There are now several Ruthenium containing drug candidates being explored for applications in the clinic, including cancer treatment, photodynamic therapy, and as antibacterial agents. However, despite outstanding in vitro activity, Ru-based compounds can suffer from a lack of aqueous solubility, and many possess a short circulation time in the body. These drawbacks drastically decrease their efficiency in vivo, leading to poor accumulation in tumor tissues. Nanoformulation of Ru complexes using polymer/lipid inclusion or adsorption on inorganic carriers offer enhanced bioavailability and pharmacokinetic properties. However, these strategies raise additional concerns about the fate of the carriers after unloading. Here, we present an alternative delivery strategy consisting of the formation of supramolecular assemblies of Ru complexes acting as reservoirs of molecules that allow for a progressive release of the bio-active molecule. We report a facile way to prepare size-controlled particles using a controlled precipitation method, an approach well adapted for molecular materials such as Ru(II) coordination complexes. This technique was successfully applied to the [Ru(bpy)₃](PF₆)₂ (bpy: 2,2’-bipyridine) complex and its derivative [Ru(bpy)₂(dmbpy)](PF₆)₂ (dmbpy: 6,6’-dimethyl-2,2’-bipyridine) for treatment by photodynamic therapy (PDT) and photoactivated chemotherapy (PACT), respectively. Negatively-charged particles ranging from tens of nanometers to several microns were obtained by controlling just two parameters: temperature and precipitation in presence of confining polymers. The cytotoxicity of the particles in the dark or after light activation were evaluated in vitro using HL60, Hela, and A549 cells as well as their cellular uptake, localization and dissolution rate in biological medium. Results showed similar or enhanced biological activity of the particles compared to the solubilized complex depending on the mode of treatment. The particles showed an improved cellular uptake and progressive dissolution, with a complete release of the molecular complex after 72 hours of incubation. Electron microscopy performed on cross sections confirmed the delivery of dissolved species inside the nucleus of the cells. These preliminary results open new possibilities toward the nanoformulation of Ru-based compounds for their clinical application as anticancer agents.

Sarah Kriger

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