Sensitizers For Photodynamic Therapy Research Articles

Synthesis, Characterization, and Biological Evaluation of a Porphyrin-Based Photosensitizer and Its Isomer for Effective Photodynamic Therapy against Breast Cancer.

A photosensitizer with high phototoxicity, low dark toxicity, and good water solubility is crucial for effective photodynamic therapy (PDT). In this study, a novel class of porphyrin-based water-soluble derivative and its isomers, named photohexer-1 (P-1) and photohexer-2 (P-2), were synthesized and investigated for anticancer activity. Both of the isomers, P-1 and P-2, could be utilized as potential sensitizers for PDT not only owing to their definite constituents but predominantly due to their good absorption in the phototherapeutic window and high generation of intracellular ROS. Therein, P-2 exhibited stronger phototoxicity against breast cancer cells with weaker dark toxicity than P-1; however, both P-1 and P-2 were highly phototoxic as compared to their homologous compound, hematoporphyrin monomethyl ether (HMME). These findings were consistent with the antitumor efficacy in vivo. Moreover, P-1 and P-2 could both effectively localize in multiple subcellular organelles, triggering increased cellular apoptosis or necrosis under laser irradiation as compared to HMME. In conclusion, the findings of the study suggest that the two highly water-soluble porphyrin derivatives may serve as promising putative photosensitizers for improving the therapeutic efficiency of PDT.

The design, synthesis, and evaluation of organic dithienopyrrole-based D-π-A dyes for use as sensitizers in photodynamic therapy

Dithienopyrrole-based organic dyes that combine an electron-donating moiety (D), a π-conjugated bridge moiety (π), and an electron-accepting moiety (A) were designed and synthesized in short steps by previously developed one-pot Suzuki-Miyaura coupling approach. Absorption wavelengths of the dyes were readily tuned by altering the D and A moieties. The use of a strongly electron-withdrawing cyanopyridone acceptor enabled NIR absorption. A synthesized sensitizer, 2j, exerted potent phototoxicity mainly via a Type I mechanism in cells. A nitrogen atom in the dithienopyrrole ring serves as a connecting point for the introduction of functional building blocks that can improve the properties of sensitizers, which makes this D-π-A sensitizer a valuable template for the further development of sensitizers.

Zinc pthalocyanine-loaded chitosan/mPEG-PLA nanoparticles-mediated photodynamic therapy for the treatment of cutaneous squamous cell carcinoma.

Zinc pthalocyanine (ZnPc) is a second-generation photodynamic therapy (PDT) sensitizer with sufficient PDT activity for squamous cell carcinoma (SCC). ZnPc is hydrophobic and insoluble in water, which creates hurdles in systemic administration and hence restricts its use in clinic. Here we have loaded ZnPc on chitosan/methoxy polyethylene glycol-polylactic acid (CPP) nanoparticles to form Z-CPP to enhance PDT efficacy. In vitro and in vivo studies were performed to see dark toxicity of the compounds ZnPc, CPP and Z-CPP. Then PDT was done and its growth inhibitory effect on SCC cells was evaluated. In addition, reactive oxygen species (ROS) formation and apoptosis of cancer cells following PDT were studied. The results showed that the tested compounds exhibit no dark toxicity and the effect of PDT was significantly better with Z-CPP when compared to free ZnPc (P < .05). Photoactivation of Z-CPP led to a dose-dependent growth inhibition of cancer cells of >50% at 1 μM to >80% at 10 μM concentration. Also Z-CPP-treated cells had highest number of apoptotic cells and produced more ROS compared to free ZnPc-treated cells (P < .05). Hence, this study suggests that Z-CPP is a suitable pharmaceutical compound to increase PDT efficacy.

Porphyrazine Structures with Electron-Withdrawing Substituents as the Base for Materials for Photonics and Biomedicine

A survey of the studies dealing with the development of new porphyrazine type tetrapyrrole dyes promising for the application in photonics and biophotonics is presented. An original synthetic approach to the template assembly of the porphyrazine macrocycle at room temperature in high yield has been proposed. A porphyrazine macrocycle containing eight nitrile groups at the periphery has been prepared for the first time. The replacement of four nitrile groups in the macrocycle by aryl groups has been found to generate a unique porphyrazine structure demonstrating a fluorescent molecular rotor behavior, i.e., a strong dependence of fluorescence parameters (quantum yields and lifetimes) on the viscosity of the medium. Some aspects of possible applications of the obtained compounds in biophotonics are described. Good prospects for the use of these compounds as efficient agents for tumor diagnosis, sensitizers for photodynamic therapy, and probes for intracellular viscosity are outlined.

