Ruthenium(ii) polypyridyl complexes with π-expansive ligands: synthesis and cubosome encapsulation for photodynamic therapy of non-melanoma skin cancer

Abstract

In photodynamic therapy (PDT), Ru(II) polypyridyl complexes (RPCs) featuring the popular π-expansive benzo[i]dipyrido[3,2-a:2′,3′-c]phenazine (dppn) ligand have attracted much attention, mainly due to the good singlet oxygen sensitizing properties imparted by this peculiar ligand. However, notwithstanding the intriguing perspectives, much remains to be explored about the use of RPC-based photosensitizing agents (PSs) with more than a dppn ligand in their scaffolds. Herein, two bis-heteroleptic RPCs of the general formula [Ru(dppn)₂L]ⁿ⁺ (L = 4,4′-dimethyl-2,2′-bipyridine, n = 2, Ru1 or 2,2′-bipyridine-4,4′-dicarboxylate, n = 0, Ru2) were prepared in good yields by adopting an alternative synthetic approach to previously reported methods. The optimal singlet oxygen sensitizing properties and capabilities to interact with DNA displayed by Ru1 and Ru2 were paralleled by a potent light-triggered toxicity (λ_max = 462 nm) exerted on squamous epithelial carcinoma cells. To improve the biopharmaceutical properties of these compounds, Ru1 and Ru2 were encapsulated into cubosomes, soft nanoparticles with a lyotropic liquid crystalline core. In vitro studies probed the effectiveness of these formulations against light-irradiated cancer cells and confirmed intracellular ROS generation as the mechanism likely to be responsible for the observed PDT efficacy. This work highlights the potential of [Ru(dppn)₂L]-based PSs in PDT, beyond providing a general and straightforward synthetic route for the preparation of this class of compounds. To the best of our knowledge, this is also the first example of the encapsulation of a RPC into cubosome nanostructures, paving the way for the development of nano-formulations with augmented biopharmaceutical properties for PDT application.