Potential Photosensitizers For Photodynamic Therapy Research Articles

Novel Zn(II) phthalocyanine with tyrosine moieties for photodynamic therapy: Synthesis and comparative study of light-associated properties

Octa-(4-tyrosylamido) phenyl substituted Zn(II) phthalocyanine (ZnPcTyr8) was synthesized and characterized as potential photosensitizer for photodynamic therapy (PDT). The new ZnPcTyr8 was evaluated in comparison to recently synthesized tetra-(4-tyrosylamido) phenyl substituted Zn(II) phthalocyanine (ZnPcTyr) and used as a standard unsubstituted Zn(II) phthalocyanine (ZnPc). The photophysical properties of absorption and fluorescence, and photochemical properties of singlet oxygen generation and photostability as well as in vitro photocytotoxicity property were investigated. The irradiation from a light-emitting diode (LED 665 nm) with a dose of 50 J cm−2 and a fluence of 60 mW cm−2 was applied. The obtained results suggested improved photophysicochemical properties of singlet oxygen generation for tyrosine-conjugated Zn(II)-phthalocyanines. In addition the tyrosine substitution to ZnPc is liable for gentle photocytotoxicity which is in contrast to the harsh phototoxic effect determined for ZnPc on tumor and normal cell lines. Among both tyrosine substituted Zn(II) phthalocyanines, a novel ZnPcTyr8 has advantages of water solubility and proper values of the main photophysicochemical properties responsible for PDT efficacy.

Synthesis, photodynamic activities, and cytotoxicity of new water-soluble cationic gallium(III) and zinc(II) phthalocyanines

The cationic Ga(III) and Zn(II) phthalocyanines carrying N-methyl-pyridinium groups at eight peripheral β-positionshave been synthesized. These complexes are highly soluble in dimethyl sulfoxide (DMSO) and moderately soluble in water and phosphate buffered saline (PBS); both Ga(III)Cl and Zn(II) complexes have shown no aggregation in water up to 1.2 × 10−4 and 1.5 × 10−5 M, respectively. A higher water-solubility of Ga(III)Cl complex as compared to Zn(II) complex is ascribed to the presence of an axially coordinated chloride. The spectroscopic properties, photogeneration of singlet oxygen (1O2), and cytotoxicity of these complexes have been investigated. The absolute quantum yields (ΦΔabsolute) for the photogeneration of singlet oxygen using Ga(III)Cl and Zn(II) complexes have been determined to be 4.4 and 5.3%, respectively, in DMSO solution. The cytotoxicity and intracellular sites of localization of Ga(III)Cl and Zn(II) complexes have been evaluated in human HEp2 cells. Both complexes, localized intracellularly in multiple organelles, have shown no cytotoxicity in the dark. Upon exposure to a low light dose (1.5 J/cm2), however, Zn(II) complex has exhibited a high photocytotoxicity. The result suggests that Zn(II) complex can be considered as a potential photosensitizer for Photodynamic therapy (PDT).

Design and synthesis of symmetrical pentamethine cyanine dyes as NIR photosensitizers for PDT

Herein, we report the synthesis and spectroscopic characterization of novel Near Infra-Red (NIR) pentamethine cyanine dyes, as potential photosensitizers for Photodynamic Therapy (PDT) characterized by a strong absorption in the tissue transparency window (600–800 nm). The heteroaromatic benzoindolenine ring of various symmetrical cyanine dyes has been differently functionalized and quaternarized as a result of a structure-activity study and to determine the substituent effect on the cellular uptake, ROS production and photodynamic activity. These probes present low cytotoxicity in dark, but promote phototoxic effect, upon irradiation, in human fibrosarcoma cell line (HT-1080) with interesting and unexpected structure to property activity.

Trifluoromethyl Boron Dipyrromethene Derivatives as Potential Photosensitizers for Photodynamic Therapy.

In this study, two novel boron dipyrromethene-based photosensitizers (BDP3 and BDP6) substituted with three or six trifluoromethyl groups have been synthesized and characterized with various spectroscopic methods, and their photo-physical, photo-chemical, and photo-biological properties have also been explored. The two photosensitizers are highly soluble and remain nonaggregated in N,N-dimethylformamide as shown by the intense and sharp Q-band absorption. Under red light irradiation (λ = 660 nm, 1.5 J/cm2), both photosensitizers show high and comparable cytotoxicity towards HepG2 human hepatocarcinoma and HeLa human cervical carcinoma cells with IC50 values of 0.42–0.49 μM. The high photocytotoxicity of BDP3 and BDP6 can be due to their high cellular uptake and low aggregation tendency in biological media, which result in a high efficiency to generate reactive oxygen species inside the cells. Confocal laser fluorescence microscopic studies indicate that they have superior selective affinities to the mitochondria and lysosomes of HepG2 and HeLa cells. The results show that these two trifluoromethyl boron dipyrromethene derivatives are potential anticancer agents for photodynamic therapy.