Conjugated Polymer Nanotherapeutics for Next Generation Photodynamic Therapy

First and second-generation photosensitizers for Photodynamic Therapy (PDT) are in clinical trials, with a few approved for clinical application. While effective, several drawbacks have remained unaddressed that could increase the impact of PDT as an efficient therapy, including lack of selectivity to diseased tissue, toxicity, low to moderate light absorption, and poor solubility of the sensitizers that results in low bioavailability. It’s likely that a new generation of PDT sensitizers must be developed to improve on these shortcomings. In this review, we summarize our progress in the development of Conjugated Polymer Nanoparticles as a next generation nanotherapeutic for Photodynamic Therapy (PDT). We show that their unprecedented light absorption, efficient ROS generation, high level of targeted delivery and selective uptake, absence of dark toxicity and high percentage of PDT induced cell mortality observed indicate a promising next generation PDT sensitizer. The simple design and ease of fabrication of the Conjugated Polymer Nanoparticles holds promise for broad applicability.

Crown-Containing Phthalocyanines are Potential Sensibilizers for Photodynamic Therapy. Synthesis, Properties and Role of Non-Covalent Interactions

Phthalocyanines (Pc) and their supramolecular aggregates are widely used in molecular electronics, chemical sensors, and catalysis, as well as in biology and medicine, including photodynamic therapy (PDT). One of the possibilities of preventing Pc aggregation in an aqueous medium is using surfactants: with their molecules are self-organized various supramolecular complexes. This results in formation of the required microheterogeneous Pc environment compatible with the biological medium. The monomolecular state of Pc in an aqueous medium is especially important for their use as sensitizers in fluorescence diagnostics and PDT. We have summarized here the results of investigations of distinctive features of the supramolecular aggregation of octa-[(4′-benzo-15-crown-5)oxy]phthalocyaninates (Mcr8Pc) and tetra-[(4′-benzo-15-crown-5)oxy]phthalocyaninates (Mcr4Pc) in electrolytic solutions and solutions of synthetic cetyltrimethylammonium bromide (CTAB), sodium dodecyl sulfate (SDS), sodium dodecylbenzenesulfonate (SDBS). Biocompatible surfactants such as carboxymethylcellulose sodium salt (Na-CMC) and sodium deoxycholate (SDC) were also studied. Using the electron absorption spectra it has been shown that formation of Mсr8Pc monomers in micellar solutions of SDC is affected by both increased surfactant concentration and by changes in the ionic strength of solution after sodium chloride is added. The effect of the chemical structure of the biocompatible anionic surfactant on monomerization of crown_containing phthalocyanines has been identified; this fact opens new possibilities for using this family of compounds for fluorescent diagnosis and PDT.

Efficient Singlet Oxygen Generation in Metal Nanoclusters for Two-Photon Photodynamic Therapy Applications.

The generation of singlet oxygen (1O2) has been established as the principal mechanism of photodynamic therapy (PDT). Various dyes, metal nanoparticles, and clusters have been shown to sensitize 1O2. However, metal nanoclusters are even more promising candidates as photosensitizers for this purpose. By understanding the optical properties that lead to efficient 1O2 generation, one can fully realize their potential as PDT photosensitizers. Three different metal nanoclusters, Au25, Ag32, and Au144, are investigated for their 1O2 generation efficiency. The Au144 showed a 1O2 generation rate that is 2 orders of magnitude higher than that for Au25 and Ag32, and several orders of magnitude higher than nanoparticles (>5 nm) due to Au144's high absorption cross section-to-volume ratio. The effectiveness of PDT in live cells with nanoclusters was demonstrated by two-photon excitation compared to one-photon excitation. The implication of these results points toward new efficient two-photon 1O2 sensitizers for photodynamic therapy.

