S-seco-porphyrazine as a new member of the seco-porphyrazine family – Synthesis, characterization and photocytotoxicity against cancer cells

An important subgroup within the porphyrazine (Pz) family constitutes seco-porphyrazines, in the chemical structure of which one pyrrole unit is opened in the oxidative process. So far, there are only limited data on N-seco- and C-seco-Pzs. Here, the synthesis of a novel member of the Pzs seco-family, represented by an S-seco-tribenzoporphyrazine analogue, 22,23-bis(4-(3,5-dibutoxycarbonylphenoxy)butylsulfanyl)tribenzo[b,g,l]-22,23-dioxo-22,23-seco-porphyrazinato magnesium(II), is reported, with moderate 34% yield. The new derivative was characterized using NMR spectroscopy, UV–Vis spectroscopy, and mass spectrometry. In the photochemical study performed following the indirect chemical method with 1,3-diphenylisobenzofuran, S-seco-Pz revealed a high singlet oxygen quantum yield of 0.27 in DMF. Potential photocytotoxicity of S-seco-Pz was assessed in vitro on three cancer cell lines – two oral squamous cell carcinoma cell lines derived from the tongue (CAL 27, HSC-3) and human cervical epithelial adenocarcinoma cells (HeLa). In the biological study, the macrocycle was tested in its free form and after loading into liposomes. It is worth noting that S-seco-Pz was found to be non-toxic in the dark, with cell viability levels over 80%. The photocytotoxic IC50 values for free S-seco-Pz were 0.61, 0.18, and 4.1 µM for CAL 27, HSC-3 and HeLa cells, respectively. Four different liposomal compositions were analyzed, and the cationic liposomes revealed the highest photokilling efficacy, with the IC50 values for CAL 27, HSC-3, and HeLa cells at 0.24, 0.25, and 0.31 µM, respectively. The results of the photocytotoxicity study indicate that the new S-seco-tribenzoporphyrazine can be considered as a potential photosensitizer in photodynamic therapy of cancer, along with the developed cationic liposomal nanocarrier

Porphyrazines containing styryldiazepine rings and their liposomal formulations: preparation, photochemical properties and photodynamic activity against oral cancer cell lines

Photodynamic therapy (PDT) is a novel, alternative, anticancer treatment, which has also been used to cure cardiovascular, dermatological, and ophthalmic diseases as well as various microbial infections. PDT consists of three factors: compound (photosynthesizer), oxygen, and light. Upon irradiation with light of specific wavelength the photosynthesizer undergoes activation and produces reactive oxygen species such as singlet oxygen. As a consequence, it leads to the death of the treated tissue. Here we present our data to the synthesis of prophyrazines and tribenzoporphyrazines containing styryldiazepine rings. Condensation reactions of known dicyanodiazepins with 3,4,5-trimetoxybenzaldehyde and 1-methyl-2-imidazolecarbaldehyde led to the novel 1,4-diazepine-2,3-dicarbonitriles containing arylvinyl substituents. However, only diazepines with 3,4,5-trimetoxyphenyl groups subjected to macrocyclization reactions gave the desired macrocycles of sufficient stability. Novel macrocyclic compounds were characterized using various spectroscopic methods and extensively investigated in photochemical studies. Moreover, their photodynamic activity was examined in vitro using two human oral squamous cell carcinoma cell lines, HSC-3 cells derived from the tongue and H413 cells from the buccal mucosa. Magnesium tribenzoprophyrazine (Pz1) revealed high activity against cancer cells even at low concentrations and low light dose. Moreover, significantly higher cytotoxicity of Pz1 was observed after its incorporation into negatively charged liposomes

Chitosan Composites Containing Boron-Dipyrromethene Derivatives for Biomedical Applications

The work is devoted to preparing and characterizing the properties of photosensitive composites, based on chitosan proposed for photodynamic therapy. Chitosan films with a 5% addition of two BODIPY dyes were prepared by solution casting. These dyes are dipyrromethene boron derivatives with N-alkyl phthalimide substituent, differing in the presence of iodine atoms in positions 2 and 6 of the BODIPY core. The spectral properties of the obtained materials have been studied by infrared and UV-vis absorption spectroscopy and fluorescence, both in solutions and in a solid state. Surface properties were investigated using the contact angle measurement. The morphology of the sample has been characterized by Scanning Electron and Atomic Force Microscopy. Particular attention was paid to studying the protein absorption and kinetics of the dye release from the chitosan. Adding BODIPY to the chitosan matrix leads to a slight increase in hydrophilicity, higher structure heterogeneity, and roughness, than pure chitosan. The presence of iodine atoms in the BODIPY structure caused the bathochromic effect, but the emission quantum yield decreased in the composites. It has been found that BODIPY-doped chitosan interacts better with human serum albumin and acidic α-glycoprotein than unmodified chitosan. The release rate of dyes from films immersed in methanol depends on the iodine present in the structure

