Water soluble distyryl-boradiazaindacenes as efficient photosensitizers for photodynamic therapy

We introduce a novel class of water soluble, extended conjugation boradiazaindacene dyes which are efficient singlet oxygen generators and have spectacular photoinduced cytotoxicity when excited in the "therapeutic window" of the electromagnetic spectrum.     

Combinatorial synthesis and characterization of new asymmetric porphyrins as potential photosensitizers in photodynamic therapy

Porphyrins play a major role as active photosensitizers in noninvasive optical photodynamic therapy (PDT). In a modular approach, this paper presents a short review of the recent developments of porphyrin structures and materials with improved photosensitizing properties and then presents the synthesis and characterization of a series of new second generation asymmetrical meso-tetraphenylporphyrins varied by substituent in the meta positions of the phenyl rings with either -OH or -OCH3 groups, whereas in the para positions only with -OCH3 groups. The new series of differentially functionalized porphyrins were obtained by a combinatorial multicomponent synthesis (Adler-Longo method) by simultaneously using two different aldehydes: 3,4-dimethoxybenzaldehyde and 3-hydroxybenzaldehyde. The porphyrins were isolated, purified and characterized by HPLC, TLC, UV-vis, fluorescence, MS, 1H-NMR, and 13C-NMR analysis, accompanied by DEPT 135 experiments. Because of the fact that the medium in cancerous tissues is often more acidic than in normal tissues, the capacity of these porphyrins to exist simultaneously in aggregated and protonated forms was also investigated, in tetrahydrofuran (THF) and acid THF-water systems, underlying the changes in the photophysical behaviour. The relative fluorescence quantum yields (Phif) were calculated in comparison with meso-tetraphenylporphyrin (TPP), and the values between 0.14-0.26 were found to be promising for further trials. The series of asymmetrically substituted tetraphenylporphyrins, as the new class of supramolecular materials, are suitable for further functionalization in order to improve their photophysical properties, and they could represent interesting potential PDT photosensitizers.     

Synthesis of demethoxy-amino-substituted hypocrellins: novel photosensitizers for photodynamic therapy

Gastric cancer was one of the most common malicious diseases around the world1. Photodynamic therapy (PDT) has been applied to the treatment of gastric tumors since 1980’s and desirable results has been obtained. Hypocrellin B (HB), the natural perylenequinone pigment (PQP), was found to be new effective sensitizer in the photodynamic therapy by virtue of its photophysical, photochemical and photobiological properties2. Scheme 1. The structures of AHBDs AHBDsNevertheless, natural PQP…     

meso-tetraphenylporphyrin dimer derivatives as potential photosensitizers in photodynamic therapy. Part 2

Studies on the synthesis, singlet oxygen and fluorescence yields and pharmacokinetic properties of three different dimeric porphyrins with an amide linkage (D2-D4) are described and compared with the results recently reported for a dimeric porphyrin (D1). The pharmacokinetic behavior of all dimers were examined in Balb/c mice bearing MS-2 fibrosarcomas. The maximal efficiency and selectivity of photosensitizer accumulation in each tumor tissue takes place at 24 h after drug administration of 1.0 mg kg-1 into DL-alpha-dipalmitoylphosphatidylcholine liposomes by intravenous injection. Since the dimeric porphyrins exhibit high quantum yields of singlet oxygen generation, long triplet lifetimes and high photostability, the results obtained suggest that the evaluated dimeric structures may be promising candidates for further use in PDT experiments. The results also allow the possibility to establish a correlation between the chemical structure of the dyes and the efficiency/selectivity of the tumor accumulation and can be used for building up optimal photosensitizing agents for tumors.     

Synthesis of beta-galactose-conjugated chlorins derived by enyne metathesis as galectin-specific photosensitizers for photodynamic therapy.

A first report on the synthesis and biological evaluation of the beta-galactose-conjugated purpurinimides (a class of chlorins containing a six-membered fused imide ring system) as Gal-1 (galectin-1) recognized photosensitizers, prepared from purpurin-N-propargylimide via enyne metathesis, is discussed. On the basis of examination of the available crystal structure of the galectin-1 N-acetyllactose amine complex, it was considered that the chlorin-based photosensitizers could be introduced into a carbohydrate skeleton to expand the repertoire of the galectin-1-specific ligands. Preliminary molecular modeling analysis utilizing the modeled photosensitizers and the available crystal structures of galectin-carbohydrate complexes indicated that addition of the photosensitizer to the carbohydrate moiety at an appropriate position does not interfere with the galectin-carbohydrate recognition. Under similar drug and light doses, compared to the free purpurinimide analogue, the purpurinimides conjugated either with galactose or with lactose (Gal(beta1-4)-Glc) produced a considerable increase in photosensitizing efficacy in vitro. This indicates the possibility for development of a new class of specific photosensitizers for photodynamic therapy (PDT) based on recognition of a cellular receptor.     

Mixed acenannellated metallotetraazaporphins: a new class of amphiphilic photosensitizers for the photodynamic therapy of cancer

The first synthesis of amphiphilic mixed acenannellated metallotetraazaporphins compounds, designed with the aim of improving cell membrane penetration, is described and the preliminary results on their photocytotoxicity are presented.     

