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Visualizing the presence and distribution of multiple specific molecular markers within a tumor can reveal the composition of its microenvironment, inform diagnosis, stratify patients, and guide treatment. Raman imaging with multiple molecularly-targeted surface enhanced Raman scattering (SERS) nanoprobes could help investigate emerging cancer treatments preclinically or enable personalized treatment assessment. Here, we report a comprehensive strategy for multiplexed imaging using SERS nanoprobes and machine learning (ML) to monitor the early effects of immune checkpoint blockade (ICB) in tumor-bearing mice. We used antibody-functionalized SERS nanoprobes to visualize 7 + 1 immunotherapy-related targets simultaneously. The multiplexed images were spectrally resolved and then spatially segmented into superpixels based on the unmixed signals. The superpixels were used to train ML models, leading to the successful classification of mice into treated and untreated groups, and identifying tumor regions with variable responses to treatment. This method may help predict treatment efficacy in tumors and identify areas of tumor variability and therapy resistance.

Chalcogenopyrylium monomethine (CGPM) dyes represent a class of environmentally activated singlet oxygen generators with applications in photodynamic therapy (PDT) and photoassisted chemotherapy (PACT). Upon binding to genomic material, the dyes are presumed to rigidify, allowing for intersystem crossing to outcompete excited state deactivation by internal conversion. This results in large triplet yields and hence large singlet oxygen yields. To understand the nature of the internal conversion process that controls the activity of the dyes, femtosecond transient absorption experiments were performed on a series of S-, Se-, and Te-substituted CGPM dyes. For S- and Se-substituted species in methanol, rapid internal conversion from the singlet excited state, S1, occurs in ∼5 ps, deactivating the optically active excited state. The internal conversion produces a distorted ground-state species that returns to its equilibrium structure in ∼20 ps. For Te-substituted species, the internal conversion competes with rapid intersystem crossing to the lowest triplet state, T1, which occurs with a ∼ 100 ps time constant in methanol. In more viscous methanol/glycerol mixtures, the internal conversion to the ground state slows by 2 orders of magnitude, occurring in 500–600 ps. For Se- and Te-substituted species in viscous environments, the slower internal conversion rate allows a larger triplet yield. Using femtosecond stimulated Raman spectroscopy (FSRS) and time-dependent density functional theory (TD-DFT), the internal conversion is determined to occur by twisting of the pyrylium rings about the monomethine bridge. Evolution from the distorted ground state occurs by twisting back to the S0equilibrium structure. The environmentally dependent photoactivity of CGPM dyes is discussed in the context of PDT and PACT applications.

Aerobic oxidation of 2-aryl-1,2,3,4-tetrahydroisoquinolines was achieved photocatalytically using chalcogenorosamine photocatalysts and LED irradiation. The photocatalytic aza-Henry reaction between these substrates and nitromethane was more efficient with selenorosamine and tellurorosamine photocatalysts than with thiorosamine and rosamine photocatalysts, corresponding to the propensity of the photocatalysts to generate singlet oxygen (1O2). Appropriately, yields for the photocatalytic aza-Henry reaction were greatly reduced when the reactions were conducted under a nitrogen atmosphere. The 2-aryl-1,2,3,4-tetrahydroisoquinolines were oxidized to the corresponding 2-aryl-3,4-dihydroisoquinolones 13a–13cwith selenorosamine and tellurorosamine photocatalysts in 2% aqueous acetonitrile. Di-2-aryl-1,2,3,4-tetrahydroisoquinolin-1-yl peroxides 14aand 14bwere shown to be intermediates in this reaction. Thiorosamine photocatalysts, which do generate 1O2upon irradiation, did not give 2-aryl-3,4-dihydroisoquinolones. These results suggested that the exciplex between 1O2and the chalcogen atom of the chalcogenorosamines (the corresponding pertelluoxide, perselenoxide, or persulfoxide) and/or the hydrated perchalcogenoxide [hydroxy (perhydroxy)tellurane, -selenane, or -thiane] might be an active oxidant in the formation of 13a–13c. Computational methods were employed to provide support for the observed photocatalytic reactivity of the tellurorhodamine and selenorhodamine chromophores compared to the thiorosamine chromophores. ΔGvalues were determined for the oxidation and hydration of 10-Te, 10-Se, and 10-Sfor formation of perchalcogenoxides and hydroxyl(perhydroxy)chalcogenanes, respectively. Calculations indicate formation of the pertelluroxide perselenoxide, and persulfoxide exciplex intermediates are energetically favorable. Hydration of the exciplexes of 10-Teand 10-Sehave similarly small ΔGof −3.49 and 4.51 kcal/mol, respectively. However, a significantly higher ΔGvalue of +22.4 kcal/mol is observed for the hydration of 10-S, which suggests that this reactive intermediate is not readily formed.