Cytotoxicity modulation of ruthenium(II) tris-bathophenanthroline complexes with systematically varied charge

A series of four ruthenium(II) complexes Ru(bp)n(bps)3-n (n = 0-3; bp = 4,7-diphenyl-1,10-phenanthroline or bathophenanthroline; and bps = disulfonated 4,7-diphenyl-1,10-phenanthroline or bathophenanthroline disulfonate) bearing different charges were synthesized and characterized. In aqueous media, all complexes displayed similar photophysical properties which makes this series ideal to study the effect of charge on the cytotoxicity of Ru(II) complexes. Ru(bp)32+ (1) and Ru(bps)34− (4) are known photosensitizers that penetrate cancer cells and possess a significant light-induced cytotoxicity. The newly conceived neutral Ru(bp)2(bps)0 (2) and dianionic Ru(bp)(bps)22− (3) were also found to have significant uptake as well as light-activation properties. Importantly, the cytotoxicity in the dark was successfully tuned upon systematic charge modulation of the complexes. The cationic complex 1 was potent against 5 out of 6 cell lines tested (MDA-MB-231, MCF-7, B16, SF and ML2) and displayed the highest cytotoxicity among the tested complexes with IC50 values of 4.0, 3.6, 1.7, 1.0 and 2.9 μM, respectively. The two anionic complexes, 3 and 4, with respective overall charges of −2 and −4, were not potent against any of the cell lines in the dark (IC50 > 200 μM), whereas the neutral molecule, complex 2, was potent against 3 out of 6 cell lines in the dark (B16, SF and ML2) and exhibited an intermediate activity with IC50 values of 12.8, 3.0 and 10.3 μM, respectively. All complexes presented significant phototoxicity when activated at 6 h post-incubation, which is consistent with their fast uptake and ability to produce singlet oxygen. The localization of complexes 1–4 within the cells was found to be dependent on the charge and photoexcitation conditions. The charge-activity relationship elucidated in this work facilitates the development of new sensitizers for photodynamic therapy.

Thiophene‐Based Organic D–π–A Dyes as Potent Sensitizers for Photodynamic Therapy

In this study, synthetically readily accessible, thiophene‐based organic D–π–A sensitizers exerted high phototoxicity and are valuable as sensitizer templates for use in photodynamic therapy (PDT). Evaluation of the antitumor activity of our previously synthesized D–π–A sensitizers under photoirradiation revealed their potent phototoxicity. The structural requirements of the D–π–A sensitizer for phototoxicity were elucidated with the rapid synthesis of structurally simplified analogues and evaluation of their antitumor activity under photoirradiation. Our developed sensitizers mainly accumulated in mitochondria and damaged cancer cells through both Type I and Type II mechanisms. The developed new template could be useful in the future development of sensitizers that could fulfil the requirements for PDT.

A proton-activatable aminated-chrysophanol sensitizer for photodynamic therapy

Exploiting the tumor microenvironment provides a new strategy for cancer treatment. In order to develop the microenvironment-selective photosensitiser, we rationally designed a proton-activatable aminated-chrysophanol derivative-compound 3, which combines fluorescence and reactive oxygen species regulated by the tumor acidic microenvironment for the first time. Furthermore, two PET tertiary amine substituents introduced by compound 3 enhance the cellular uptake, prolong the wavelength of the absorption, and increase the phototoxicity. Not only can compound 3 distinguish the cancer cells from normal cells but also the tumor from the normal tissue by the higher fluorescence intensity in cancer cells and tissues. Additionally, lysosome destruction test proves cell necrosis in lysosomal related pathway. We believe that the proton-activatable photosensitiser modulated by tumor acidic microenvironment offers a good chance for the cancer treatment in clinic.

Thioxanthene dyes as triplet sensitizers for photodynamic therapy

Thioxanthene dyes as triplet sensitizers for photodynamic therapy

Tectona grandis leaf extract, free and associated with nanoemulsions, as a possible photosensitizer of mouse melanoma B16 cell

Over the past six years we have been studying extracts from tropical, specially Amazon, plants, to search for new sensitizers for photodynamic therapy of cancer and infectious diseases. Tectona grandis is a genus of tropical hardwood trees in the mint family, Lamiaceae. That is native to south and southeast Asia, but since the end of the 20th century is also gaining ground in the Amazon. The present work aims to evaluate the photodynamic potential of hydro-alcoholic extract from Tectona grandis LF leaves (TGE) and the same extract prepared as the oil-water nanoemulsion (TGE-NE) against melanoma B16 F10 cells. The method for preparation of a stable nanoemulsion with ~20nm particles associated to the TGE (TGE-NE) was successfully developed. We have shown that both free and nanostructured presentations possess the ability to sensitize B16 F10 cells to red light of the LED in vitro. Photodynamic effect was observed for both TGE and TGE-NE because toxicity increased under illumination with red light. While TGE was highly toxic towards melanoma cells under illumination with red light of the LED, it also possessed significant dark toxicity towards both B16 F10 and murine fibroblast NIH3T3 cells. The TGE-NE showed reasonable photocytotoxicity and was much less toxic towards normal cells in the dark compared to free TGE.

