Photosensitizers For Photodynamic Therapy Applications Research Articles

Plants-occurring Anthraquinones as Photosensitive Compounds for Photodynamic Method: A Critical Overview.

The review focuses on the recent knowledge on natural anthraquinones (AQs) of plant origin and their potential for application in an exclusive medicinal curative and palliative method named photodynamic therapy (PDT). Green approach to PDT is associated with photosensitizers (PS) from plants or other natural sources and excitation light in visible spectrum. The investigations of plants are of high research interests due to their unique health supportive properties as herbs and the high percentage availability to obtain compounds with medical value. Up-to-date many naturally occurring compounds with therapeutic properties are known and are still under investigations. Some natural quinones have already been evaluated and clinically approved as anti-tumor agents. Recent scientific interests are beyond their common medical applications but also in directions to their photo-properties as natural PSs. The study presents a systematic searches on the latest knowledge on AQ derivatives that are isolated from the higher plants as photosensitizers for PDT applications. The natural quinones have been recognized with functions of natural dyes since the ancient times. Lately, AQs have been explored due to their biological activity including the photosensitive properties useful for PDT especially towards medical problems with no other alternatives. The existing literature' overview suggests that natural AQs possess characteristics of valuable PSs for PDT. This method is based on an application of a photoactive compound and light arrangement in oxygen media, such that the harmful general cytotoxicity could be avoided. Moreover, the common anticancer and antimicrobial drug resistance has been evaluated with very low occurrence after PDT. Natural AQs have been focused the scientific efforts to further developments because of the high range of natural sources, desirable biocompatibility, low toxicity, minimal side effects and low accident of drug resistance, together with their good photosensitivity and therapeutic capacity. Among the known AQs, only hypericin has been studied in anticancer clinical PDT. Currently, the natural PSs are under intensive research for the future PDT applications for diseases without alternative effective treatments.

Exploring Thioxanthone Derivatives as Singlet Oxygen Photosensitizers for Photodynamic Therapy at the Near-IR Region.

In the lowest excited triplet state, the excited photosensitizer reacts with tissue oxygen and forms reactive oxygen species (ROS), which kills tissue cells in photodynamic therapy (PDT). Metal-free thio-based pure organic molecules and analogous nucleobases can be used as photosensitizers for PDT applications. Using quantum chemical methods, we studied one- and two-photon optical absorptions, fluorescence, and other excited-state properties of substituted thioxanthone derivatives for their potential as photosensitizers for PDT. Our calculated values were compared with the available experimental data. The calculation of the intersystem crossing rate constant for these photosensitizers explains the high quantum yield of the formation of ROS, as reported experimentally. The excited triplet-state population of the photosensitizer occurs through the 1π-π* → 3n-π* channel of intersystem crossing and increases in the presence of halogen substitution.

Thiophene BODIPY-substituted cyclotriphosphazene-derived photosensitizers for photodynamic therapy applications

Molecular design and synthesis of cyclotriphosphazene-BODIPY-based PSs based on a halogen atom-enhanced ISC process were carried out and their photophysical behaviors, ROS production abilities and finally in vitro PDT potentials were investigated.

Carbon-based dot-capped gold nanoparticles hybridized with manganese dioxide for enhanced photodynamic cancer therapy

Composite material nanohybrids (FA/MnO2/CDs@AuNPs/CDs) have been synthesized and proven to be excellent photosensitizers for photodynamic therapy applications.

Synthesis and characterization of photosensitive gelatin-based hydrogels for photodynamic therapy in HeLa-CCL2 cell line

BackgroundHydrogel systems are increasingly gaining visibility involving biomedicine, tissue engineering, environmental treatments, and drug delivery systems. These systems have a three-dimensional network composition and high-water absorption capacity, are biocompatible, allowing them to become an option as photosensitizer carriers (PS) for applications in Photodynamic Therapy (PDT) protocols. MethodsA nanohydrogel system (NAHI), encapsulated with chloroaluminium phthalocyanine (ClAlPc) was synthesized for drug delivery.. NAHI was synthesized using gelatin as based polymer by the chemical cross-linking technique. The drug was encapsulated by immersing the hydrogel in a 1.0 mg.mL−1 ClAlPc solution. The external morphology of NAHI was examined by scanning electron microscopy (SEM). The degree of swelling of the synthesized system was evaluated to determine the water absorption potential. The produced nanohydrogel system was characterized by photochemical, photophysical and photobiologial studies. ResultsThe images from the SEM analysis showed the presence of three-dimensional networks in the formulation. The swelling test demonstrated that the nanohydrogel freeze-drying process increases its water holding capacity. All spectroscopic results showed excellent photophysical parameters of the drug studied when served in the NAHI system. The incorporation efficiency was 70%. The results of trypan blue exclusion test have shown significant reduction (p < 0.05) in the cell viability for all groups treated with PDT, in all concentrations tested. In HeLa cells, PDT mediated by 0,5 mg.mL−1 ClAlPc encapsulated in NAHI showed a decrease in survival close to 95%. In the internalization cell study was possible to observe the internalization of phthalocyanine after one hour of incubation, at 37 °C, with the the accumulation of PS in the cytoplasm and inside the nucleus at both concentrations tested. ConclusionsGiven the peculiar performance of the selected system, the resulting nanohydrogel is a versatile platform and display potential applications as controlled delivery systems of photosensitizer for photodynamic therapy application.

