Bioconjugate Supramolecular Pd<sup>2+</sup> Metallacages Penetrate the Blood Brain Barrier <i>In Vitro</i> and <i>In Vivo</i>
Ben Woods, Rúben D. M. Silva, Claudia Schmidt, Darren Wragg, Marco Cavaco, Vera Neves, Vera F. C. Ferreira, Lurdes Gano, Tânia S. Morais, Filipa Mendes, João D. G. Correia, Angela Casini
Abstract
The biomedical application of discrete supramolecular metal-based structures, specifically self-assembled metallacages, is still an emergent field of study. Capitalizing on the knowledge gained in recent years on the development of 3-dimensional (3D) metallacages as novel drug delivery systems and theranostic agents, we explore here the possibility to target [Pd 2 L 4 ] 4+ cages (L = 3,5-bis(3-ethynylpyridine)phenyl ligand) to the brain. In detail, a new water-soluble homoleptic cage ( C PepH3 ) tethered to a blood brain barrier (BBB)-translocating peptide was synthesized by a combination of solid-phase peptide synthesis (SPPS) and self-assembly procedures. The cage translocation efficacy was assessed by inductively coupled mass spectrometry (ICP-MS) in a BBB cellular model in vitro . Biodistribution studies of the radiolabeled cage [[ 99m TcO 4 ] − ⊂ C PepH3 ] in the CD1 mice model demonstrate its brain penetration properties in vivo . Further DFT studies were conducted to model the structure of the [[ 99m TcO 4 ] − ⊂ cage] complex. Moreover, the encapsulation capabilities and stability of the cage were investigated using the [ReO 4 ] − anion, the “cold” analogue of [ 99m TcO 4 ] −, by 1 H NMR spectroscopy. Overall, our study constitutes another proof-of-concept of the unique potential of supramolecular coordination complexes for modifying the physiochemical and biodistribution properties of diagnostic species.