Research advances in the use of tetrapyrrolic photosensitizers for photodynamic therapy

Photodynamic therapy (PDT) is a promising new treatment modality for several diseases, most notably cancer. In PDT, light, O2, and a photosensitizing drug are combined to produce a selective therapeutic effect. Lately, there has been active research on new photosensitizer candidates, because the most commonly used porphyrin photosensitizers are far from ideal with respect to PDT. Finding a suitable photosensitizer is crucial in improving the efficacy of PDT. Recent synthetic activity has created such a great number of potential photosensitizers for PDT that it is difficult to decide which ones are suitable for which pathological conditions, such as various cancer species. To facilitate the choice of photosensitizer, this review presents a thorough survey of the photophysical and chemical properties of the developed tetrapyrrolic photosensitizers. Special attention is paid to the singlet-oxygen yield (PhiDelta) of each photosensitizer, because it is one of the most important photodynamic parameters in PDT. Also, in the survey, emphasis is placed on those photosensitizers that can easily be prepared by partial syntheses starting from the abundant natural precursors, protoheme and the chlorophylls. Such emphasis is justified by economical and environmental reasons. Several of the most promising photosensitizer candidates are chlorins or bacteriochlorins. Consequently, chlorophyll-related chlorins, whose PhiDelta have been determined, are discussed in detail as potential photosensitizers for PDT. Finally, PDT is briefly discussed as a treatment modality, including its clinical aspects, light sources, targeting of the photosensitizer, and opportunities.     

State of the art in the delivery of photosensitizers for photodynamic therapy

In photodynamic therapy, one of the problems limiting the use of many photosensitizers (PS) is the difficulty in preparing pharmaceutical formulations that enable their parenteral administration. Due to their low water solubility, the hydrophobic PS cannot be simply injected intravenously. Different strategies, including polymer-PS conjugation or encapsulation of the drug in colloidal carriers such as oil-dispersions, liposomes and polymeric particles, have been investigated. Although these colloidal carriers tend to accumulate selectively in tumour tissues, they are rapidly taken up by the mononuclear phagocytic system. In order to reduce this undesirable uptake by phagocytic cells, long-circulating carriers that consist of surface modified carriers have been developed. Moreover, considerable effort has been directed towards using other types of carriers to improve tumour targeting and to minimize the side effects. One of the approaches is to entrap PS into the lipophilic core of low-density lipoproteins (LDL) without altering their biological properties. The LDL receptor pathway is an important factor in the selective accumulation of PS in tumour tissue owing to the increased number of LDL receptors on the proliferating cell surface. Specific targeting can also be achieved by binding of monoclonal antibodies or specific tumour-seeking molecules to PS or by the coating of PS loaded carriers.     

New cyclometalated transition-metal based photosensitizers for singlet oxygen generation and photodynamic therapy

The aim of this review article is to introduce recent studies on an emergent class of singlet oxygen photosensitizers of potential applications to the photodynamic therapy,with a primary focus on the cyclometalated transition-metal complexes.Singlet oxygen photosensitization performances of various cyclometalated Ir and Pt scaffolds are reviewed,and the general photophysical properties of relevant systems and the mechanisms of singlet oxygen production via photo-sensitization are also briefly discussed.Thus far,investigations of singlet oxygen sensitization by such Ir and Pt complexes are mainly carried out in organic solvents and under non-physiological conditions,while some research efforts have been made at examining the feasibility of applying pertinent cyclometalated complexes to photodynamic therapy.     

Mitochondria-localized iridium(III) complexes with anthraquinone groups as effective photosensitizers for photodynamic therapy under hypoxia

Science China Chemistry - Photodynamic therapy (PDT) is a potential way for the tumor treatment. However, it notably suffers the limitation of hypoxia in solid tumors. Thus, it is significant to...     

Optimal photosensitizers for photodynamic therapy of infections should kill bacteria but spare neutrophils

Photodynamic therapy (PDT) for localized microbial infections exerts its therapeutic effect both by direct bacterial killing and also by the bactericidal effects of host neutrophils stimulated by PDT. Therefore, PDT-induced damage to neutrophils must be minimized, while direct photoinactivation of bacteria is maintained to maximize the therapeutic efficacy of antimicrobial PDT in vivo. However, there has been no study in which the cytocidal effect of PDT on neutrophils was investigated. In this study, the cytocidal effects of PDT on neutrophils were evaluated using different antimicrobial photosensitizers to find suitable candidate photosensitizers for antimicrobial PDT. PDT on murine peripheral-blood neutrophils was performed in vitro using each photosensitizer at a concentration that exerted a maximum bactericidal effect on methicillin-resistant Staphylococcus aureus, and morphological alteration and viability of neutrophils were studied. Most neutrophils were viable (>80%) after PDT using toluidine blue-O (TB) or methylene blue (MB), while neutrophils showed morphological change and their viabilities were decreased (<70%) after PDT using other photosensitizers (erythrosine B, rose bengal, crystal violet, Photofrin, new methylene blue and Laserphyrin). These results suggest that PDT using TB or MB can preserve host neutrophils while exerting a significant therapeutic effect on in vivo localized microbial infection.     