Synthesis of Water-Soluble Phthalocyanines and Modification of their Peripheral Fragments as a Method of Directed Changes in Lipophilic-Hydrophilic Properties

This article brief by describes results of studies devoted to synthesis of water-soluble phthalocyanines derivatives, which are carried out by the Complexing Agents Chemistry group of IPAC RAS. Metal-free ligands and metallophthalocyanines, containing peripheral substituents with fragments of pyridine, oxybenzoic and hydroxyphenylphosphonic acids are potential photosensitizers for photodynamic therapy of cancer diseases. Methods for the modification of peripheral substituents have been developed that make it possible to synthesize phthalocyanine ligands and complexes soluble in organic solvents, or soluble in aqueous media and also possess amphiphilic properties.

Functionalization of chlorins towards potential photosensitizers for photodynamic therapy

Photophysical properties of chlorins predestine this type of hydroporphyrins for photodynamic therapy and other diagnostic/therapeutic applications. Artificial chlorins 3a and 4a derived from the red blood pigment heme form a platform for functionalizations with respect towards potentially biologically active photosensitizers and fluorescense markers. Chlorin estrogen derivatives 8a, 8b might be useful as sensitizers which bind selectively to (tumor) cell tissue containing estrogen receptors, [Formula: see text] breast cancer cells.

Synthesis and investigation of photophysicochemical properties of novel ketone-substituted gallium (III) and indium (III) phthalocyanines with high singlet oxygen yield for photodynamic therapy

This work reports on the synthesis and characterization of phthalocyanines (M = Ga(III) and In(III)) which is peripherally tetra-substituted with 4-(4-hydroxyphenyl)butan-2-one and also with 1-(4-hydroxyphenyl)propan-1-one. Confirmation of the synthesized phthalocyanine structures performed with a combination of elemental analysis, FTIR, 1H NMR, 13C NMR, UV–vis and MALDI-MS spectral data. Also, investigated and discussed the effects of peripherally tetra-substitution with different ketones which contain reactive carbonyl groups on the photochemical (Singlet oxygen quantum yields and photodegradation quantum yields) and photophysical properties (Fluorescence quantum yields and fluorescence behavior) which is very important for biological cell studies on PDT. The singlet oxygen quantum yields give an indication of the efficiency of potential photosensitizers in photodynamic therapy (PDT). That's why the high results (ΦΔ; 0.90, 0.88, 0.60 and 0.80 in DMSO) of spectral measurements showed that all of the complexes can have potential to be used as sensitizers.

A Computational Way To Achieve More Effective Candidates for Photodynamic Therapy.

The purpose of the work described herein is to design highly efficient photosensitizers (PS) for photodynamic therapy (PDT) in theory. A series of expanded Zn porphyrins have been studied as light-activated PS. Their main photophysical properties are systematically calculated by using density functional theory and its time-dependent extension. The mechanisms of PDT are discussed. All the considered candidates exhibit intense absorption in the therapeutic window (600-800 nm), efficient intersystem crossing, and sufficient energy for singlet molecular oxygen production. Accordingly, the designed Zn pentaphyrins and sapphyrins would be proposed as potential PS for PDT. Moreover, the therapeutic effects of Zn pentaphyrins and sapphyrins are better than those of the referenced Zn iso-pentaphyrin. It is expected that the results could provide a new way to design and develop PS for PDT application.

Theoretical investigation of NˆCˆN-coordinated Pt(II) and Pd(II) complexes for long-lived two-photon photodynamic therapy

Transition metal complexes capable of near-infrared light triggered-cytotoxicity are actively being developed as potential photosensitizers (PS) for photodynamic therapy (PDT) of cancers. In the present work, the structures and photophysical properties of complexes Pt(NˆCˆN)Cl and Pd(NˆCˆN)Cl (NˆCˆN = 2,6-dipyrido-4-methyl-benzenechloride) are investigated with a theoretical approach. The features of low-lying singlet and triplet excited states are discussed in detail. Their potential therapeutic use as two-photon PS in PDT is proposed on the basis of their strong absorbance in near-infrared region (NIR), vertical triplet energies resulting higher than 0.98 eV, and the spin-orbit matrix elements lager than 0.24 cm−1. Moreover, an evaluation of triplet excited states lifetime is presented. The longer lifetime of the triplet excited states would lead to higher 1O2 yields for Pd(NˆCˆN)Cl compared to Pt(NˆCˆN)Cl. It is expected that the low-cost Pd(NˆCˆN)Cl will replace the reported Pt(NˆCˆN)Cl as a promising two-photon PS for improving clinical PDT efficacy.

TMPyP4 promotes cancer cell migration at low doses, but induces cell death at high doses.

