Anticancer Photodynamic Therapy Using Ruthenium(II) and Os(II)-Based Complexes as Photosensitizers

Abstract

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 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 [19]. 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) [21]. Importantly, they can have their properties fine-tuned by choosing the central metal and organic ligands (such as bipyrid...

Metal Coordination Effects on the Photophysics of Dipyrrinato Photosensitizers

“…Therefore, it is important to develop alternative PSs. Among others, the use of transition metal complexes with non-tetrapyrrolic ligands is gaining attention [ 34 , 35 , 36 ]. For example, the Ru(II) polypyridine complex TLD-1433 ( Figure 4 ) entered phase II clinical trials against non-muscle invasive bladder cancer (ClinicalTrials.gov Identifier: NCT03053635) [ 37 , 38 ].…”

“…Progress has been made over the years on investigating TM-complexes as triplet PSs alternatively to currently accepted PSs, for applications such as PDT [ 34 , 35 , 36 ]. It was shown that the introduction of metal ions into clinically accepted PSs could sometimes overcome the present limitations and drawbacks [ 64 , 65 ].…”

Phototoxicity of Tridentate Ru(II) Polypyridyl Complex with Expanded Bite Angles toward Mammalian Cells and Multicellular Tumor Spheroids

“…Non-specific localization can result in the activation of the phototherapeutic effects off-target, and thus, in PDT applications, damage to the surrounding cells. 37 , 38 The mechanism of cellular uptake of ruthenium complexes can vary depending on complex properties, such as its size, charge, and lipophilicity. 39 Increasing the lipophilicity of a ruthenium complex should increase the uptake via passive diffusion as was demonstrated by Park and co-workers.…”