Co-delivery of enzymes and photosensitizers via metal-phenolic network capsules for enhanced photodynamic therapy

The intrinsic hypoxic tumor microenvironment and limited accumulation of photosensitizers（PSs） result in unsatisfied efficiency of photodynamic therapy（PDT）.To enhance the PDT efficiency against solid tumors,a functional oxygen self-supplying and PS-delivering nanosystem is fabricated via the combination of catalase（CAT）,chlorin e6（Ce6） and metal-phenolic network（MPN） capsule.It is demonstrated that the CAT encapsulated in the capsules（named CCM capsules） could catalyze the degradation of hydrog...     

Iodine substituted phosphorus corrole complexes as possible photosensitizers in photodynamic therapy: Insights from theory

The search for new dyes to be used as photosensitizers in photodynamic therapy (PDT) is a field of great interest from both experimental and theoretical viewpoints. In this study, the main photophysical properties (excitation energies, singlet-triplet energy gap, and spin orbit coupling matrix elements) of some unsubstituted and iodine substituted phosphorus corrole complexes have been determined by using density functional theory and its time-dependent formulation. Results show that these compounds can be proposed as photosensitizers in PDT. The heavy atom effects have been rationalized on the basis of El-Sayed rules.     

Chemically modified fullerene derivatives as photosensitizers in photodynamic therapy: A first‐principles study

The first‐principles density functional theory (DFT) and its time‐dependent approach (TD‐DFT) are used to characterize the electronic structures and optical spectra properties of five chemically modified fullerenes. It is revealed that the metal fullerene derivatives possess not only stronger absorption bands in visible light regions than organically modified fullerene but also the large energy gaps (ΔE_S–T > 0.98 eV) between the singlet ground state and the triplet state, which imply their significant aspect of potential candidates as a photosensitizer. We have found that a new metal‐containing bisfullerene complexes (Pt(C₆₀)₂), with the extended conjugated π‐electrons, much degenerate orbitals and a uniform electrostatic potential surface, behave more pre‐eminent photosensitizing properties than other examined fullerene derivatives. © 2012 Wiley Periodicals, Inc.     

Functionalization of OEP-based benzochlorins to develop carbohydrate-conjugated photosensitizers. Attempt to target beta-galactoside-recognized proteins

meso-(2-Formylvinyl)octaethylporphyrin on reaction with cyanotrimethylsilane in the presence of various catalysts [copper triflate [Cu(OTf)(2)], indium triflate [In(OTf)(3)], or magnesium bromide diethyl etherate (MgBr(2).Et(2)O)] produced a mixture of the intermediate 3-hydroxy-3-cyanopropenoporphyrin, the corresponding trimethylsilyl ether derivative, and the unexpected propenochlorins. The yields of the reaction products were found to depend on the reaction conditions and the catalysts used. The intermediate porphyrins on treatment with concentrated sulfuric acid yielded the free-base cyanobenzochlorins in major quantity along with several other novel benzochlorins as minor products. Reduction of ethyl-3-hydroxy-1-pentenoate-porphyrin with DIBAL-H/NaBH(4) and subsequent acid treatment provided the corresponding free-base 10(3)-(2-hydroxyethyl)benzochlorin, which upon a sequence of reactions gave a free-base benzochlorin bearing a carboxylic acid functionality in good yield. It was then condensed with a variety of carbohydrates (glucosamine, galactosamine, and lactosamine), and the related conjugates were screened using the galectin-binding-ability assay. Among the carbohydrate conjugates investigated, the lactose and galactose analogues displayed the galectin-binding ability with an enhancement of about 300-400-fold compared to lactose. In preliminary studies, all photosensitizers (with or without carbohydrate moieties) were found to be active in vitro [radiation-induced fibrosarcoma (RIF) tumor cells]. However, the cells incubated with lactose (known to bind to beta-galactoside-recognized proteins) prior to the addition of the photosensitizers containing the beta-galactose moiety (e.g., galactose and lactose) produced a 100% decrease in their photosensitizing efficacy. Under similar experimental conditions, benzochlorin without a beta-galactoside moiety or the related glucose conjugate did not show any inhibition in its photosensitizing efficacy. These results in combination with the galectin-binding data indicate a possible beta-galactoside-recognized protein specificity of the galactose- and lactose-benzochlorin conjugates.     

A first comparative study of purpurinimide-based fluorinated vs. nonfluorinated photosensitizers for photodynamic therapy

A first report on the synthesis and comparative in vitro-in vivo photosensitizing efficacy of various fluorinated and the corresponding nonfluorinated, purpurinimide-based photosensitizers is discussed. In preliminary in vivo screening, compared with the nonfluorinated analogs, purpurinimides bearing trifluoromethyl substituents showed enhanced photosensitizing efficacy. Among compounds (isomers) with similar lipophilicity, the position of the substituents was found to play a decisive role in biological efficacy.