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Two dual stimuli-activated photosensitizers were developed, in which two or three glutathione (GSH)-responsive 2,4-dinitrobenzenesulfonate (DNBS)-substituted zinc(II) phthalocyanine units were connected via one or two cathepsin B-cleavable Gly-Phe-Leu-Gly peptide linker(s). These dimeric and trimeric phthalocyanines were fully quenched in the native form due to the photoinduced electron transfer to the DNBS substituents and the self-quenching of the phthalocyanine units. In the presence of GSH and cathepsin B, or upon internalization into A549 and HepG2 cancer cells, these probes were activated through the release of free phthalocyanine units. The intracellular fluorescence intensity was increased upon post-incubation with GSH ester or reduced upon pre-treatment with a cathepsin B inhibitor. Upon light irradiation, these photosensitizers became highly cytotoxic with IC 50 values of 0.21-0.39 μM. The photocytotoxicity was also dependent on the intracellular GSH and cathepsin B levels. The results showed that these conjugates could serve as smart photosensitizers for targeted photodynamic therapy.

A combined stimulus-responsive photosensitiser and drug release system based on mesoporous silica nanoparticles was prepared. This nanoplatform encapsulated molecules of zinc(ii) phthalocyanine substituted with a glutathione-cleavable 2,4-dinitrobenzenesulfonate quencher and doxorubicin linked via a singlet-oxygen-cleavable 9,10-dialkoxyanthracene linker. In the presence of glutathione (in mM range) and upon irradiation (λ > 610 nm), the phthalocyanine units were activated by detaching from the quenching component to emit fluorescence and generate singlet oxygen. The latter subsequently cleaved the 9,10-dialkoxyanthracene linker to trigger the release of a doxorubicin derivative. The glutathione- and light-controlled activation and drug-release processes on this nanoplatform were demonstrated in phosphate buffered saline. The activation in fluorescence emission by intracellular thiols was also shown inside HepG2 human hepatocellular carcinoma cells. Upon irradiation, the nanosystem exhibited high cytotoxicity due to the photodynamic effect of the activated phthalocyanine units, but the cytotoxic effect of the released Dox moieties was not notable probably due to their reduced cytotoxicity as a result of the pendant substituent and the low drug loading in the nanoparticles.

A zinc(II) phthalocyanine substituted with three 2,4-dinitrobenzenesulfonate (DNBS) groups and a cyclic arginine-glycine-aspartic acid (cRGDfK) moiety was prepared and characterized. With three strongly electron-withdrawing DNBS groups, this compound was fully quenched in terms of fluorescence emission and singlet oxygen generation in N,N-dimethylformamide and phosphate buffered saline due to the strong photoinduced electron transfer effect. In the presence of glutathione (GSH), which is the most abundant intracellular thiol particularly in tumor cells, the DNBS moieties were cleaved, thereby restoring these photoactivities and making the conjugate as a GSH-activated photosensitizer. Being a well-known integrin antagonist, the cyclic RGD peptide sequence could enhance the localization of the conjugate in integrin-upregulated tumor cells. As shown by confocal laser scanning microscopy and flow cytometry, the intracellular fluorescence intensity of the conjugate was significantly higher in the integrin-positive A549 and MDA-MB-231 cells than in the integrin-negative MCF-7 and HEK293 cells. The photocytotoxicity of the conjugate against MDA-MB-231 cells was also higher than that toward MCF-7 cells. The results suggest that this dual-functional photosensitizer is a promising candidate for targeted photodynamic therapy., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A series of disulfide-linked dendritic phthalocyanines were synthesized by using the Cu I -catalyzed alkyne-azide cycloaddition reaction as the key step. Whereas these compounds were essentially nonaggregated in N,N-dimethylformamide, they were stacked in citrate solution (pH 7.4, with 1 % Cremophor EL), as shown by the broad appearance of their Q-band absorption. Having two-to-six zinc(II) phthalocyanine units in a molecule, these compounds were significantly self-quenched, particularly in citrate solution. Both the fluorescence intensity and singlet-oxygen generation efficiency were significantly lower than those of the monomeric counterparts, and the self-quenching efficiency increased as the number of phthalocyanine units increased. Upon interaction with 5 mm glutathione (GSH) in citrate solution, the fluorescence intensity of these compounds increased as a result of cleavage of the disulfide linkages and separation of the phthalocyanine units, which thereby reduced the self-quenching effect. The "on/off" ratios were found to be 7, 18, 23, and 21 for the dimeric (PC2), trimeric (PC3), tetrameric (PC4), and hexameric (PC6) systems, respectively. GSH also enhanced the fluorescence emission inside human colon adenocarcinoma HT29 cells and promoted the formation of singlet oxygen of these compounds. Upon irradiation, their half maximal inhibitory concentration (IC 50 ) values were found to be in the range of 0.18 to 0.38 μm. Finally, the biodistribution and activation of PC2 and PC6 were also examined in HT29 tumor-bearing nude mice. For both compounds, the fluorescence intensity per unit area at the tumor was found to grow gradually during the first 24 h. Whereas the intensity then dropped for PC2, the intensity for PC6 remained steady over the following 6 d, which might have been a result of the enhanced permeability and retention effect arising from the larger molecular mass of the hexameric system., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A biotin-conjugated disulfide-linked tris(phthalocyanine) has been synthesised and characterised. As shown by electronic absorption and steady-state fluorescence spectroscopy methods, the compound remains non-aggregated in N,N-dimethylformamide, but is significantly aggregated in phosphate buffered saline with 1% Cremophor EL. The reduction in fluorescence intensity and singlet oxygen generation efficiency as compared with the monomeric counterpart suggests that the tris(phthalocyanine) exhibits an excellent self-quenching effect, particularly in an aqueous medium. Upon interaction with glutathione, both the fluorescence emission and singlet oxygen production can be restored as a result of the cleavage of the disulfide linkages, thereby releasing the phthalocyanine units and reducing their aggregation and self-quenching effects. With a biotin moiety, this tris(phthalocyanine) is preferentially taken up by the biotin-receptor-positive HeLa cells and activated by the intracellular glutathione, resulting in fluorescence recovery and photocytotoxicity with an IC 50 value of 0.68 μM. This compound can therefore act as a dual functional photosensitiser.

