Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

Abstract

The utilization of Photodynamic Therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted towards the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside the tissue and therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of the DFT guided search for efficient PDT PSs with a substantial spectral red shift towards the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex, which causes phototoxicity in the very-low micromolar-to-nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids.<br>

Rationally designed ruthenium complexes for 1- and 2-photon photodynamic therapy

“…In addition, the ligands L-H, L-NMe 2 , and L-OMe as well as 3 were characterized using single-crystal X-ray crystallography (Supplementary Tables 5-6, Supplementary Figs. [26][27][28][29].…”

“…Despite these remarkable properties, the vast majority of Ru(II) polypyridine complexes are excited using either blue or UV-A light. As the light tissue penetration depth is rather poor at these wavelengths, the application of these compounds to treat deepseated or large tumors is limited [26][27][28][29][30] . To circumvent this drawback, there is a need for the development of PSs with an absorption towards the biological spectral window (600-900 nm), which can be achieved by a red-shifted one-photon (1P) absorption or the use of a two-photon (2P) absorption process for 2P PDT, a technique that is not employed yet in the clinic.…”

The crystal structure of (E)-1-(quinolin-2-ylmethyl)-2-((1-(quinolin-2-ylmethyl)pyridin-2(1H)-ylidene)amino)pyridin-1-ium, C30H25BrN5

“…This practice is often an attempt to alter and/or improve the chemical properties of the ligand; be it the electronic or steric properties [8]. Pyridyl based type of ligands have contributed a great deal across many fields [9][10][11][12]. Subsequently, a great deal of interest towards multi-dentate pyridyl based ligands has grown over the decades across many disciplines including photoluminescence [13], medicinal chemistry [14], catalysis [15,16] and radiopharmaceutical [17] chemistry, also as pursued in our research group [18][19][20].…”

Ruthenium Complexes for 1- and 2-Photon Photodynamic Therapy: From In Silico Prediction to In Vivo Applications

“…As the light tissue penetration depth is rather poor at these wavelengths, the application of these compounds to treat deep-seated or large tumors is limited. [26][27][28][29][30] To circumvent this drawback, there is a need for the development of PSs with an absorption towards the biological spectral window (600-900 nm), which can be achieved by a red shifted one photon (1P) absorption or the use of two photon (2P) absorption for 2P PDT, a technique that is not employed yet in the clinics. However, the ability of Ru(II) polypyridine complexes to absorb 2P simultaneously, expressed as the 2P cross section, remains relatively poor (~ 40-250 Goeppert-Mayer (GM)), limiting their applications in this field of research.…”