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A new series of di-α-substituted zinc(II) phthalocyanine derivatives have been prepared by mixed cyclisation of the corresponding 1,4-disubstituted phthalonitriles or naphthalonitriles with an excess of unsubstituted phthalonitrile in the presence of Zn(OAc)2.2H2O and 1,8-diazabicyclo[5.4.0]undec-7-ene. Having a large hydrophobic macrocyclic core substituted with two hydrophilic triethylene glycol chains or glycerol moieties, these compounds are amphiphilic in nature. They are highly soluble and remain non-aggregated in DMF as shown by the intense and sharp Q-band absorption. Compared with the unsubstituted zinc(II) phthalocyanine, these di-α-substituted analogues exhibit a red-shifted Q band (at 689-701 nm), a relatively weaker fluorescence emission, and a higher efficiency to generate singlet oxygen. Upon illumination, these compounds are highly cytotoxic towards HT29 human colorectal carcinoma and HepG2 human hepatocarcinoma cells with IC50 values as low as 0.06 mM. The high photocytotoxicity of these compounds can be attributed to their high cellular uptake and low aggregation tendency in the biological media, leading to a high efficiency to generate reactive oxygen species inside the cells. [ABSTRACT FROM AUTHOR]

Two novel glucoconjugated silicon(IV) phthalocyanines (compounds 3and 4) have been prepared and examined for their photophysical and biological properties. With two axial 1,2:5,6-di-O-isopropylidene--d-glucofuranose substituents linked to the silicon center through the tetraethylene glycol chain, both compounds are highly soluble and remain nonaggregated in N,N-dimethylformamide. The dichloro-substituted phthalocyanine 4exhibits a weaker fluorescence emission and higher efficiency to generate singlet oxygen compared with the nonchlorinated counterpart 3as a result of the heavy atom effect. Both compounds are highly photocytotoxic against HT29 human colorectal carcinoma and HepG2 human hepatocarcinoma cells, particularly the nonchlorinated phthalocyanine 3, of which the IC50values are as low as 6 nM. The lower photodynamic activity of the chlorinated derivative (IC5017−21 nM) can be attributed to its higher aggregation tendency in the biological media, leading to a lower efficiency to generate reactive oxygen species inside the cells. Fluorescence microscopic studies have also revealed that compound 3has a high and selective affinity to the lysosomes, but not the mitochondria, of HT29 cells. [ABSTRACT FROM AUTHOR]

A series of unsymmetrical distyryl BODIPYs have been prepared which function as highly potent photosensitisers with in vitro IC50values as low as 15 nM. Their cellular uptake, subcellular localisation and photocytotoxicity depend greatly on the styryl substituents. [ABSTRACT FROM AUTHOR]

Eye size is a key parameter of visual function, but the precise mechanisms of eye size control remain poorly understood. Here, we discovered that the lipogenic transcription factor sterol regulatory element-binding protein 2 (SREBP2) has an unanticipated function in the retinal pigment epithelium (RPE) to promote eye size in postnatal mice. SREBP2 transcriptionally represses low density lipoprotein receptor-related protein 2 (Lrp2), which has been shown to restrict eye overgrowth. Bone morphogenetic protein 2 (BMP2) is the downstream effector of Srebp2 and Lrp2, and Bmp2 is suppressed by SREBP2 transcriptionally but activated by Lrp2. During postnatal development, SREBP2 protein expression in the RPE decreases whereas that of Lrp2 and Bmp2 increases as the eye growth rate reduces. Bmp2 is the key determinant of eye size such that its level in mouse RPE inversely correlates with eye size. Notably, RPE-specific Bmp2 overexpression by adeno-associated virus effectively prevents the phenotypes caused by Lrp2 knock out. Together, our study shows that rapid postnatal eye size increase is governed by an RPE-derived signaling pathway, which consists of both positive and negative regulators of eye growth. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs), spherical biological vesicles, mainly contain nucleic acids, proteins, lipids and metabolites for biological information transfer between cells. Microparticles (MPs), a subtype of EVs, directly emerge from plasma membranes, and have gained interest in recent years. Specific cell stimulation conditions, such as ultraviolet and X-rays irradiation, can induce the release of MPs, which are endowed with unique antitumor functionalities, either for therapeutic vaccines or as direct antitumor agents. Moreover, the size of MPs (100-1000 nm) and their spherical structures surrounded by a lipid bilayer membrane allow MPs to function as delivery vectors for bioactive antitumor compounds, with favorable phamacokinetic behavior, immunostimulatory activity and biological function, without inherent carrier-specific toxic side effects. In this review, the mechanisms underlying MP biogenesis, factors that influence MP production, properties of MP membranes, size, composition and isolation methods of MPs are discussed. Additionally, the applications and mechanisms of action of MPs, as well as the main hurdles for their applications in cancer management, are introduced. [ABSTRACT FROM AUTHOR]