Rhodamine photosensitizers (PSs) substituting S or Se for O in the xanthene ring give turnover numbers (TONs) as high as 9000 for the generation of hydrogen via the reduction of water using [CoIII(dmgH)2(py)Cl] (where dmgH = dimethylglyoximate and py = pyridine) as the catalyst and triethanolamine as the sacrificial electron donor. The turnover frequencies were 0, 1700, and 5500 mol H2/mol PS/h for O, S, and Se derivatives, respectively (ΦH2= 0%, 12.2%, and 32.8%, respectively), which correlates well with relative triplet yields estimated from quantum yields for singlet oxygen generation. Phosphorescence from the excited PS was quenched by the sacrificial electron donor. Fluorescence lifetimes were similar for the O- and S-containing rhodamines (∼2.6 ns) and shorter for the Se analog (∼0.1 ns). These data suggest a reaction pathway involving reductive quenching of the triplet excited state of the PS giving the reduced PS−that then transfers an electron to the Co catalyst. The longer-lived triplet state is necessary for effective bimolecular electron transfer. While the cobalt/rhodamine/triethanolamine system gives unprecedented yields of hydrogen for the photoreduction of water, mechanistic insights regarding the overall reaction pathway as well as system degradation offer significant guidance to developing even more stable and efficient photocatalytic systems.

Molecules with a strong two-photon response have gained significant interest because of their applications in two-photon imaging, all-optical switching, and energy up-conversion. The surface-enhanced hyper-Raman scattering (SEHRS) of tetramethyl chalcogenorosamines are taken on- and off-resonance and compared to time-dependent density functional theory calculations. Specifically, changes in the SEHRS spectra are tracked as a function of structural geometry because of perturbations induced by larger chalcogen atom substitutions to the xanthene ring. Here we show that the spectral changes and non-Condon effects can be understood by tracking the vibrational normal modes and the vibrationally induced changes to the highest occupied molecular orbitals. With a system in place to explore the relationship between structural geometry and nonlinear properties, various rhodamine derivatives can be characterized as a means to optimally design a series of two-photon bright compounds.

Various modern solar light-harvesting systems, including those used in photovoltaics and solar fuel production, depend on efficient electron transfer from a surface-bound molecular dye to nanoscopic semiconductor particles. However, the productive electron transfer competes with a variety of other relaxation pathways for the dye, and the dominant pathway can change dramatically depending on its environment. A new sulfur-substituted thiorhodamine dye was synthesized having exceptional light-harvesting qualities for solar energy applications and for solar hydrogen production in particular. The dye was created with a thiophene spacer bearing a phosphonate-ester (1-Ester) or phosphonic-acid (1-Acid) allowing for excellent solubility in MeCN or the ability to functionalize metal oxide semiconductor nanoparticles such as TiO2. While 1-Esteris found to be fully monomeric in MeCN, 1-Acidreadily forms H-aggregated dimers which, upon photoexcitation, undergo charge separation to an ion pair (IP) in 1.5 ps. For 1-Aciddimers, the stabilization of the IP causes an increase in lifetime to 270 ps compared to the 75 ps lifetime of the monomer. When 1-Acidis attached to TiO2, the inhomogeneous surface creates a distribution of chromophore packing structures where a range of transition dipole coupling environments is present such that both excimers and IPs can form. In a variety of solvent environments, ultrafast electron injection was found to occur in <300 fs from the dye to the semiconductor while IP formation occurs in 2–4 ps. For all aggregates studied, the photophysics was the same whether pumped at 620 nm, exciting to the 0–0 absorption band, or at 565 nm to the 0–1 transition that is dramatically enhanced by transition-dipole coupling in the H-aggregate. Surprisingly, the long-time, >2 ns, persistent formation of the charge-separated state following charge injection to TiO2only accounts for ∼10% of the photoexcited population, with the dominant relaxation pathways being IP and excimer formation. IP and excimer formation lower the total energy of the aggregate below the conduction band edge of TiO2, deactivating the electron transfer process. The implications of IP and excimer formation in systems for solar light harvesting are discussed.

Correction for ‘Multiplexed molecular imaging with surface enhanced resonance Raman scattering nanoprobes reveals immunotherapy response in mice viamultichannel image segmentation’ by Chrysafis Andreou et al., Nanoscale Horiz., 2022, 7, 1540–1552, https://doi.org/10.1039/d2nh00331g.