Multifunctional carbon dots derived from dansyl chloride for ratiometric thermal sensor and reactive oxygen generation

Carbon quantum dots (CDs) have emerged as a promising alternative of metal-free nanomaterials for a great variety of sensor applications. In this context, the present study is devoted to the characterization of morphological and spectroscopic properties of carbon dots derived from 5-(dimethylamino)naphthalene-1-sulfonyl chloride (dansyl chloride). By using the hydrothermal synthetic method, we obtain carbon dots (CD-DsCl) co-doped with nitrogen and sulfur, which exhibit a blue emission with a good quantum yield (16%) upon photoexcitation at 320 nm. The thermal and pH effects on CD-DsCl photoluminescence are also investigated, where a pronounced modification in the fluorescence spectrum takes place as the temperature and pH are varied. Our results indicate a relevant contribution of a thermally-activated mechanism to the CD-DsCl fluorescence. Furthermore, we analyze the possibility of using CD-DsCl in nanothermometry applications, determining the absolute and relative thermal sensitivities and thermal stability of nanoparticles in the temperature range of biological systems. In addition, it is also investigated the possibility of using CD-DsCl to generate reactive oxygen species (ROS) upon photoexcitation, envisaging their use as photosensitizers in photodynamic therapy applications. Within the above scenario, the present study shows that carbon dots derived from dansyl chloride possess interesting fluorescent properties, which can be exploited as a multifunctional material.

Sulfur Bridged New Metal-Free and Metallo Phthalocyanines Carrying 1,2,4-Triazole Rings and Their Photophysicochemical Properties

The novel metal-free (4 ) zinc(II) (5), lead(II) (6), cobalt(II) (7) and copper(II) (8) phthalocyanines containing 1,2,4-triazole groups connected to the phthalocyanine ring by S-bridge were synthesized and characterized. For this purpose, the original 2-(4-chlorobenzoyl)-N-(4-fluorophenyl)hydrazinecarbothioamide (1) was synthesized as a result of the reaction of 4-chlorobenzyl hydrazide and 4-fluorophenyl isothiocyanate. It was obtained 5-(4-chlorophenyl)-4-(4-fluorophenyl)-4H-1,2,4-triazole-3-thiol (2), which is a new compound by the ring closure reaction of 1. The other original compound 4-[5-(4-chlorophenyl)-4-(4-fluorophenyl)-4H-[1,2,4]triazol-3-yl sulfanyl]-phthalonitrile (3) was synthesized by the nucleophilic aromatic substitution reaction of 4-nitrophthalonitrile and compound 2. Starting from the new phthalonitrile (3), the metal-free (4), zinc(II) (5), lead(II) (6), cobalt(II) (7) and copper(II) (8) phthalocyanines were prepared. Totally eight new compounds were synthesized, and their structures were characterized by 1H NMR, 13C NMR, FT-IR, MALDI-TOF MS and UV-vis spectral data in this work. The photophysical and photochemical properties of the synthesized phthalocyanines were investigated for determination of their usability as photosensitizers for photodynamic therapy applications. Thus, remarkable results were obtained.

In vitro Studies of Antitumor Effect, Toxicity/Cytotoxicity and Skin Permeation/Retention of a Green Fluorescence Pyrene-based Dye for PDT Application.

