Anticancer Photodynamic Therapy Using Ruthenium(II) and Os(II)-Based Complexes as Photosensitizers
Tumor Progression and Metastasis
Photodynamic therapy (PDT) is an approved procedure using a photosensitizer (PS) activated by light to selectively destroy malignant/premalignant cells. Transition metal complexes, such as Ru(II)-and Os(II)-based PSs (Theralase Technologies Inc., Ontario. Canada), are activated in a wide range of wavelengths, are resistant to photobleaching and have a high singlet oxygen quantum yield and ability to produce cytotoxic reactive oxygen species (ROS). Their design allows fine-tuning of the
... ing of the photophysical and photochemical properties. They demonstrate Type I and II photoreactions, and some are activated in hypoxia. High PDT potency and activation under NIR light and even X-ray may provide an advantage over the approved PSs. Their ability to associate with transferrin (Tf) as an endogenous delivery system increases photobleaching resistance, ROS production, selective cellular uptake, and PDT efficacy in combination with a decreased systemic toxicity. This makes these PSs attractive for systemic therapy of recurrent/progressive cancers. Their PDT efficacy has been demonstrated in various in vitro and in vivo clinically relevant models. The unique properties of the mentioned PSs allow bypassing such limitations of PDT as low specific uptake ratio, insufficiently broad absorption band, and low efficacy in hypoxia. One of these PSs (TLD-1433) was successful against non-muscle invasive urinary bladder cancer unresponsive to contemporary anticancer therapies. extensive hypoxic regions, which are also associated with the tumor aggressiveness [15, 16] . Although hypoxic regions still can be treated (at a slower rate) by application of fractionated exposure or inducing reperfusion [17, 18] , hypoxia severely decreases PDT efficacy  . Together with the limited light penetration, this is another reason why PDT in its current state is usually limited to relatively superficial lesions. This problem could be bypassed by PSs employing photoreactions that have little or no dependency on oxygen. Considering the said above, an advanced PS should have the ability for targeted delivery; penetration through the blood-brain barrier (BBB) and blood-tumor cell barrier (BTCB); activation by a wide range of wavelengths, including NIR light; and employing of different types of photoreactions enabling induction of immune responses to tumor antigens. Solubility in water and/or saline is a great asset for a successful PS as it makes its delivery both easier and safer, without the use of excipients with potential toxicity/side effects on their own. Metal-based coordination complexes are among the obvious candidates to satisfy these requirements. Specifically, transition metal complexes possess a wide range of metal oxidation states and the complex geometries [5, 20] . These complexes (e.g., Ru(II) polypyridyl complexes) are of increasing interest as PSs in photodynamic therapy (PDT) and, more recently, for photochemotherapy (PCT)  . Importantly, they can have their properties fine-tuned by choosing the central metal and organic ligands (such as bipyridine and 2,2′-biquinoline). These PSs can employ a great variety of excited states associated with the central metal, ligands, or metal-ligand interactions. This is manifested in photoreactions that are ROS-dependent (Type I/II) or ROS-independent (electron transfer to substrates other than molecular oxygen), excitation at different wavelengths, solubility, systemic toxicity, and finally PDT efficacy. Historically, Pt(IV)-, Ru(II)-, and Rh(III)-based complexes were most actively studied as PSs followed by Ir(III) and Os(II) complexes; see the review by Monro et al.  . The examples of the most recent studies      include a summary on the use of ruthenium complexes as PSs in PDT . This chapter reviews the results obtained by our group and collaborators. The properties and PDT efficacy of Theralase Technologies Inc. PSs  and Ru(II)-and Os(II)-based complexes are discussed in the perspective of their clinical application.