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>

A Multi‐action and Multi‐target RuII–PtIV Conjugate Combining Cancer‐Activated Chemotherapy and Photodynamic Therapy to Overcome Drug Resistant Cancers

“…Importantly, the spectra showed an absorption tail towards the biological spectral window potentially enabling the treatment of deep‐seated and large tumours as the light penetration depth directly correlates with the used wavelengths. Worthy of note, previous studies have shown that PSs can show a phototoxic effect although their extinction coefficients are below 100 m −1 cm −1 . The conjugate was found to have a large Stokes shift, implying minimal interference between excitation and emission.…”

“…To tackle this issue, some of us have recently reported the DFT‐guided design of Ru II polypyridine complexes with a strong absorption red shift towards the biological spectral window (600–900 nm). In this pursuit, the complex [Ru(4,7‐diphenyl‐1,10‐phenanthroline) 2 (4,4′‐dimethyl‐2,2′‐bipyridine)] 2+ , which showed a phototoxic effect from 480 nm up to clinically relevant 595 nm, was unveiled …”

Metal dipyrrin complexes as potential photosensitizers for photodynamic therapy

“…Therefore, much efforts are devoted towards the development of transition metal complexes as PDT PSs. 40 The majority of complexes studied are based on Ru(II), [41][42][43][44][45][46][47][48][49][50][51] Os(II), [52][53][54] Ir(III), [55][56][57][58][59][60][61] Rh(III) [62][63][64] and Re(I). [65][66][67][68][69] As these metals are expensive, it would be of high interest to develop PSs based on cheap, abundant metals.…”

Light‐Driven Cascade Mitochondria‐to‐Nucleus Photosensitization in Cancer Cell Ablation

“…As shown in Figure S11, Supporting Information, at the buffer solution with pH 6.8, the absorption of the ABDA in the presence of BT-Ir decreased significantly within 2 min, indicating highly efficient ROS generation in the acidic environment, which is more conducive to kill cancer cells as the tumor microenvironment is acidic. [15] Although 1 O 2 (type II) is considered to be the predominant primary ROS involved in PDT, there is growing evidence that other ROS (type I, including superoxide anion (O 2 − ), hydroxyl radical (HO • ), hydrogen peroxide (H 2 O 2 ), etc. ), may also be produced during the PDT process and play important roles in cell death.…”

“…Photodynamic therapy (PDT) involves the production of reactive oxygen species (ROS) by the irradiation of photosensitizers (PSs), which is considered as one of the most momentous strategies to eliminate cancer cells with minimal invasiveness and precise spatiotemporal selectivity. [1][2][3][4] The primary cytotoxic agents involved in this photodynamic process are reactive oxygens, such as singlet oxygen ( 1 O 2 ), hydroxyl radicals (OH • ), etc. [5,6] The incorporation of heavy atoms into the molecular structures is one of the widely used approaches to improve the ROS yield of PSs.…”