Multidrug resistance proteins (MRPs) mediate the ATP-dependent efflux of structurally diverse compounds, including anticancer drugs and physiologic organic anions. Five classes of chalcogenopyrylium dyes (CGPs) were examined for their ability to modulate transport of [3H]estradiol glucuronide (E217βG; a prototypical MRP substrate) into MRP-enriched inside-out membrane vesicles. Additionally, some CGPs were tested in intact transfected cells using a calcein efflux assay. Sixteen of 34 CGPs inhibited MRP1-mediated E217βG uptake by >50% (IC50values: 0.7–7.6 µM). Of 9 CGPs with IC50values ≤2 µM, two belonged to class I, two to class III, and five to class V. When tested in the intact cells, only 4 of 16 CGPs (at 10 µM) inhibited MRP1-mediated calcein efflux by >50% (III-1, V-3, V-4, V-6), whereas a fifth (I-5) inhibited efflux by just 23%. These five CGPs also inhibited [3H]E217βG uptake by MRP4. In contrast, their effects on MRP2 varied, with two (V-4, V-6) inhibiting E217βG transport (IC50values: 2.0 and 9.2 µM) and two (V-3, III-1) stimulating transport (>2-fold), whereas CGP I-5 had no effect. Strikingly, although V-3 and V-4 had opposite effects on MRP2 activity, they are structurally identical except for their chalcogen atom (Se versus Te). This study is the first to identify class V CGPs, with their distinctive methine or trimethine linkage between two disubstituted pyrylium moieties, as a particularly potent class of MRP modulators, and to show that, within this core structure, differences in the electronegativity associated with a chalcogen atom can be the sole determinant of whether a compound will stimulate or inhibit MRP2.

We used transient absorption spectroscopy to characterize excited-state electron injection from a 2,7-bis(dimethylamino)-9-(2-thienyl-5-carboxy)selenoxanthylium dye (1-Se) and a 2,7-bis(dimethylamino)-9-(3-thienyl-2-carboxy)selenoxanthylium dye (2-Se) to TiO2. Monolayers of 1-Seon nanocrystalline TiO2films consisted of both H-aggregated and nonaggregated dyes, whereas 2-Seunderwent little or no aggregation upon adsorption. Two transient spectral signals were correlated with the dication radicals (1-Se+and 2-Se+) generated by electron injection: an absorption at wavelengths shorter than 540 nm and a bleach from approximately 540−650 nm. Relative quantum yields for electron injection (ϕinj) were calculated from the measured amplitudes of these signals. The value of ϕinjfor H-aggregated 1-Sewas approximately 2-fold greater than ϕinjfor nonaggregated 1-Seand approximately 3-fold greater than ϕinjfor nonaggregated 2-Se. Thus, H-aggregation can increase both the light-harvesting efficiencies and the electron-injection yields of rhodamine derivatives. Our findings suggest that controlled aggregation of organic dyes may represent an attractive strategy for improving the global energy-conversion efficiencies of organic dye-sensitized solar cells and photocatalysts.

Photodynamic therapy is a relatively recent addition to the clinic, primarily for the treatment of cancer but also for psoriasis, age-related macular degeneration and other diseases. Photodynamic therapy utilises a photosensitiser that targets the disease site to produce a photochemical reaction following delivery of light. The properties of the photosensitiser are critical to the outcome of the technique and numerous classes have been developed in the past decade, including porphyrins and related compounds, chlorins, phthalocyanines, naphthalocyanines, texaphyrins, core-modified porphyrins and various cationic dyes. The potential of this technique is apparent from the extensive number of patents that have been awarded over the past three years.