TMPyP4 is widely considered as a potential photosensitizer in photodynamic therapy and a G-quadruplex stabilizer for telomerase-based cancer therapeutics. However, its biological effects including a possible adverse-effect are poorly understood. In this study, whole genome RNA-seq analysis was used to explore the alteration in gene expression induced by TMPyP4. Unexpectedly, we find that 27.67% of changed genes were functionally related to cell adhesion. Experimental evidences from cell adhesion assay, scratch-wound and transwell assay indicate that TMPyP4 at conventional doses (≤0.5 μM) increases cell-matrix adhesion and promotes the migration of tumor cells. In contrast, a high dose of TMPyP4 (≥2 μM) inhibits cell proliferation and induces cell death. The unintended “side-effect” of TMPyP4 on promoting cell migration suggests that a relative high dose of TMPyP4 is preferred for therapeutic purpose. These findings contribute to better understanding of biological effects induced by TMPyP4 and provide a new insight into the complexity and implication for TMPyP4 based cancer therapy.

PDT-correlated photophysical properties of thienopyrrole BODIPY derivatives. Theoretical insights

Absorption electronic spectra, singlet-triplet energy gaps and spin–orbit matrix elements of thienopyrrole BODIPY derivatives, recently synthesized and proposed as potential photosensitizers in photodynamic therapy (PDT), have been computed by means of density functional theory (DFT) and time-dependent DFT approaches. A benchmark on structural parameters and maximum absorption wavelengths of different exchange-correlation functionals in combination with two basis set has been performed. The singlet-triplet energy gaps found are consistent with their possible application in PDT. The investigated molecules possess two excited triplet states (T1 and T2) that lie below and approximately at the same energy of the excited singlet one (S1), respectively. Both the radiationless transitions between S1 and triplet states contribute to the intersystem spin crossing efficiency, which in turn increases the production of singlet oxygen. Comparing their properties with those of agents currently used in PDT, one of them could be potentially used as photosensitizer for singlet oxygen production.

Water-soluble porphyrin-phosphonate conjugates as potential photodynamic therapy photosensitizers

Two novel water-soluble porphyrin-phosphonate conjugates were synthesized and characterized. Although both conjugates showed significant potential in photodynamic therapy, the variety of their structure induced the obvious differences in the binding manner with calf thymus DNA, the cytotoxicity and the cellular sublocalization.

Photophysical properties of free and metallated meso-substituted tetrabenzotriazaporphyrin from density functional theory investigation

Density functional theory and its Time-dependent extension have been herein employed to elucidate the photophysical properties of a meso-substituted tetrabenzotriazaporphyrin and its magnesium and zinc complexes. Absorption electronic spectra, singlet-triplet energy gaps and spin–orbit matrix elements, have been provided. The investigated compounds have been found to possess two excited triplet states (T1 and T2) lying below the energy of the excited singlet one (S1). The Spin–Orbit matrix elements for both the radiationless S1 → T1 and S1 → T2 couplings have been thus computed. On the basis of our results, the Zn(II) complex shows i) a singlet-triplet energy gap higher than that required to generate the cytotoxic singlet oxygen species, ii) a significant coupling between S1 and T2 states and, accordingly, it could be proposed as a potential photosensitizer in photodynamic therapy.

Physicochemical properties of potential porphyrin photosensitizers for photodynamic therapy

This research evaluated the suitability of synthetic photosensitizers for their use as potential photosensitizers in photodynamic therapy using steady state and time-resolved spectroscopic techniques. Four tetraphenylporphyrin derivatives were studied in ethanol and dimethyl sulfoxide. The spectroscopic properties namely electronic absorption and emission spectra, ability to generate singlet oxygen, lifetimes of the triplet state, as well as their fluorescence quantum yield were determined. Also time-correlated single photon counting method was used to precisely determine fluorescence lifetimes for all four compounds. Tested compounds exhibit high generation of singlet oxygen, low generation of fluorescence and they are chemical stable during irradiation. The studies show that the tested porphyrins satisfy the conditions of a potential drug in terms of physicochemical properties.

Multifunctional Anticancer Platform for Multimodal Imaging and Visible Light Driven Photodynamic/Photothermal Therapy

As a potential photosensitizer for photodynamic therapy (PDT), pure titanium dioxide has the drawbacks of low tissue penetration and possible damage to skin due to the triggered UV light. To realize near-infrared (NIR) laser-induced multimodal imaging guided therapy, we constructed a multifunctional core–shell structure (TiO2@Y2Ti2O7@YOF:Yb,Tm) by a facile coprecipitation route, followed by an annealing process. Under a single NIR laser irradiation, the highly cytotoxic reactive oxygen species (ROS) required for PDT can be generated due to the energy transfer from YOF:Yb,Tm to the Y2Ti2O7 photocatalyst which is responsive to blue emission (visible light), and the thermal effect can be simultaneously produced due to the nonradiative transition and the recombination of electron–hole pairs. The NIR light induced PDT and photothermal therapy (PTT) can efficiently suppress tumor growth, which was evidenced by both in vitro and in vivo results. Moreover, the rare earth ions in the composite make the material ha...

