39 research outputs found
It takes three to tango: The length of the oligothiophene chain determines the nature of the longâlived excited state and the resulting photocytotoxicity of a ruthenium(II) Photodrug
Abstract TLD1433 is the first Ru(II) complex to be tested as a photodynamic therapy agent in a clinical trial. In this contribution we study TLD1433 in the context of structurallyârelated Ru(II)âimidozo[4,5âf][1,10]phenanthroline (ip) complexes appended with thiophene rings to decipher the unique photophysical properties which are associated with increasing oligothiophene chain length. Substitution of the ip ligand with terâ or quaterthiophene changes the nature of the longâlived triplet state from metalâtoâligand chargeâtransfer to 3 ĎĎ* character. The addition of the third thiophene thus presents a critical juncture which not only determines the photophysics of the complex but most importantly its capacity for 1 O 2 generation and hence the potential of the complex to be used as a photocytotoxic agent
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Intracellular Photophysics of an Osmium Complex bearing an Oligothiophene Extended Ligand
This contribution describes the excited-state properties of an Osmium-complex when taken up into human cells. The complex 1 [Os(bpy)2(IP-4T)](PF6)2 with bpy=2,2â˛-bipyridine and IP-4T=2-{5â˛-[3â˛,4â˛-diethyl-(2,2â˛-bithien-5-yl)]-3,4-diethyl-2,2â˛-bithiophene}imidazo[4,5-f][1,10]phenanthroline) can be discussed as a candidate for photodynamic therapy in the biological red/NIR window. The complex is taken up by MCF7 cells and localizes rather homogeneously within in the cytoplasm. To detail the sub-ns photophysics of 1, comparative transient absorption measurements were carried out in different solvents to derive a model of the photoinduced processes. Key to rationalize the excited-state relaxation is a long-lived 3ILCT state associated with the oligothiophene chain. This model was then tested with the complex internalized into MCF7 cells, since the intracellular environment has long been suspected to take big influence on the excited state properties. In our study of 1 in cells, we were able to show that, though the overall model remained the same, the excited-state dynamics are affected strongly by the intracellular environment. Our study represents the first in depth correlation towards ex-vivo and in vivo ultrafast spectroscopy for a possible photodrug. Š 2020 The Authors. Published by Wiley-VCH Gmb
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It Takes Three to Tango - the length of the oligothiophene determines the nature of the long-lived excited state and the resulting photocytotoxicity of a Ru(II) photodrug
TLD1433 is the first Ru(II) complex to be tested as a photodynamic therapy agent in a clinical trial. In this contribution we study TLD1433 in the context of structurally-related Ru(II)-imidozo[4,5-f][1,10]phenanthroline (ip) complexes appended with thiophene rings to decipher the unique photophysical properties which are associated with increasing oligothiophene chain length. Substitution of the ip ligand with ter- or quaterthiophene changes the nature of the long-lived triplet state from metal-to-ligand charge-transfer to 3ĎĎ* character. The addition of the third thiophene thus presents a critical juncture which not only determines the photophysics of the complex but most importantly its capacity for 1O2 generation and hence the potential of the complex to be used as a photocytotoxic agent
It Takes Three to Tango: The Length of the Oligothiophene Chain Determines the Nature of the LongâLived Excited State and the Resulting Photocytotoxicity of a Ruthenium(II) Photodrug
TLD1433 is the first Ru(II) complex to be tested as a photodynamic therapy agent in a clinical trial. In this contribution we study TLD1433 in the context of structurally-related Ru(II)-imidozo[4,5-f][1,10]phenanthroline (ip) complexes appended with thiophene rings to decipher the unique photophysical properties which are associated with increasing oligothiophene chain length. Substitution of the ip ligand with ter- or quaterthiophene changes the nature of the long-lived triplet state from metal-to-ligand charge-transfer to (3)ĎĎ* character. The addition of the third thiophene thus presents a critical juncture which not only determines the photophysics of the complex but most importantly its capacity for (1)O(2) generation and hence the potential of the complex to be used as a photocytotoxic agent. ENTRY FOR THE TABLE OF CONTENTS: A low-lying triplet intraligand state ((3)IL) determines the properties of the long-lived excited states in a series of Ru(II) complexes. The (3)IL state can be accessed by increasing the length of an oligothiophene chain. The (3)IL state is extremely efficient at generating (1)O(2) and thus enhances the potency of the complexes as PDT agents. [Image: see text
Photodynamic Inactivation of Human Coronaviruses
