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From Chemotherapy to Phototherapy - Changing the Therapeutic Action of a Metallo-Intercalating Ru^II -Re^I Luminescent System by Switching its Sub-Cellular Location.

ABSTRACT: The synthesis of a new heterodinuclear Re^I Ru^II metallointercalator containing Ru^II (dppz) and Re^I (dppn) moieties is reported. Cell-free studies reveal that the complex has similar photophysical properties to its homoleptic M(dppz) analogue and it also binds to DNA with a similar affinity. However, the newly reported complex has very different in-cell properties to its parent. In complete contrast to the homoleptic system, the Ru^II (dppz)/Re^I (dppn) complex is not intrinsically cytotoxic but displays appreciable phototoxic, despite both complexes displaying very similar quantum yields for singlet oxygen sensitization. Optical microscopy suggests that the reason for these contrasting biological effects is that whereas the homoleptic complex localises in the nuclei of cells, the Ru^II (dppz)/Re^I (dppn) complex preferentially accumulates in mitochondria. These observations illustrate how even small structural changes in metal based therapeutic leads can modulate their mechanism of action.

SUBMITTER: Saeed HK

PROVIDER: S-EPMC10946911 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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From Chemotherapy to Phototherapy - Changing the Therapeutic Action of a Metallo-Intercalating RuII -ReI Luminescent System by Switching its Sub-Cellular Location.

Saeed Hiwa K HK Jarman Paul J PJ Sreedharan Sreejesh S Mowll Rachel R Auty Alexander J AJ Chauvet Adrien A P AAP Smythe Carl G W CGW de la Serna Jorge Bernardino JB Thomas Jim A JA

Chemistry (Weinheim an der Bergstrasse, Germany) 20230502 34

The synthesis of a new heterodinuclear ReI RuII metallointercalator containing RuII (dppz) and ReI (dppn) moieties is reported. Cell-free studies reveal that the complex has similar photophysical properties to its homoleptic M(dppz) analogue and it also binds to DNA with a similar affinity. However, the newly reported complex has very different in-cell properties to its parent. In complete contrast to the homoleptic system, the RuII (dppz)/R ...[more]

PMID: 37013945

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Project description:Ru(II) polypyridyl complexes have gained widespread attention as photosensitizers for photodynamic therapy (PDT). Herein, we systematically investigate a series of the type [Ru(phen)2(IP-nT)]2+, featuring 1,10-phenanthroline (phen) coligands and imidazo[4,5-f][1,10]phenanthroline ligands tethered to n = 0-4 thiophene rings (IP-nT). The complexes were characterized and investigated for their electrochemical, spectroscopic, and (photo)biological properties. The electrochemical oxidation of the nT unit shifted by -350 mV as n = 1 → 4 (+920 mV for Ru-1T, +570 mV for Ru-4T); nT reductions were observed in complexes Ru-3T (-2530 mV) and Ru-4T (-2300 mV). Singlet oxygen quantum yields ranged from 0.53 to 0.88, with Ru-3T and Ru-4T being equally efficient (∼0.88). Time-resolved absorption spectra of Ru-0T-1T were dominated by metal-to-ligand charge-transfer (3MLCT) states (τTA = 0.40-0.85 μs), but long-lived intraligand charge-transfer (3ILCT) states were observed in Ru-2T-4T (τTA = 25-148 μs). The 3ILCT energies of Ru-3T and Ru-4T were computed to be 1.6 and 1.4 eV, respectively. The phototherapeutic efficacy against melanoma cells (SK-MEL-28) under broad-band visible light (400-700 nm) increases as n = 0 → 4: Ru-0T was inactive up to 300 μM, Ru-1T-2T were moderately active (EC50 ∼ 600 nM, PI = 200), and Ru-3T (EC50 = 57 nM, PI > 1100) and Ru-4T (EC50 = 740 pM, PI = 114,000) were the most phototoxic. The activity diminishes with longer wavelengths of light and is completely suppressed for all complexes except Ru-3T and Ru-4T in hypoxia. Ru-4T is the more potent and robust PS in 1% O2 over seven biological replicates (avg EC50 = 1.3 μM, avg PI = 985). Ru-3T exhibited hypoxic activity in five of seven replicates, underscoring the need for biological replicates in compound evaluation. Singlet oxygen sensitization is likely responsible for phototoxic effects of the compounds in normoxia, but the presence of redox-active excited states may facilitate additional photoactive pathways for complexes with three or more thienyl groups. The 3ILCT state with its extended lifetime (30-40× longer than the 3MLCT state for Ru-3T and Ru-4T) implicates its predominant role in photocytotoxicity.

Dataset Information

From Chemotherapy to Phototherapy - Changing the Therapeutic Action of a Metallo-Intercalating Ru^II -Re^I Luminescent System by Switching its Sub-Cellular Location.

Publications

From Chemotherapy to Phototherapy - Changing the Therapeutic Action of a Metallo-Intercalating Ru<sup>II</sup> -Re<sup>I</sup> Luminescent System by Switching its Sub-Cellular Location.

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