ECM Composition and Rheology Regulate Growth, Motility, and Response to Photodynamic Therapy in 3D Models of Pancreatic Ductal Adenocarcinoma.

ECM-infiltrating and chemoresistant pancreatic tumor populations exhibit increased sensitivity to PDT. Mol Cancer Res; 15(1); 15-25. ©2016 AACR.

Smaragdyrins and Sapphyrins Analogues.

Porphyrins and expanded porphyrins have attracted the attention of chemists for a long time in view of their diverse applications in catalysis; as anion, cation, and neutral substrate receptors; as ligands to coordinate large metal ions; as nonlinear optical materials, MRI contrasting agents, and sensitizers for photodynamic therapy (PDT); and more recently as models for aromaticity (both Hückel and Möbius). A diverse range of synthetic expanded porphyrins containing up to 96π electrons have been reported, and their properties have been exploited for various applications. The present Review is only confined to 22π electron expanded porphyrins containing five pyrrole/heterocyclic rings such as sapphyrins and smaragdyrins. Even though these two macrocycles contain 22π electrons and five pyrrole/heterocyclic rings, they are structurally different. In sapphyrins, the five pyrrole/heterocyclic rings are connected through four meso-carbon bridges and one direct pyrrole-pyrrole bond, whereas in smaragdyrins, the five pyrrole/heterocyclic rings are connected through three meso-carbon bridges and two direct pyrrole-pyrrole bonds. The chemistry of sapphyrins has been well-established in recent years due to the availability of easy and efficient synthetic methods. On the other hand, smaragdyrins are not explored significantly because of their unstable nature. However, recently it was shown that smaragdyrins can be stabilized if one of the pyrrole rings is replaced with a furan ring to afford stable oxasmaragdyrin. The availability of oxasmaragdyrin allowed the exploration of smaragdyrin in recent years. Thus, an attempt has been made in this Review to describe the chemistry of both sapphyrins and smaragdyrins in terms of their synthesis, characterization, metal ion coordination, and anion-recognition properties.

Over expression of 5-aminolevulinic acid synthase 2 increased protoporphyrin IX in nonerythroid cells

Protoporphyrin IX has been used as an efficient sensitizer in photodynamic diagnosis, photodynamic therapy, and sonodynamic therapy. The level of protoporphyrin IX is very important for diagnostic or therapy effects. 5-aminolevulinic acid synthase 2 (ALAS2) is the key enzyme upstream of protoporphyrin IX synthesis. To increase protoporphyrin IX accumulation, ALAS2 over-expression transgenic mice were generated. Plasmid containing alas2 gene was transfected in colonic carcinoma cell lines. Both in tissues of transgenic mice and in colonic carcinoma cells, the amount of protoporphyrin IX accumulation did increase. In addition, the level of heme, which is down stream of protoporphyrin IX did not change. Overexpression ALAS2 in nonerythriod cells may become a novel approach to cause protoporphyrin IX accumulation.

Sulfanyl porphyrazines: Molecular barrel-like self-assembly in crystals, optical properties and in vitro photodynamic activity towards cancer cells

Novel sulfanyl porphyrazines with peripheral 4-bromobenzyl and 4-biphenylylmethyl substituents were synthesized, characterized by photochemical methods and evaluated as sensitizers for photodynamic therapy (PDT). The X-ray crystallography study performed for sulfanyl porphyrazine with 4-biphenylylmethyl substituents revealed that the biphenylyl residues from two consecutive molecules form barrel-like cages with a macrocyclic core constituting a bottom and a top of the barrel and pyridine molecules enclosed inside. The optical properties of both porphyrazines were evaluated in various protic and aprotic solvents. To complement the conventional fluorescence measurements excitation-emission maps were recorded. The potential photosensitizing efficiency of the novel sulfanyl porphyrazines was evaluated by assessing the quantum yields of photosensitized singlet oxygen production. For this purpose the emission of light specific for the transition of singlet oxygen to ground state oxygen was measured. Photodynamic activities of porphyrazines and their liposomal formulations with different surface charge toward two oral squamous cell carcinoma cells (CAL 27, HSC-3) and human cervical epithelial adenocarcinoma cells (HeLa) were determined. Sulfanyl porphyrazines incorporated in cationic liposomes showed high activity, in contrast to the lack of activity of the free form porphyrazines in solution. Thus, cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium-propane and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine can be considered as a promising drug delivery system for the sulfanyl porphyrazines for the photodynamic therapy of cancers.