The heavy atom effect on Zn(ii) phthalocyanine derivatives: a theoretical exploration of the photophysical properties.

Absorption electronic spectra, singlet-triplet energy gaps and spin-orbit matrix elements have been computed at DFT and TDDFT levels of theory for a series of substituted Zn(ii)-phthalocyanines (ZnPcs), recently proposed as potential photosensitizers in photodynamic therapy (PDT). Their photophysical properties have been rationalized in the light of the substitution pattern which includes the position, the donor or withdrawing nature, and the relative donating force of peripheral and non-peripheral ligands. Moreover, the effects of heavy substituents on these properties have been investigated by introducing a different number of iodine atoms on the phthalocyanine macrocycle. The results show that the substitution pattern significantly affects the absorption spectra, but just slightly modifies the ΔES-T values. The presence of heavy atoms produces a significant effect on the photophysical properties of the investigated compounds enhancing the spin-orbit coupling (SOC) values.

The different kinetic behavior of two potential photosensitizers for PDT

Photodynamic therapy (PDT) efficiency is affected by the nature of the binding between the photosensitizer and serum albumin. The kinetic interaction between two potential PDT dyes with bovine serum albumin was studied providing not only the rate constants but also demonstrating that the kinetic of the interaction of the two dyes is very different.

Synthesis and characterization of novel zinc phthalocyanines as potential photosensitizers for photodynamic therapy of cancers.

Two novel zinc phthalocyanines (Pcs): tetramethyl tetrakis-2,(3)-[(4-methyl-2-pyridyloxy)phthalocyaninato] zinc(II) (4) and (the negatively charged form) tetrakis-2,(3)-[(3-carboxylicacid-6-sulfanylpyridine)phthalocyaninato] zinc(II) (5), water soluble by virtue of their ionic substituent groups were synthesized. The spectroscopic properties of both compounds were determined and their photodynamic activities were investigated in a human tumor cell model. In aqueous media the two peripherally substituted water soluble Pcs are highly aggregated. The phototoxic activity of the two novel Pcs (Pc 4 and Pc 5; 0-20 μM) was shown to be time- and dose-dependent in human pancreatic carcinoid BON cells, leading to a reduction of tumor cells of >80% compared to the controls. The effectiveness of the treatment appeared to be attenuated by the aggregation of Pcs under aqueous conditions. Interestingly, even those cells that were not immediately killed by the photoactivated photosensitizer seemed to be affected by the Pc photodynamic activity, as a single PDT induced long-lasting effects on cell survival. Even 4 days after PDT, the number of surviving cells did not re-increase or still dropped, as compared to control cells. The underlying mechanism of this observation has to be deciphered in future investigations.

Interaction of eosin and its ester derivatives with aqueous biomimetic micelles: Evaluation of photodynamic potentialities

Abstract In this paper, the physicochemical and photophysical properties of xanthene dyes interacting with micelles were evaluated. Xanthenes are potential photosensitizers for photodynamic therapy. The dyes were eosin Y and its ester derivatives with methyl, butyl and decyl alkyl groups. In aqueous media at physiological pH eosin is present as dianionic protolytic form while its esters are monoanionic. Analysis of the water/octanol partition coefficient showed that the eosin is the most hydrophilic compound and the hydrophobicity increases as the alkyl chain of the ester increases: eosin

β-Lactonization of fluorinated porphyrin enhances LDL binding affinity, cellular uptake with selective intracellular localization

Porpholactones, with one porphyrin β,β′-double bond replaced by a lactone moiety, possess unusual electronic states and photophysical properties between porphyrin and chlorin. However, such optical properties and unique structural characteristics have rarely been investigated within biological studies. In this work, we report that β-lactonization of porphyrin decreases the lipophilicity (log Po/w), due to the lower pKa value of pyrrollic nitrogen arising from the electron-withdrawing lactone moiety, and increases singlet oxygen quantum yields. Attaching glucose conjugates to the fluorinated porpholactones results in a high binding affinity with low density lipoprotein (LDL), which facilitates cellular-uptake efficacy through an LDL-dependent pathway and selective intracellular localization (lysosome). More importantly, β-lactonization of porphyrin endows higher photocytotoxicity against Hela cells through apoptosis, this is highly associated with increasing intracellular ROS levels. These results increase the understanding of the relationship between the basic structural characteristics and biological activity of porphyrins containing a non-pyrrolic moiety and will be important to expand the scope of β-modified porphyrinoids as potential photosensitizers for photodynamic therapy.