Series of 5,10,15,20-tetraarylporphyrins 1 and 5,10,15,20-tetrakis[4-(arylethynyl)phenyl]porphyrins 2 were prepared via condensation of pyrrole with the appropriate benzaldehyde or 4-(arylethynyl)benzaldehyde derivative (3). Condensation of meso-phenyldipyrromethane with mixtures of benzaldehyde and 4-(trimethylsilyl-ethynyl)benzaldehyde gave a separable mixture of mono- (6), bis- (both cis-7 and trans-8) and tris[4-(trimethylsilylethynyl)phenyl]porphyrin (9). Following removal of the trimethylsilyl groups of 6–9, the 4-ethynylphenyl groups of 11–14 were coupled to 1-iodo-3,5-di(trifluoromethyl)benzene with Pd(OAc)2 to give 15–18 bearing one, two (both cis- and trans-) and three 4-[bis-3,5-(trifluoromethyl)phenylethynyl]phenyl groups respectively. Coupling of 11 and 1-iodo-4-nitrobenzene with Pd(OAc)2 gave porphyrin 19 with one 4-(4-nitrophenylethynyl)phenyl group. Porphyrin 24 with a p-quinone linked to the porphyrin core via a phenylethynyl group was prepared via similar chemistry. The absorbance spectra, emission maxima, excited-state fluorescence lifetimes, quantum yields of fluorescence, rates of fluorescence and rates of non-radiative decay were measured for each of the porphyrins. Absorbance spectra and emission maxima were nearly identical for all the porphyrins of this study, which suggests that the aryl groups and 4-(arylethynyl)phenyl groups are not strongly coupled to the porphyrin core in these metal-free compounds. Fluorescence quantum yields and rates of radiative decay were larger for porphyrins bearing 4-(arylethynyl)phenyl groups, while excited-state fluorescence lifetimes were somewhat shorter. These effects were additive for each additional 4-(arylethynyl)phenyl group. Copyright © 2000 John Wiley & Sons, Ltd.

Series of 5,10,15,20-tetraarylporphyrins 1and 5,10,15,20-tetrakis[4-(arylethynyl)phenyl]porphyrins 2were prepared via condensation of pyrrole with the appropriate benzaldehyde or 4-(arylethynyl)benzaldehyde derivative (3). Condensation of meso-phenyldipyrromethane with mixtures of benzaldehyde and 4-(trimethylsilyl-ethynyl)benzaldehyde gave a separable mixture of mono- (6), bis- (both cis-7and trans-8) and tris[4-(trimethylsilylethynyl)phenyl]porphyrin (9). Following removal of the trimethylsilyl groups of 6–9, the 4-ethynylphenyl groups of 11–14were coupled to 1-iodo-3,5-di(trifluoromethyl)benzene with Pd(OAc)2to give 15–18bearing one, two (both cis- and trans-) and three 4-[bis-3,5-(trifluoromethyl)phenylethynyl]phenyl groups respectively. Coupling of 11and 1-iodo-4-nitrobenzene with Pd(OAc)2gave porphyrin 19with one 4-(4-nitrophenylethynyl)phenyl group. Porphyrin 24with a p-quinone linked to the porphyrin core via a phenylethynyl group was prepared via similar chemistry. The absorbance spectra, emission maxima, excited-state fluorescence lifetimes, quantum yields of fluorescence, rates of fluorescence and rates of non-radiative decay were measured for each of the porphyrins. Absorbance spectra and emission maxima were nearly identical for all the porphyrins of this study, which suggests that the aryl groups and 4-(arylethynyl)phenyl groups are not strongly coupled to the porphyrin core in these metal-free compounds. Fluorescence quantum yields and rates of radiative decay were larger for porphyrins bearing 4-(arylethynyl)phenyl groups, while excited-state fluorescence lifetimes were somewhat shorter. These effects were additive for each additional 4-(arylethynyl)phenyl group.

Enol ethers 9are formed as a mixture of E and Zisomers from the addition of ethanol to 1,4pentadiyn3ones 2in sodium ethoxideethanol. The enol ethers react with disodium chalcogenides to give the corresponding 2,6disubstituted chalcogenopyranones 1bearing alkyl, aryl, or heteroaryl substituents in high yield as the only heterocyclic product of reaction. Diynones 2react with disodium chalcogenides to give mixtures of products in which the chalcogenopyranones 1are minor components and the dihydrochalcogenophenes 3are the major products. The addition of hydrogen sulfide to diynone 2bin ethanol gives a product mixture nearly identical to that observed for the addition of disodium sulfide in sodium ethoxide in ethanol to 2b. Intermediates for the addition of hydrogen chalcogenides and disodium chalcogenides to both 2and 9are described, which lead to the heterocyclic products.

Asymmetric synthesis of (3 S,4 S)-3-phenylsulfonyl-4-phenylazetidin-2-ones in up to 46% ee from achiral amines and 2-phenylsulfonyl-3-phenylpropenoyl chloride was achieved with chiral Lewis-acid catalysis by salen-copper(II) complexes derived from (1 R,2 R)-(−)-1,2-diaminocyclohexane. The absolute configuration was assigned by single crystal, X-ray crystallographic analysis of enantiomerically pure (3 S,4 S)-(−)-3-phenylsulfonyl-4-phenylazetidin-2-one ( 7).

No relevant conflicts of interest to declare.