A series of silicon(IV) phthalocyanines substituted axially with different polyamine moieties have been prepared. Their fluorescence quantum yields (ΦF= 0.03−0.08) in N,N-dimethylformamide are low because of reductive quenching by the amino moieties. The values are significantly increased in aqueous media (ΦF= 0.12−0.21) as a result of protonation of the amino substituents. All the compounds are highly photocytotoxic against human colon adenocarcinoma HT29 cells and Chinese hamster ovary cells with IC50values as low as 1.1 nM. Flow cytometric studies of two selected compounds (2and 5) against HT29 cells have shown that they induce apoptosis extensively. As shown by confocal microscopy, these two compounds also show high affinity toward the lysosomes, but not the mitochondria, of the cells. Their in vivo photodynamic activity has also been investigated using HT29 tumor bearing nude mice. Both of them can effectively inhibit the growth of the tumor without causing apparent injury to the liver of the mice. [ABSTRACT FROM AUTHOR]

Photodynamic therapy is a treatment that combines the use of three non-toxic components, viz. photosensitiser, light and oxygen to cause localised oxidative photodamage. In the present study, the antifungal effect of the photosensitiser, BAM-SiPc, an unsymmetrical bisamino phthalocyanine, was investigated. BAM-SiPc was effective in photo-inactivating Candida albicans in a dose-dependent manner. The cell viability as determined by the clonogenic assay was reduced to c. 10% at 0.02 μmol l−1 BAM-SiPc with a total fluence of 12 J cm−2 at a cell density of 107 cells ml−1. A short incubation time of 5–15 min was sufficient to allow the photosensitiser to exert its optimal antifungal activity. Microscopical analysis showed that BAM-SiPc was effectively internalised by the fungal cells. Photodynamic treatment led to an increase in the intracellular reactive oxygen species level and disturbed the membrane integrity of the fungal cells. [ABSTRACT FROM AUTHOR]

We report a new class of photodynamic molecular beacon (PMB) with tumor specific mRNA-triggered control of singlet oxygen (1O2) production. The beacon contains a single-stranded oligonucleotide linker that forms a stem-loop structure (hairpin) in which the sequence is an antisense oligonucleotide (AS-ON) complementary to a target mRNA. The stem is formed by the annealing of two complementary arm sequences that are on either side of the loop sequence. A photosensitizer molecule (PS) is attached to the end of one arm and a quencher (Q) is similarly attached to the other end. The conformationally-restricted hairpin forces Q to efficiently silence the photoreactivity of PS. In the presence of target mRNA, the hairpin opens and the PS is no longer silenced. Upon irradiating with light, the PS then emits fluorescence and generates cytotoxic 1O2. To show proof of concept, we have synthesized a c-raf-1 mRNA-triggered PMB using pyropheophorbide (Pyro) as PS, carotenoid as Q and c-raf-1 mRNA-targeted AS-ON as the loop sequence. We show that the 1O2 production of Pyro is quenched in its native state by 15-fold and is restored 9-fold by the addition of the target RNA. Comparing this to our recently reported self-folding peptide linker-based PMB, the hairpin effect results in an enhanced 1O2 quenching efficiency that decreases the residual 1O2 production by over 3-fold, thus providing enhanced control of 1O2 production upon target-linker interactions. When incubated with c-raf-1 expressing MDA-MB-231 cancer cells, the PMB displayed efficient cellular uptake and subsequently effective PDT activation in targeted cells. [ABSTRACT FROM AUTHOR]