Photodynamic inactivation (PDI) employs a photosensitizer, light, and oxygen to create a local burst of reactive oxygen species (ROS) that can inactivate microorganisms. The botanical extract PhytoQuinTM is a powerful photosensitizer with antimicrobial properties. We previously demonstrated that photoactivated PhytoQuin also has antiviral properties against herpes simplex viruses and adenoviruses in a dose-dependent manner across a broad range of sub-cytotoxic concentrations. Here, we report that human coronaviruses (HCoVs) are also susceptible to photodynamic inactivation. Photoactivated-PhytoQuin inhibited the replication of the alphacoronavirus HCoV-229E and the betacoronavirus HCoV-OC43 in cultured cells across a range of sub-cytotoxic doses. This antiviral effect was light-dependent, as we observed minimal antiviral effect of PhytoQuin in the absence of photoactivation. Using RNase protection assays, we observed that PDI disrupted HCoV particle integrity allowing for the digestion of viral RNA by exogenous ribonucleases. Using lentiviruses pseudotyped with the SARS-CoV-2 Spike (S) protein, we once again observed a strong, light-dependent antiviral effect of PhytoQuin, which prevented S-mediated entry into human cells. We also observed that PhytoQuin PDI altered S protein electrophoretic mobility. The PhytoQuin constituent emodin displayed equivalent light-dependent antiviral activity to PhytoQuin in matched-dose experiments, indicating that it plays a central role in PhytoQuin PDI against CoVs. Together, these findings demonstrate that HCoV lipid envelopes and proteins are damaged by PhytoQuin PDI and expands the list of susceptible viruses
Enabling In Vivo Optical Imaging of an Osmium Photosensitizer by Micellar Formulation
Osmium (Os)-based photosensitizers (PSs) exhibit unique broad, red-shifted absorption, favoring PDT activity at greater tissue depths. We recently reported on a potent Os(II) PS, rac-[Os(phen)2(IP-4T)](Cl)2 (ML18J03) with submicromolar hypoxia activity. ML18J03 exhibits a low luminescence quantum yield of 9.8 × 10−5 in PBS, which limits its capacity for in vivo luminescence imaging. We recently showed that formulating ML18J03 into 10.2 nm DSPE-mPEG2000 micelles (Mic-ML18J03) increases its luminescence quantum yield by two orders of magnitude. Here, we demonstrate that Mic-ML18J03 exhibits 47-fold improved accumulative luminescence signals in orthotopic AT-84 head and neck tumors. We show, for the first time, that micellar formulation provides up to 11.7-fold tumor selectivity for ML18J03. Furthermore, Mic-ML18J03 does not experience the concentration-dependent quenching observed with unformulated ML18J03 in PBS, and formulation reduces spectral shifting of the emission maxima during PDT (variance = 6.5 and 27.3, respectively). The Mic-ML18J03 formulation also increases the production of reactive molecular species 2–3-fold. These findings demonstrate that micellar formulation is a versatile and effective approach to enable in vivo luminescence imaging options for an otherwise quenched, yet promising, PS
Excited State Dynamics of a Photobiologically Active Ru(II) Dyad Are Altered in Biologically Relevant Environments
In
this study femtosecond and nanosecond time-resolved transient
absorption spectroscopy was used to investigate the influence of ionic
strength and complexity on the excited state dynamics of a RuÂ(II)-based
metalâorganic dyad. The bis-heteroleptic complex [RuÂ(bpy)<sub>2</sub>(ippy)]<sup>2+</sup> (<b>1</b>), where bpy = 2,2â˛-bipyridine
and ippy = 2-(1-pyrenyl-1<i>H-</i>imidazoÂ[4,5-<i>f</i>]Â[1,10]Âphenanthroline, is a potent photosensitizer for in vitro photodynamic
therapy (PDT) and photodynamic inactivation (PDI) of microorganisms
owing to a long-lived triplet excited state derived from a metal-to-ligand
charge-transfer (<sup>3</sup>MLCT) state that is equilibrium with
an intraligand (<sup>3</sup>IL) state. The prolonged lifetime provides
ample opportunity for bimolecular quenching of this state by oxygen;
thus singlet oxygen (<sup>1</sup>O<sub>2</sub>) sensitization is very
efficient. In simple aqueous solution, fast cooling within the <sup>3</sup>MLCT manifold is followed by energy transfer to an <sup>3</sup>IL state, which is facilitated by rotation of a pyrenyl unit about
the imidazoâpyrenyl (ip) coannular bond. For solutions of <b>1</b> in high ionic strength simulated biological fluid (SBF),
a more physiologically relevant solvent that contains a complex mixture
of ions at pH 7.4, femtosecond studies revealed an additional excited
state, possibly based on an ionâligand interaction. This new
state appearing in high ionic strength SBF was not observable in water,
simple buffers, or low ionic strength SBF. These photoinduced dynamics
were also affected by the presence of biomolecules such as DNA in
simple buffer, whereby relaxation on the picosecond time scale was
accelerated from 39 to 18 ps with DNA intercalation by <b>1</b>. The increased rate of coplanarization of the pyrene and the imidazole
units was attributed to DNA-induced conformational restriction of
the pyrenyl unit relative to the ip bond. Quantitative changes to
excited state decay rates of <b>1</b> in solutions of high ionic
strength were also observed when probed on the microsecond time scale.
