Ru(II) complexes that undergo photosubstitution reactions from triplet metal-centered (3MC) excited states are of interest in photochemotherapy (PCT) due to their potential to produce cytotoxic effects in hypoxia. Dual-action systems that incorporate this stoichiometric mode to complement the oxygen dependent photosensitization pathways that define photodynamic therapy(PDT) are poised to maintain antitumor activity regardless of the oxygenation status. Herein, we examine the way in which these two pathways influence photocytotoxicity in normoxia and in hypoxia using the [Ru(dmp)2(IP-nT)]2+ series (where dmp=2,9dimethyl-1,10-phenanthroline and IP-nT= imidazo[4,5-f][1,10]phenanthroline tetheredt on=0−4thiophene rings) toswitchthe dominantexcitedstatefromthemetal-based3MCstateinthecase ofRu-phen−Ru-1Ttotheligand-based3ILCTstateforRu-3TandRu-4T.Ru-phen−Ru-1T,havingdominant3MCstatesandthe largestphotosubstitutionquantumyields,areinactiveinbothnormoxiaandhypoxia.Ru-3TandRu-4T,withdominant3IL/3ILCT statesandlongtripletlifetimes(τTA=20−25μs),havethepoorestphotosubstitutionquantumyields,yetareextremelyactive.Inthe best instances, Ru-4Texhibit attomolar phototoxicity toward SKMEL28 cells in normoxia and picomolar in hypoxia, with phototherapeutic index values in normoxia of 10 5−10 12 and 10 3−10 6 in hypoxia. While maximizing excited-state deactivation through photodissociative 3MC states did not result in bonafide dual-action PDT/PCT agents, the study has produced the most potent photosensitizer we know of to date. The extraordinary photosensitizing capacity of Ru-3T and Ru-4T may stem from a combination of very efficient 1O2 production and possibly complementary typeI pathways via 3ILCT excited states.
Intraligand Excited States Turn a Ruthenium Oligothiophene Complex into a Light-Triggered Ubertoxin with Anticancer Effects in Extreme Hypoxia
Marta Erminia Alberto
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2022-01-01
Abstract
Ru(II) complexes that undergo photosubstitution reactions from triplet metal-centered (3MC) excited states are of interest in photochemotherapy (PCT) due to their potential to produce cytotoxic effects in hypoxia. Dual-action systems that incorporate this stoichiometric mode to complement the oxygen dependent photosensitization pathways that define photodynamic therapy(PDT) are poised to maintain antitumor activity regardless of the oxygenation status. Herein, we examine the way in which these two pathways influence photocytotoxicity in normoxia and in hypoxia using the [Ru(dmp)2(IP-nT)]2+ series (where dmp=2,9dimethyl-1,10-phenanthroline and IP-nT= imidazo[4,5-f][1,10]phenanthroline tetheredt on=0−4thiophene rings) toswitchthe dominantexcitedstatefromthemetal-based3MCstateinthecase ofRu-phen−Ru-1Ttotheligand-based3ILCTstateforRu-3TandRu-4T.Ru-phen−Ru-1T,havingdominant3MCstatesandthe largestphotosubstitutionquantumyields,areinactiveinbothnormoxiaandhypoxia.Ru-3TandRu-4T,withdominant3IL/3ILCT statesandlongtripletlifetimes(τTA=20−25μs),havethepoorestphotosubstitutionquantumyields,yetareextremelyactive.Inthe best instances, Ru-4Texhibit attomolar phototoxicity toward SKMEL28 cells in normoxia and picomolar in hypoxia, with phototherapeutic index values in normoxia of 10 5−10 12 and 10 3−10 6 in hypoxia. While maximizing excited-state deactivation through photodissociative 3MC states did not result in bonafide dual-action PDT/PCT agents, the study has produced the most potent photosensitizer we know of to date. The extraordinary photosensitizing capacity of Ru-3T and Ru-4T may stem from a combination of very efficient 1O2 production and possibly complementary typeI pathways via 3ILCT excited states.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
