20 Å between La³⁺ and Lu³⁺ and ca. 0.02 Å between two consecutive lanthanides), it can have important chemical consequences on the nature and features of supramolecular complexes.

Recently, a group headed by Marzio Rancan of ICMATE-CNR (Italy) and collaborators from the University of Padova (Italy) and Dortmund University (Germany) have demonstrated that ΔEIR strongly affects the kinetics of Ln ions exchange between preassembled quadruple-stranded [Ln₂L₄]^2– cages (Figure 1).

The process has been qualitatively and quantitatively characterized by time-dependent electrospray ionization mass spectrometry (ESI-MS). Mixing a series of two homonuclear [Ln^A₂L₄]²⁻ and [Ln^B₂L₄]²⁻ with increasing Ln³⁺ ΔEIR always leads to the formation of a statistical mixture of homo- and heteronuclear helicates due to the Ln exchange. All the studied systems have an equilibrium constant close to K = 4. The Ln³⁺ ΔEIR, hence, does not affect the thermodynamics of the process that is mainly governed by statistical factors and entropy-driven. On the other hand, they demonstrate that the rate of the dynamic ion exchange is Ln radius-dependent (Figure 1b). The kinetic constants of the forward and backward reactions revealed an exponential trend depending on the Ln³⁺ ΔEIR of the two homonuclear pre-assembled cages (Figure 1c): from the minimum to the maximum value of ΔEIR, the kinetic constants increase by three orders of magnitude. This fundamental study hints new tools and guidelines to study dynamic processes in metallo-supramolecular ensembles, and for the precise preparation and control of lanthanide-based mixed coordination-driven systems.

Corresponding author:

Marzio Rancan is a Research Fellow at ICMATE-CNR (Italy). He received his PhD in Molecular Sciences at the University of Padova in 2009. He did post-doctoral studies at CNR, University of Padova and spent one year in the Molecular Magnetism Group at The University of Manchester (UK).  His current research is focused on the synthesis and characterization of coordination-driven molecular and supramolecular architectures with functional properties. He is the author of about 60 articles.

WEBSITE: http://wwwdisc.chimica.unipd.it/FMNLab/index.html

ORCID: https://orcid.org/0000-0001-9967-5283

RESEARCHGATE: https://www.researchgate.net/profile/Marzio-Rancan

Zirconium-89 complexation chemistry is an important area of research in the context of developing radiolabelled proteins for applications in diagnostic positron emission tomography (PET) imaging. For this imaging technology, the metalloradionuclide ⁸⁹Zr⁴⁺ ion needs to be sequestered by a ligand to form a coordination complex that is thermodynamically, kinetically, and metabolically stable in biological systems. In this regard, desferrioxamine B (DFO), a natural bacterial siderophore, is one of the outstanding hexadentate linear chelator for zirconium-89, used in clinical trials with ⁸⁹ZrDFO-radiolabeled antibodies (mAbs). Nevertheless, preclinical studies have demonstrated that ⁸⁹ZrDFO-mAbs can suffer from dissociation and metal ion release in vivo resulting in partial bone uptake in mice which could be partially due to the incomplete coordination sphere around the metallic cation. Driven by the goal of increasing the stability of the ⁸⁹Zr⁴⁺ coordination complex toward demetallation in vivo, several groups around the world have explored the synthesis and coordination chemistry of novel multidentate chelates with coordination numbers from 6 to 8 but the development of heptadentate remained unexplored.

Recently, a collaborative work between the group of Prof. Dr Jason P. Holland (University of Zurich, Switzerland) and a team from the Institut Plurisdisciplinaire Hubert Curien (IPHC, CNRS, University of Strasbourg, France) have demonstrated that photoactivatable heptadentate chelates could be a new alternative for the ultra-fast, light-induced production of stable ⁸⁹Zr-mAbs in vivo (Figure 1). The researchers synthesise new chelates, used density functional theory to predict the thermodynamic stability, and studied the in vitro stability of the radiolabelled complexes to find the most promising candidate for in vivo application.

The researchers also selected the most stable complex (Zr-2) and produced ⁸⁹Zr-radiolabelled onartuzumab (the monoclonal antibody component of MetMAb^TM which binds to the human hepatocyte growth-factor receptor c-MET) using photoradiochemical methods. Finally, the pharmacokinetic profile and c-MET targeting was evaluated in vivo and ex vivo by using PET imaging and biodistribution studies in female athymic nude mice bearing subcutaneous MKN-45 human gastric cancer xenografts (Figure 2).

 

Overall, the researchers proved that [⁸⁹Zr]Zr-2-onartuzumab provides specific tumour targeting and high tumour-to-organ contrast on the PET pictures and from the biodisitribution analysis. The results obtained in the study confirm that heptadentate complexes of ⁸⁹Zr display improved stability in vivo compared with hexadentate analogs and are promising candidates for future ⁸⁹Zr-radiotracer design.

About the corresponding author

Jason P. Holland is from Yorkshire in the UK and is currently an SNSF Professor for Medicinal Radiochemistry at the University of Zurich. Research activities in the Holland group focus on advancing radiolabelling methods through novel bioconjugation approaches for labelling bioactive molecules with various radionuclides (¹⁸F, ⁶⁴Cu, ^67/68Ga, ^86/90Y, ^99mTc, ¹¹¹In, ¹⁷⁷Lu, ¹⁸⁸Re, etc).

E-mail: jason.holland@chem.uzh; Twitter: @HollandLab_