Photosensitizers (PS) are compounds that can generate reactive oxygen species under irradiation of appropriate light and are widely used in photodynamic therapy (PDT). Currently, topical PDT is an effective treatment for several skin diseases, including bacterial infections, fungal mycoses and psoriasis. In addition, PDT is also used to treat nonmelanoma skin cancer and can be a potential tool for melanoma, associated with other treatments. In this work, we evaluated the antitumor photoactivity of a new pyrene-based PS (TPPy) by using the murine melanoma cell line (B16F10). The in vitro permeation/retention tests in porcine ear skin were also performed in order to evaluate the potential application of the PS for topical use in skin cancer. Moreover, to determine the toxicity in vivo, we used the Galleria mellonella as an alternative animal model of study. The results showed that TPPy is a promising PS for application in PDT, with potential antitumor photoactivity (IC50 6.5μmol L-1 ), absence of toxicity in the G. mellonella model at higher concentration (70.0mmol L-1 ) and the accumulation tendency in the epidermis plus dermis sites (165.20±4.12ngcm-2 ).

1,2,3-Triazole incorporated coumarin carrying metal-free, Zn(II), Mg(II) phthalocyanines: Synthesis, characterization, theoretical studies, photophysical and photochemical properties

In this study, the preparation of two novel phthalonitrile compounds, 7-(propargyloxy)-3-(3,4-dicyanophenoxyphenyl)coumarin (1), and 7-(propargyloxy)-3-(2,3-dicyanophenoxyphenyl)coumarin (2) were performed. Two new coumarinyl-1,2,3-triazole hybrids, (1-phenethyl-1H-[1,2,3]-triazole-4-yl)-7-methyleneoxy-3-[p-(3,4-dicyanophenoxy)phenyl]-coumarin (3), and (1-phenethyl-1H-[1,2,3]-triazole-4-yl)-7-methyleneoxy-3-[p-(2,3-dicyanophenoxy)phenyl]-coumarin (4), were synthesized by the copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of 2-(azidoethyl)benzene with terminal ethynyl bearing coumarin derivatives (1 or 2). These novel phthalonitrile derivatives (3 and 4) were converted into their peripheral (5-7) and non-peripheral (8-10) metal-free, zinc(II) and magnesium(II) phthalocyanine counterparts. The synthesized phthalocyanine derivatives are first examples on the phthalocyanine-coumarin derivatives bearing triazole ring.The structures of all these novel compounds were characterized by variety of spectroscopic techniques including FT-IR, UV-vis, 1H NMR, MALDI-TOF MS and elemental analysis. The photophysicochemical properties of all studied Pcs (5-10) were determined in dimethyl sulfoxide. The zinc(II) and magnesium(II) phthalocyanines bearing triazole containing coumarin substituents appear to be useful as Type II photosensitizers because the singlet oxygen quantum yields ranged in acceptable values from 0.17 to 0.49 confirmed that these phthalocyanines can be suggested as photosensitizers in Photodynamic Therapy applications. Geometry optimization, frequency analysis and molecular orbital energy values of coumarin/triazole substituted phthalocyanine were performed in Density Functional Theory method using the B3LYP/LANL2DZ level of theory.

Enhanced Cellular Uptake and Photodynamic Effect with Amphiphilic Fluorinated Porphyrins: The Role of Sulfoester Groups and the Nature of Reactive Oxygen Species

A class of amphiphilic photosensitizers for photodynamic therapy (PDT) was developed. Sulfonate esters of modified porphyrins bearing—F substituents in the ortho positions of the phenyl rings have adequate properties for PDT, including absorption in the red, increased cellular uptake, favorable intracellular localization, low cytotoxicity, and high phototoxicity against A549 (human lung adenocarcinoma) and CT26 (murine colon carcinoma) cells. Moreover, the role of type I and type II photochemical processes was assessed by fluorescent probes specific for various reactive oxygen species (ROS). The photodynamic effect is improved not only by enhanced cellular uptake but also by the high generation of both singlet oxygen and oxygen-centered radicals. All of the presented results support the idea that the rational design of photosensitizers for PDT can be further improved by better understanding the determinants affecting its therapeutic efficiency and explain how smart structural modifications can make them suitable photosensitizers for application in PDT.

Synthesis and Photodynamic Activity of Vitamin-Chlorin Conjugates at Nanomolar Concentrations against Prostate Cancer Cells.

