New Australian Study Discusses TLD1433Full text: Photoactive and Luminescent Transition Metal Complexes as Anticancer Agents: A Guiding Light in the Search for New and Improved Cancer Treatments biomedicines 2022 Received: 31 January 2022 / Revised: 23 February 2022 / Accepted: 26 February 2022 / Published: 1 March 2022
(This article belongs to the Special Issue Metal-Based Complexes in Cancer Treatment) Brondwyn S. McGhie and Janice R. Aldrich-Wright Nanoscale Organisation and Dynamics Group, School of Science, Western Sydney University "3. Ruthenium Complexes
Ruthenium complexes are a favorite when it comes to alternatives to the “traditional” platinum-based chemotherapeutics. Ruthenium complexes commonly have large Stoke shifts, high chemical, and photochemical stability; are typically highly water-soluble; and are resistant to photobleaching. In 2017, TLD1433, a ruthenium complex created by the McFarland group, became the first transition-metal-based complex to enter human clinical trials for the PDT treatment of cancer; in 2018, it succeeded in its goals in the trial and was terminated early [50].
A phase-III clinical study of TDL1433 commenced in 2019, which is expected to take 2–3 years to complete [51]. TLD1433, like many Ru(II) complexes, is inspired by the complex [Ru(bpy)3]2+, but other structures have been suggested for luminescent anticancer agents. Alternative structures include the addition of cyclometallated ligands, so-called piano stool geometry, and derivatives with appended peptides or long-chain hydrophilic groups.
3.1. Tris(bipyridine)ruthenium(II)-Inspired Complexes
Tris(bipyridine)ruthenium(II) ([Ru(bpy)3]2+)-inspired complexes were reviewed in detail at the end of 2018 and included in an account of the early development of TDL1433 by McFarland and colleagues [50]. Here, we provide a brief overview of TDL1433, focus on innovations within the past 5 years, and refer readers to McFarland’s review for seminal details [50]. TDL1433 contains functionalized aromatic chromophores with a low-lying triplet intra-ligand state, which makes them ideal for PDT. It is highly photosensitive and has long lifetimes, as well as 1O2 generation in both normoxic and hypoxic cells, despite having weak absorption within the biological window. This complex was designed with non-muscle-invasive bladder cancer in mind. This was done in a multidisciplinary approach described as “lateral”, as opposed to creating novel photosensitizers to find a suitable tumor target or retro-designing tumor specific complexes based on tumor properties. TDL1433 was part of a family of complexes tested with a range of different photophysical properties (Figure 5: TDL1433). The strategy of making premeditated incremental changes to the structure of tris NˆN Ru complexes is well established; for example, the Gasser group published two complexes with the structure [Ru(phen)2(7R,8R-dppz-)]2+, where R was either OH or OMe. Both complexes displayed intense phosphorescence, good 1O2 quantum yields, but different cellular accumulation, as well as toxicity......"