Photophysical Characterization and in Vitro Phototoxicity Evaluation of 5,10,15,20-Tetra(quinolin-2-yl)porphyrin as a Potential Sensitizer for Photodynamic Therapy.

Photodynamic therapy (PDT) is a selective and minimally invasive therapeutic approach, involving the combination of a light-sensitive compound, called a photosensitizer (PS), visible light and molecular oxygen. The interaction of these per se harmless agents results in the production of reactive species. This triggers a series of cellular events that culminate in the selective destruction of cancer cells, inside which the photosensitizer preferentially accumulates. The search for ideal PDT photosensitizers has been a very active field of research, with a special focus on porphyrins and porphyrin-related macrocycle molecules. The present study describes the photophysical characterization and in vitro phototoxicity evaluation of 5,10,15,20-tetra(quinolin-2-yl)porphyrin (2-TQP) as a potential PDT photosensitizer. Molar absorption coefficients were determined from the corresponding absorption spectrum, the fluorescence quantum yield was calculated using 5,10,15,20-tetraphenylporphyrin (TPP) as a standard and the quantum yield of singlet oxygen generation was determined by direct phosphorescence measurements. Toxicity evaluations (in the presence and absence of irradiation) were performed against HT29 colorectal adenocarcinoma cancer cells. The results from this preliminary study show that the hydrophobic 2-TQP fulfills several critical requirements for a good PDT photosensitizer, namely a high quantum yield of singlet oxygen generation (Φ∆ 0.62), absence of dark toxicity and significant in vitro phototoxicity for concentrations in the micromolar range.

A Self-Assembled Metallomacrocycle Singlet Oxygen Sensitizer for Photodynamic Therapy.

Although metal-ion-directed self-assembly has been widely used to construct a vast number of macrocycles and cages, it is only recently that the biological properties of these systems have begun to be explored. However, up until now, none of these studies have involved intrinsically photoexcitable self-assembled structures. Herein we report the first metallomacrocycle that functions as an intracellular singlet oxygen sensitizer. Not only does this Ru2 Re2 system possess potent photocytotoxicity at light fluences below those used for current medically employed systems, it offers an entirely new paradigm for the construction of sensitizers for photodynamic therapy.

SPIO@SiO2–Re@PEG nanoparticles as magneto-optical dual probes and sensitizers for photodynamic therapy

A superparamagnetic iron oxide core and a photoluminescent rhenium complex embedded in a silica shell are the active components of a dual magneto-optical nanoprobe, also able to generate singlet oxygen upon irradiation.

New Sensitizers Developed on a Methylpheophorbide a Platform for Photodynamic Therapy: Synthesis, Singlet Oxygen Generation and Modeling of Passive Membrane Transport

This study focuses on the behavior of new potential sensitizers for photodynamic therapy of cancer developed on a chlorophyll a platform. Pheophorbide a 17-(3) methylester and its two glycol derivatives have been synthesized from chlorophyll and identified via visible, UV-, NMR- and MS-spectra. The behavior of photosensitizers in solutions has been studied with various experimental techniques. They are found to generate singlet oxygen with a sufficient quantum yield and reveal a tendency to effectively penetrate into cell membranes due to high lipophilicity. Thermodynamic analysis indicates that the sensitizer transfer from a water-like to a lipid-like medium is controlled by a large and negative enthalpic term excepting the case of the most polar solute, where for phosphate saline buffer the favorable entropic term dominates. Our study highlights the important feature dealing with the temperature dependence of partition coefficients between saline buffer and 1-octanol which is found to be surprisingly strong for hydrophobic solutes and temperature independent for the species containing both H-donor and H-acceptor groups.