Phototoxicity response of synthesized vitamin–chlorin conjugates and their zinc and indium complexes was determined in the human PC-3 prostate cancer cell line, which was previously demonstrated to overexpress vitamin receptors on the cell surface. Pantothenic acid (Vit B5) and lipoic acid (or thioctic acid) were covalently linked to methyl pheophorbide (a chlorophyll derivative) and subsequently metallated with zinc and indium. Cell survival assay indicated that the vitamin–chlorin conjugates have better photodynamic activity against the PC-3 prostate cancer line at the nanomolar concentration range than the commercially available starting precursor methyl pheophorbide. Fluorescence and transmission electron microscopy studies indicated some formation of apoptotic cells and cytoplasmic vacuoles of photosensitized prostatic cells. Targeting vitamin receptors in prostatic cancer cells can be utilized to enhance specificity of photosensitizers for photodynamic therapy applications.

New peripherally substituted lutetium mono and bis phthalocyanines: Synthesis and comparative photophysical and photochemical properties

In this study, the synthesis and characterization of mono-(phthalocyaninato) lutetium(III) (1-Cl and 1-F) [Lu[Formula: see text](AcO)(Pc)] (Pc [Formula: see text] phthalocyaninato, AcO [Formula: see text] acetate) and bis-(phthalocyaninato) lutetium(III) (2-Cl and 2-Br) [Lu[Formula: see text]Pc[Formula: see text]] bearing halogenated (F, Cl and Br) phenoxy–phenoxy groups are described and verified by IR, [Formula: see text]H-NMR, UV-vis and mass spectrometry. Photochemical and photophysical properties of 1-F, 1-Cl 2-Cl and 2-Br in DMSO are also presented. A comparison between photophysical and photochemical parameters of mono and bis derivatives showed that mono phthalocyanines are better photosensitizers than bis phthalocyanines. Photophysical and photochemical properties of phthalocyanines are very useful for photodynamic therapy applications. Singlet oxygen quantum yields [Formula: see text] give an indication of the potential of the complexes as photosensitizers in photodynamic therapy applications. The chloro, fluoro, bromo-phenoxy–phenoxy substituted mono-(phthalocyaninato) lutetium(III) complexes (1-Cl and 1-F) gave good singlet oxygen quantum yields (from 0.86 to 0.80) in DMSO. Thus, these complexes show potential as Type II photosensitizers for PDT of cancer.

Ring-Fused Diphenylchlorins as Potent Photosensitizers for Photodynamic Therapy Applications: In Vitro Tumor Cell Biology and in Vivo Chick Embryo Chorioallantoic Membrane Studies.

Ring-fused diphenylchlorins as potent low-dose photosensitizers for photodynamic therapy of bladder carcinoma and esophageal adenocarcinoma are described. All studied molecules were very active against HT1376 urinary bladder carcinoma and OE19 esophageal adenocarcinoma cell lines, showing IC50 values below 50 nM. The in vivo evaluation of the more promising photosensitizer, using an OE19 tumor/chick embryo chorioallantoic membrane model, showed a tumor weight regression of 33% with a single photodynamic therapy treatment with the photosensitizer dose as low as 37 ng/embryo.

Preparation and investigation of aggregation, fluorescence and singlet oxygen generation properties of gallium and metal-free phthalocyanines

The synthesis, characterization, aggregation, optical, fluorescence and singlet oxygen generation properties of 2-furylmethoxy substituted gallium and metal-free phthalocyanines (2 and 3, respectively) are reported for the first time. Characterization of the novel synthesized compounds was performed with elemental analysis, ultraviolet-visible spectrophotometry, fourier transform infrared spectrometry, 1H-NMR spectroscopy and mass spectrometry. When the concentration behavior of the synthesized complexes is examined in a certain concentration range in THF, it has been shown that the phthalocyanines predominantly consist of monomeric species. Furyl-containing new phthalocyanines are quite soluble in common organic solvents and this makes them possible to be used in several important applications. Fluorescence behavior of these phthalocyanines were investigated. In this study, the metal ion’s effect on the UV-Vis and photophysical features of the MPcs is also cited. These results show that the metal in the core of the phthalocyanine is an important factor in the fluorescence behavior and quantum yield (ΦF) of the complexes. In singlet oxygen generation studies showed that the phthalocyanines containing the 2-furylmethoxy group indicated a high level of photosensitization and singlet oxygen generation capacity. Consequently, these gallium and metal-free complexes are promising photosensitizer for photodynamic therapy applications.