An efficient ferrocenyl BODIPY based dark quencher has been developed and employed to construct a FRET-based fluorescent probe that contains a biotin moiety as a potential directing ligand for cancer cells and a glutathione-cleavable disulfide linker connecting the quencher and a distyryl BODIPY fluorophore. This molecular probe is deactivated in the native form through FRET followed by intramolecular charge transfer due to the ferrocenyl unit. However, upon interaction with glutathione in phosphate buffered saline and inside cancer cells, the fluorescence emission is significantly increased due to detachment of the fluorophore from the quencher. As shown by flow cytometry, this probe also exhibits preferential uptake by the biotin-receptor-expressing A549 human lung adenocarcinoma epithelial cells over the Chinese hamster ovary CHO-K1 cells used as the negative control. On the basis that both biotin receptor and GSH level are often overexpressed or elevated in cancer cells, this dual functional fluorescent probe serves as a promising agent for cancer imaging.

A zinc(II) phthalocyanine substituted with a 2,4-dinitrobenzenesulfonate group has been prepared. Its fluorescence emission and reactive oxygen species generation can be greatly enhanced by glutathione in phosphate-buffered saline and inside MCF-7 cells. This compound thus functions as a highly efficient molecular-based activatable photosensitizer., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A multifunctional photodynamic molecular beacon (PMB) has been designed and synthesized which contains an epidermal growth factor receptor (EGFR)‐targeting cyclic peptide and a trimeric phthalocyanine skeleton in which the three zinc(II) phthalocyanine units are each substituted with a glutathione (GSH)‐responsive 2,4‐dinitrobenzenesulfonate (DNBS) quencher and are linked via two cathepsin B‐cleavable GFLG peptide chains. This tailor‐made conjugate is fully quenched in the native form due to the photoinduced electron transfer effect of the DNBS moieties and the self‐quenching of the phthalocyanine units. It can target the EGFR overexpressed in cancer cells, and after receptor‐mediated endocytosis, it can be activated selectively by the co‐existence of intracellular GSH and cathepsin B, both of which are also overproduced in cancer cells, in terms of fluorescence emission and singlet oxygen generation. The cell‐selective behavior of this PMB has been demonstrated using a range of cancer cells with different expression levels of EGFR, while the stimuli‐responsive properties have been studied both in vitro and in various aqueous media. The overall results show that this advanced PMB, which exhibits several levels of control of the tumor specificity, is a promising photosensitizer for precise antitumoral photodynamic therapy. [ABSTRACT FROM AUTHOR]