We recently introduced the concept of photodynamic molecular beacons (PMB) for selective control of photodynamic therapy (PDT). The PMB consists of a peptide linker that is sequence specific to a cancer-associated protease. A photosensitizer (PS) and a singlet oxygen (1O2) quencher are conjugated to the opposite ends of this linker. Proximity of the PS and quencher can efficiently inhibit 1O2 generation. In the presence of a targeted protease, the substrate sequence is cleaved and the PS and quencher will separate so that the PS can be photo-activated. There are two ways to optimize the PMB selectivity to cancer cells. The first is to increase the protease specificity to targeted cells and the second is to minimize the phototoxicity of intact (uncleaved) PMBs in non-targeted (normal) cells. Carotenoids (CARs) are well known in nature for their role in quenching excited states of PS and in directly scavenging 1O2. The purpose of this study is to evaluate whether the CAR with dual quenching modes (PS excited states deactivation and 1O2 scavenging) can be used to minimize the photodamage of intact PMBs to non-targeted cells. Thus, we synthesized a beacon (PPC) with a caspase-3 cleavable peptide linking a PS and a CAR quencher. It was confirmed that CAR deactivates the PS excited states and also directly scavenges 1O2. Moreover, the in vitro PDT response showed that CAR completely shuts off the photodynamic effect in non-targeted HepG2 cells, while PS without CAR (control) remains highly potent even at a much lower (30-fold) dose. [ABSTRACT FROM AUTHOR]

A stable 1:1 host−guest complex is formed between a silicon(IV) phthalocyanine conjugated axially with two permethylated -cyclodextrin units and a tetrasulfonated porphyrin. The complex exhibits a light-harvesting property and works as an efficient photosensitizing system, killing HT29 human colon adenocarcinoma cells with an IC50value of 0.09 M. [ABSTRACT FROM AUTHOR]

Two advanced boron dipyrromethene (BODIPY) based photosensitizers have been synthesized and characterized. With a glibenclamide analogous moiety, these compounds can localize in the endoplasmic reticulum (ER) of HeLa human cervical carcinoma cells and HepG2 human hepatocarcinoma cells. The BODIPY p skeleton is conjugated with two styryl or carbazolylethenyl groups, which can substantially red-shift the Q-band absorption and fluorescence emission and impart two-photon absorption (TPA) property to the chromophores. The TPA cross section of the carbazole-containing analogue reaches a value of 453 GM at 1010 nm. These compounds also behave as singlet oxygen generators with high photostability. Upon irradiation at λ > 610 nm, these photosensitizers cause photocytotoxicity to these two cell lines with IC50 values down to 0.09 μM, for which the cell death is triggered mainly by ER stress. The two-photon photodynamic activity of the distyryl derivative upon excitation at λ = 800 nm has also been demonstrated. [ABSTRACT FROM AUTHOR]

A zinc(II) phthalocyanine substituted with a triamino moiety and its tri-N-methylated analogue have been prepared and characterized with various spectroscopic methods. Both compounds remain non-aggregated in N,N-dimethylformamide and in water containing 0.05% Cremophor EL (v/v), and can generate singlet oxygen effectively. The photodynamic activities of these compounds have been examined against a range of bacterial strains, including the Gram-positive methicillin-sensitive Staphylococcus aureus ATCC 25923 and methicillin-resistant Staphylococcus aureus ATCC BAA-43, and the Gram-negative Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 27853. Both photosensitizers are highly cytotoxic, particularly for the two Gram-positive strains, for which as low as 5 nM of dye is required to induce a 4-log reduction of their viability. The tri-N-methylated derivative has also been shown to be able to effectively inhibit the growth of a series of clinical strains of Staphylococcus aureus and Escherichia coli, and biofilms of methicillin-resistant Staphylococcus aureus ATCC 67928 and ATCC 68507, and Staphylococcus epidermidis ATCC 35984. In addition, the photodynamic inactivation of a range of viruses using these two compounds has also been investigated. Both compounds are highly photocytotoxic against the enveloped viruses influenza A virus (H1N1) and herpes simplex virus type 1 (HSV1), but exhibit no significant cytotoxicity toward the non-enveloped viruses adenovirus type 3 (Ad3) and coxsackievirus (Cox B1). [ABSTRACT FROM AUTHOR]