Synthesis, Characterization and In Vitro Evaluation of Carbohydrate‐Containing Ruthenium Phthalocyanines as Third Generation Photosensitizers for Photodynamic Therapy

AbstractPyridyl ligands with one ketal‐protected carbohydrate unit (glucofuranose, galactopyranose or mannofuranose) were coordinated to the axial positions of ruthenium phthalocyanines (RuPc) in order to target the macrocycles to tumor cells. The biocompatibility of the resulting photosensitizers (PS) was enhanced by increasing their solubility in water through their peripheral and/or axial functionalization with polyether chains (PEG). All compounds generated singlet oxygen, with peripherally unsubstituted phthalocyanines displaying higher 1O2 yields. In vitro assays using the human bladder cancer cell line HT‐1376 revealed that peripherally unsubstituted phthalocyanines were also more efficient in terms of cellular uptake and therefore, phototoxicity. The protected carbohydrate functional groups at the axial positions did not improve significantly the cellular uptake of PSs, although they increased their photodynamic efficiency. Overall, mixed RuPcs functionalized with one carbohydrate unit at one of the axial positions and two PEG units at the other axial site showed promising properties as photosensitizers for photodynamic therapy applications and low toxicity in the dark.

Chlorophyll a in cyclodextrin supramolecular complexes as a natural photosensitizer for photodynamic therapy (PDT) applications

Chlorophyll a (Chl a), an amphipathic porphyrin, was employed as natural photosensitizer for photodynamic therapy applications. Due to its lacking solubility in water and high tendency to aggregate, Chl a was included into different modified cyclodextrins (CDs) to form stable water-soluble supramolecular complexes. To achieve this aim, 2-Hydroxypropyl-β-cyclodextrin (2-HP-β-CD), 2-Hydroxypropyl-γ-cyclodextrin (2-HP-γ-CD), Heptakis(2,6-di-o-methyl)-β-cyclodextrin (DIMEB) and Heptakis(2,3,6-tri-o-methyl)-β-cyclodextrin (TRIMEB) were used. The chemical physical properties of Chl a/CD complexes in cellular medium were studied by means of UV–Vis absorption spectroscopy. Results demonstrated the good aptitude of 2-HP-γ-CD, and more particularly of 2-HP-β-CD, to solubilize the Chl a in cell culture medium in monomeric and photoactive form. Then, Chl a/2-HP-β-CD and Chl a/2-HP-γ-CD complexes were evaluated in vitro on human colorectal adenocarcinoma HT-29 cell line, and cytotoxicity and intracellular localization were respectively assessed. Further tests, such as phototoxicity, ROS generation, intracellular localization and mechanism of cell death were then focused exclusively on Chl a/2-HP-β-CD system. This complex exhibited no dark toxicity and a high phototoxicity toward HT-29 cells inducing cell death via necrotic mechanism. Therefore, it is possible to affirm that Chl a/2-HP-β-CD supramolecular complex could be a promising and potential formulation for applications in photodynamic therapy.

A Local CC2 and TDA-DFT Double Hybrid Study on BODIPY/aza-BODIPY Dimers as Heavy Atom Free Triplet Photosensitizers for Photodynamic Therapy Applications.

A series of 11 different boron-dipyrromethene (BODIPY) dimers is carefully examined by means of ab initio and Tamm-Dancoff approximated density functional theory methods. Vertical and 0-0 excitation energies along with the tetraradical character of these dimers are determined. Possible application of a series of linked dimers for photodynamic therapy (PDT) was investigated through computing their excitation energies, spin-orbit coupling matrix elements, and singlet-triplet energy gaps. Finally through a systematic investigation of a series of 36 different BODIPY and aza-BODIPY dimers, a new class of near-IR heavy atom free photosensitizers for PDT action is introduced.

Enhancement of photodynamic therapy effects with mitochondrial reactive oxygen species

Enhancement of photodynamic therapy effects with mitochondrial reactive oxygen species

Synthesis and characterization of novel symmetrical and asymmetrical carboxyphthalocyanines with potential application in photodynamic therapy

Synthesis and characterization of novel symmetrical and asymmetrical carboxyphthalocyanines with potential application in photodynamic therapy

Indocyanine Green: Photosensitizer or Chromophore? Still a Debate

Indocyanine green (ICG) is a water-soluble anionic tricarbocyanine dye developed during the Second World War that was first approved for clinical use in humans in 1956. The main features of ICG that make it suitable for bioimaging applications are its near infrared absorption and its fluorescence. Although ICG is mainly used for its fluorescence emission properties, it has also been hypothesized that it can serve as a photosensitizer for photodynamic therapy applications, eliciting cytotoxic effects both in vitro and in vivo when used in combination with light at wavelengths in the region of 800-830 nm. Moreover, ICG can be used for hyperthermia of enhanced-photocoagulation of blood vessels treatment. In this paper we have gathered all the available data concerning the use of ICG for different treatments.