One‐ and Two‐Photon Phototherapeutic Effects of Ru^II Polypyridine Complexes in the Hypoxic Centre of Large Multicellular Tumor Spheroids and Tumor‐Bearing Mice**

Abstract

During the last decades, photodynamic therapy (PDT), an approved medical technique, has received increasing attention to treat certain types of cancer. Despite recent improvements, the treatment of large tumors remains a major clinical challenge due to the low ability of the photosensitizer (PS) to penetrate a 3D cellular architecture and the low oxygen concentrations present in the tumour centre. To mimic the conditions found in clinical tumors, exceptionally large 3D multicellular tumour spheroids (MCTSs) with a diameter of 800 µm were used in this work to test a series of new Ru(II) polypyridine complexes as 1-Photon and 2-Photon PSs. These metal complexes were found to fully penetrate the 3D cellular architecture and to generate singlet oxygen in the hypoxic centre upon light irradiation. While having no observed dark toxicity, the lead compound of this study showed an impressive phototoxicity upon clinically relevant 1-Photon (595 nm) or 2-Photon (800 nm) excitation with a full eradication of the hypoxic centre of the MCTSs. Importantly, this efficacy was also demonstrated on mice bearing an adenocarcinomic human alveolar basal epithelial tumour. File list (2) download file view on ChemRxiv Article.pdf (594.76 KiB) download file view on ChemRxiv SI.pdf (3.86 MiB)

Polypyridyl Ruthenium(II) Complexes with Red‐Shifted Absorption: New Promises in Photodynamic Therapy

“…In a very recent work, Gasser, Chao and co-workers developed phen-/bphen-based Ru II complexes (15-18; Figure 2) containing (E,E')-4,4-bisstyryl-2,2'-bipyridine to achieve 1P (595 nm) or 2P (800 nm) light-induced photo-cytotoxicity. [16] The complexes were able to generate 1 O 2 in the hypoxic core of 800 μm multicellular tumor spheroids of HeLa cells. Of note, due to the very limited oxygen supply at the hypoxic core of solid tumors, PDT is known to be less effective treatment modality of large tumors.…”

“…Moving forward, few crucial issues need to be addressed such as i) how to obtain more red shift so that the complexes can be activated in the PDT window. It is important to note that although few of the [15,16] ChemBioChem above complexes showed photo-cytotoxicity under 595 nm light, but under red-light (620-750 nm) irradiation photocytotoxicity is yet to be achieved. ii) fate and metabolism of the Ru II -polypyridyl complexes in the human body, iii) development of cancer selective delivery vehicles for Ru II -polypyridyl complexes, iv) how to achieve immune-responsive PDT with the polypyridyl ruthenium(II) complexes which can be activated by red light and v) development of multimodal cancer treatments with such complexes.…”

“…[9][10][11][12][13][14] To overcome these drawbacks, recently Gasser, Chao and coworkers have developed various Ru II -polypyridyl complexes with the help of computational tools to achieve red shifted longer wavelength absorption and thereafter photo-activation of Ru II based PDT agents using longer wavelength light at the target tumor site. [14][15][16] Keeping the core of the complexes as [Ru(phen) 2 (bpy)] 2 + or [Ru(bphen) 2 (bpy)] 2 + (phen = 1,10-phenanthroline; bpy = 2,2'-bipyridine; bphen = 4,7-diphenyl-1,10-phenanthroline), essentially the same core of the TLD-1433, Gasser and co-workers finetuned the photophysical properties of the complexes 1-7 by attaching various electron-donating and -withdrawing pendants to the bpy, in order to obtain a red shifted absorption towards the PDT window (Figure 1). [14] Interestingly, the complex 6 with the pendants À CH 3 and À Ph gave a moderate intensity absorption at 595 nm.…”

“…Figure 2. (E,E')-4,4-Bisstyryl-2,2'-bipyridine-based Ru II complexes with red-shifted absorption [15,16]. …”

Polymeric Encapsulation of a Ruthenium Polypyridine Complex for Tumor Targeted One- and Two-Photon Photodynamic Therapy

“…[1][2][3] During recent years, the use of transition metal complexes, and especially Ru(II) polypyridine complexes, has gained much attention due to their attractive chemical and photophysical properties (e.g., chemical stability and photostability, high water solubility, high ROS production). [4][5][6][7][8][9][10][11][12][13][14] Despite their remarkable abilities to act as PSs, these compounds have generally a poor cancer cell selectivity. As a consequence, high drug doses are needed, which can cause side effects.…”