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Senescence is a cellular response having physiological and reparative functions to preserve tissue homeostasis and suppress tumor growth. However, the accumulation of senescent cells would cause deleterious effects that lead to age‐related dysfunctions and cancer progression. Hence, selective detection and elimination of senescent cells are crucial yet remain a challenge. A β‐galactosidase (β‐gal)‐activated boron dipyrromethene (BODIPY)‐based photosensitizer (compound 1) is reported here that can selectively detect and eradicate senescent cells. It contains a galactose moiety connected to a pyridinium BODIPY via a self‐immolative nitrophenylene linker, of which the photoactivity is effectively quenched. Upon interactions with the senescence‐associated β‐gal, it undergoes enzymatic hydrolysis followed by self‐immolation, leading to the release of an activated BODIPY moiety by which the fluorescence emission and singlet oxygen generation are restored. The ability of 1 to detect and eliminate senescent cells is demonstrated in vitro and in vivo, using SK‐Mel‐103 tumor‐bearing mice treated with senescence‐inducing therapy. The results demonstrate that 1 can be selectively activated in senescent cells to trigger a robust senolytic effect upon irradiation. This study breaks new ground in the design and application of new senolytic agents based on photodynamic therapy. [ABSTRACT FROM AUTHOR]

As an effective and non‐invasive treatment modality for cancer, photodynamic therapy (PDT) has attracted considerable interest. With the recent advances in the photosensitizing agents, the fiber‐optic systems, and other aspects, its application is extended to a wide range of superficial and localized cancers. However, for the few clinically used photosensitizers, most of them suffer from the drawback of causing prolonged photosensitivity after the treatment. As a result, post‐PDT management is also a crucial issue. Herein, a facile bioorthogonal approach is reported that can effectively suppress this common side effect of PDT in nude mice. It involves the use of an antidote that contains a black‐hole quencher BHQ‐3 conjugated with a bicyclo[6.1.0]non‐4‐yne (BCN) moiety and a tetrazine‐substituted boron dipyrromethene‐based photosensitizer. By using tumor‐bearing nude mice as an animal model, it is demonstrated that after PDT with this photosensitizer, the administration of the antidote can effectively quench the photodynamic activity of the residual photosensitizer by bringing the BHQ‐3 quencher close to the photosensitizing unit through a rapid click reaction. It results in substantial reduction in skin damage upon light irradiation. The overall results demonstrate that this simple and facile strategy can provide an effective means for minimizing the photosensitivity after PDT. [ABSTRACT FROM AUTHOR]

A water‐soluble 1,2,4,5‐tetrazine‐substituted carbon‐dipyrromethene (C–DIPY) was synthesized from the previously reported carbonyl pyrrole dimer through a two‐step procedure. Owing to the presence of a tetrazine moiety, the fluorescence emission of this compound was largely quenched in phosphate‐buffered saline at pH 7.4. Upon addition of a bicyclo[6.1.0]non‐4‐yne (BCN) derivative, the tetrazine‐based quenching component of the compound was disrupted through the inverse electron‐demand Diels‐Alder reaction to restore the fluorescence in up to 6.6‐fold. This bioorthogonal activation was also demonstrated using U‐87 MG human glioblastoma cells, in which the fluorescence intensity of this C–DIPY could be enhanced by 8.7‐fold upon post‐incubation with the BCN derivative. The results showed that this tetrazine‐caged C–DIPY can serve as a bioorthogonally activatable fluorescent probe for bioimaging. The compound, however, was found to reside preferentially in the lysosomes instead of the mitochondria of the cells as predicted based on its cationic character, which could be attributed to its energy‐dependent endocytic cellular uptake pathway, for which lysosomes are the end station. [ABSTRACT FROM AUTHOR]

A series of di‐α‐substituted zinc(II) phthalocyanines with different number of galactose moieties, ranging from 1 to 8, namely Pc‐galn (n=1, 2, 4, and 8) were designed and synthesized. The synthesis involved the copper‐catalyzed azide‐alkyne cycloaddition reaction of a mono‐ or dialkynyl zinc(II) phthalocyanine with an acetyl‐protected galactosyl azide or its dendritic derivative with four acetyl‐protected galactosyl groups, followed by removal of the acetyl protecting groups via alkaline hydrolysis. In N,N‐dimethylformamide, these oligogalactosyl phthalocyanines were non‐aggregated as shown by the strong Q‐band absorption and fluorescence emission. Owing to the di‐α‐substitution, they also behaved as efficient singlet oxygen generators upon light irradiation with a singlet oxygen quantum yield of 0.84. The spectroscopic and photophysical properties were not affected by the number of galactosyl units. In contrast, the compounds became significantly aggregated and quenched in phosphate‐buffered saline. Their cellular uptake was then studied using a range of cell lines, which generally followed the order Pc‐gal1>Pc‐gal2≈Pc‐gal4>Pc‐gal8. Interestingly, the di‐galactosyl analogue exhibited selective uptake against HeLa human cervical carcinoma cells through an energy‐dependent pathway instead of the expected asialoglycoprotein receptor. Upon light irradiation, it could effectively kill the cells with a half‐maximal inhibitory concentration of 0.58 μM. [ABSTRACT FROM AUTHOR]

Targeted delivery and specific activation of photosensitizers can greatly improve the treatment outcome of photodynamic therapy. To this end, we report herein a novel dual receptor‐mediated bioorthogonal activation approach to enhance the tumor specificity of the photodynamic action. It involves the targeted delivery of a biotinylated boron dipyrromethene (BODIPY)‐based photosensitizer, which is quenched in the native form by the attached 1,2,4,5‐tetrazine unit, and an epidermal growth factor receptor (EGFR)‐targeting cyclic peptide conjugated with a bicycle[6.1.0]non‐4‐yne moiety. Only for cancer cells that overexpress both the biotin receptor and EGFR, the two components can be internalized preferentially where they undergo an inverse electron‐demand Diels–Alder reaction, leading to restoration of the photodynamic activity of the BODIPY core. By using a range of cell lines with different expression levels of these two receptors, we have demonstrated that this stepwise "deliver‐and‐click" approach can confine the photodynamic action on a specific type of cancer cells. [ABSTRACT FROM AUTHOR]

A 1H-3-benzazepine-modified aza-boron dipyrromethene dimer was synthesized by condensation of 2-amino-1H-3-benzazepine with a diamino β-isoindigo, followed by complexation with BF3·OEt2. It possesses an axial chirality with a Ci symmetry as shown by heteronuclear NMR spectroscopy. Treatment of this compound with tritylium tetrafluoroborate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone led to the unexpected mono deborylation instead of yielding the desired fully conjugated benzazepine-modified analogue. Upon mono deborylation, the electronic absorption band at 605 nm became significantly weakened and split, which could be attributed to the lowering of the molecular symmetry. [ABSTRACT FROM AUTHOR]