An efficient near‐infrared‐absorbing dark quencher based on ferrocenyl boron dipyrromethene (BODIPY) has been developed and used to construct a fluorescence resonance energy transfer (FRET)‐based activatable photosensitizer. This smart photosensitizer contains a zinc(II) phthalocyanine as the photosensitizing unit which is conjugated to this dark quencher through a glutathione‐cleavable disulfide linker. The photoactivities of the phthalocyanine unit are largely quenched through FRET to the BODIPY unit followed by photoinduced electron transfer from the attached ferrocenyl moiety. Upon exposure to glutathione in phosphate buffered saline and inside HT29 human colorectal adenocarcinoma cells, the fluorescence emission and singlet oxygen generation efficiency of the photosensitizer are significantly enhanced due to cleavage of the disulfide bond and detachment of the dark quencher from the photosensitizing unit. The activation in fluorescence emission has also been demonstrated in tumor‐bearing nude mice. The glutathione‐responsive behavior has been verified by comparison with the negative results of a non‐cleavable analogue. The results suggest that ferrocenyl BODIPYs could serve as tailorable dark quenchers and the disulfide‐linked phthalocyanine–quencher conjugate acts as an efficient glutathione‐activated photosensitizer for photodynamic therapy. [ABSTRACT FROM AUTHOR]

Abstract: A series of disulfide‐linked dendritic phthalocyanines were synthesized by using the CuI‐catalyzed alkyne–azide cycloaddition reaction as the key step. Whereas these compounds were essentially nonaggregated in N,N‐dimethylformamide, they were stacked in citrate solution (pH 7.4, with 1 % Cremophor EL), as shown by the broad appearance of their Q‐band absorption. Having two‐to‐six zinc(II) phthalocyanine units in a molecule, these compounds were significantly self‐quenched, particularly in citrate solution. Both the fluorescence intensity and singlet‐oxygen generation efficiency were significantly lower than those of the monomeric counterparts, and the self‐quenching efficiency increased as the number of phthalocyanine units increased. Upon interaction with 5 m m glutathione (GSH) in citrate solution, the fluorescence intensity of these compounds increased as a result of cleavage of the disulfide linkages and separation of the phthalocyanine units, which thereby reduced the self‐quenching effect. The “on/off” ratios were found to be 7, 18, 23, and 21 for the dimeric (PC2), trimeric (PC3), tetrameric (PC4), and hexameric (PC6) systems, respectively. GSH also enhanced the fluorescence emission inside human colon adenocarcinoma HT29 cells and promoted the formation of singlet oxygen of these compounds. Upon irradiation, their half maximal inhibitory concentration (IC50) values were found to be in the range of 0.18 to 0.38 μ m. Finally, the biodistribution and activation of PC2 and PC6 were also examined in HT29 tumor‐bearing nude mice. For both compounds, the fluorescence intensity per unit area at the tumor was found to grow gradually during the first 24 h. Whereas the intensity then dropped for PC2, the intensity for PC6 remained steady over the following 6 d, which might have been a result of the enhanced permeability and retention effect arising from the larger molecular mass of the hexameric system. [ABSTRACT FROM AUTHOR]

A zinc(II) phthalocyanine substituted with a 2,4-dinitrobenzenesulfonate group has been prepared. Its fluorescence emission and reactive oxygen species generation can be greatly enhanced by glutathione in phosphate-buffered saline and inside MCF-7 cells. This compound thus functions as a highly efficient molecular-based activatable photosensitizer. [ABSTRACT FROM AUTHOR]

Front Cover: A Phthalocyanine-Based Glutathione-Activated Photosensitizer with a Ferrocenyl Boron Dipyrromethene Dark Quencher for Photodynamic Therapy (ChemPhotoChem 10/2019) Keywords: boron dipyrromethene; dark quenchers; glutathione; photodynamic therapy; phthalocyanines Boron dipyrromethene, dark quenchers, glutathione, photodynamic therapy, phthalocyanines. [Extracted from the article]

Smart photosensitizers that can be activated selectively by tumor‐associated stimuli are of great potential for targeted photodynamic therapy. They can enhance the overall therapeutic outcome and reduce undesirable side effects. In their Communication on page 6241 ff., H. He, P.‐C. Lo, and D. K. P. Ng report a simple, yet highly efficient, phthalocyanine‐based photosensitizer. Its fluorescence emission and reactive oxygen species generation are greatly enhanced by glutathione, both in phosphate‐buffered saline and inside cancer cells. The activation of this photosensitizer has also been demonstrated in tumor‐bearing nude mice. [ABSTRACT FROM AUTHOR]