Notably, the thermalized excited state decay pathways were altered
substantially with DNA intercalation, with access to some states being
completely blocked. Experimentally, this manifested in the absence
of the slowest microsecond decay channel, which is normally observed
for <b>1</b> in solution. The quantitative and qualitative observations
from this study highlight the importance of employing biologically
relevant solvents and potential biomolecule targets when the excited
state dynamics and photophysical properties (under cell-free conditions)
responsible for the potent photobiological effects are assessed in
the context of photodynamic therapy and photodynamic inactivation
Bis[Pyrrolyl Ru(II)] Triads: a New Class of Photosensitizers for Metal-Organic Photodynamic Therapy
A new family of ten dinuclear Ru(II) complexes based on the bis[pyrrolyl Ru(II)] triad scaffold, where two Ru(bpy)2 centers are separated by a variety of organic linkers, was prepared to evaluate the influence of the organic chromophore on the spectroscopic and in vitro photodynamic therapy (PDT) properties of the compounds. The bis[pyrrolyl Ru(II)] triads absorbed strongly throughout the visible region, with several members having molar extinction coefficients (e) âĽ104 at 600â620 nm and longer. Phosphorescence quantum yields were generally less than 0.1% and in some cases undetectable. The singlet oxygen quantum yields ranged from 5% to 77% and generally correlated with their photocytotoxicities toward human leukemia (HL-60) cells regardless of the wavelength of light used. Dark cytotoxicities varied ten-fold, with EC50 values in the range of 10â100 ÂľM and phototherapeutic indices (PIs) as large as 5,400 and 260 with broadband visible (28 J cm-2, 7.8 mW cm-2) and 625-nm red (100 J cm-2, 42 mW cm-2) light, respectively. The bis[pyrrolyl Ru(II)] triad with a pyrenyl linker (5h) was especially potent, with an EC50 value of 1 nM and PI >27,000 with visible light and subnanomolar activity with 625-nm light (100 J cm-2, 28 mW cm-2). The lead compound 5h was also tested in a tumor spheroid assay using the HL60 cell line and exhibited greater photocytotoxcicity in this more resistant model (EC50=60 nM and PI>1,200 with 625-nm light) despite a lower dark cytotoxicity. The in vitro PDT effects of 5h extended to bacteria, where submicromolar EC50 values and PIs >300 against S. mutans and S. aureus were obtained with visible light. This activity was attenuated with 625-nm red light, but PIs were still near 50. The ligand-localized 3ĎĎ* state contributed by the pyrenyl linker of 5h likely plays a key role in its phototoxic effects toward cancer cells and bacteria.<br /
A spectroscopic study of substituted anthranilic acids as sensitive environmental probes for detecting cancer cells
Small-molecule fluorescent reporters of disease states are highly sought after, yet they remain elusive. Anthranilic acids are extremely sensitive environmental probes, and hold promise as general but selective agents for cancer-cell detection if they can be equipped with the appropriate targeting groups. The optical properties of a small library of N-isopropyl invariant anthranilic acids were investigated in methanol and chloroform. Points of variation included: fluoro, trifluoromethyl, or cyano substitution on the aromatic ring, and derivitization of the parent carboxylic acid as esters or secondary carboxamides. Phenylboronic acid conjugation at the carboxylic acid alongside un-, mono-, and dimethylated 2-amino groups was also explored. The boron-containing anthranilic acids were also evaluated as sensitive fluorescent probes for cancer cells using laser scanning confocal microscopy. In general, the compounds produced blue fluorescence that was strongly influenced by substitution and environment. 4-Trifluoromethyl and 4-cyano esters proved to be the most sensitive environmental probes with quantum yields as large as 100% in chloroform, and enhancements of up to 30-fold on going from methanol to chloroform. Stokes shifts ranged from 63 to 120 nm, generally increasing with ortho-substitution and environmental polarity. It was demonstrated that phenylboronic acid conjugation was an attractive method for cancer cell detection via boronate ester formation with overexpressed glycoproteins (with no interference from normal, healthy cells), presumably due to favorable boron-sialic acid interactions.Peer reviewed: YesNRC publication: Ye