Photodynamic therapy of oral cancer with liposomal zinc phthalocyanine

Objectives: Photodynamic therapy (PDT) is a medical treatment that uses photosensitizer molecules activated with light to kill cancer cells. Liposomes are nanoparticles used for transporting the photosensitizer into the target cells. We investigated the use of free or liposome-encapsulated zinc phthalocyanine (ZnPc), as a photosensitizer for PDT against CAL27 cells derived from a squamous cell carcinoma of the tongue.Methods: Liposomes were prepared by hydration of dry lipid films in isotonic buffer, either followed or not by extrusion through polycarbonate membranes. Two types of liposomes were prepared: (1) palmitoyloleoyl phosphatidylcholine (POPC) with palmitoyloleoyl phosphatidylglycerol (POPG), and (2) dioleoyl PE (DOPE) with POPG. Cells incubated with free ZnPc, and extruded and non-extruded liposomal ZnPc, were exposed to light (660 nm) for 30 min. To evaluate dark toxicity, the treated cells were shielded from light. Cells incubated with medium or drug-free liposomes were used as controls. Cell viability was assessed using the Alamar Blue assay. Results: At 0.1, 0.5 and 1 µM, free ZnPc reduced CAL27 cell viability to ~82, 38 and 24%, respectively. Extruded POPG:POPC:ZnPc liposomes were more effective than free ZnPc only at 1 µM, reducing cell viability to 14%. Non-extruded POPG:POPC:ZnPc liposomes were less effective than free ZnPc, reducing cell viability to 60% at 1 µM. The phototoxic effect of extruded and non-extruded POPG:DOPE:ZnPC liposomes was insignificant. Both free and liposomal ZnPc did not cause dark toxicity. Conclusions: PDT against CAL27 cells is effective using free ZnPc in a dose-dependent manner, following irradiation. Extruded POPG:POPC:ZnPc liposomes are more effective than non-extruded liposomes. Future studies will address the apparent resistance of cells to POPG:DOPE:ZnPc to PDT, the intracellular localization of liposomes labeled with fluorescent lipids, and the effect of PDT on other oral cancer cell lines including FaDu (squamous cell carcinoma of the pharynx)

Photodynamic therapy of cancer with liposomal photosensitizers

The photodynamic reaction involves the light-induced generation of an excited state in a photosensitizer molecule (PS), which then results in the formation of reactive oxygen species in the presence of oxygen, or a direct modification of a cellular molecule. Most PSs are porphyrinoids, which are highly lipophilic, and are administered usually in liposomes to facilitate their effective delivery to target cells. The currently available liposomal formulations are Visudyne® and Fospeg®. Novel PSs were developed and tested for their photodynamic activity against cancer cells. Several compounds were highly phototoxic to oral cancer cells both in free and liposome-encapsulated form, with nanomolar IC50 values. The lowest IC50s (7-13 nM) were obtained with a PS encapsulated in cationic liposomes

Photodynamic Therapy of Oral Cancer and Novel Liposomal Photosensitizers

Photodynamic therapy facilitates the selective destruction of cancer tissue by utilizing a photosensitizer drug, the light near the absorbance wavelength of the drug, and oxygen. Methylene Blue, 5-aminolevulinic acid (the precursor of the photosensitizer, protoporphyrin IX), porphyrin, Foscan, Chlorin e6, and HPPH have been used successfully as photosensitizers in the treatment of oral verrucous hyperplasia, oral leukoplakia, oral lichen planus, and head and neck squamous cell carcinoma. “Theranostic” liposomes can deliver a contrast agent for magnetic resonance imaging and a photosensitizer for the image-guided photodynamic therapy of head and neck cancer. Liposomes incorporating photosensitizers can be targeted to cell surface markers overexpressed on cancer cells. Novel porphyrinoids have been developed in our laboratories that are highly effective as photosensitizers. Tribenzoporphyrazines encapsulated in cationic liposomes have produced IC50 values up to 50 times lower compared to the free photosensitizers. It is anticipated that targeting these drugs to cancer stem cells, using upconversion nanoparticles for the near-infrared irradiation of tumors to activate the photosensitizers, and overcoming tumor hypoxia will enhance the efficacy of photodynamic therapy of tumors accessible to light sources

Current status of liposomal porphyrinoid photosensitizers

The complete eradication of various targets, such as infectious agents or cancer cells, while leaving healthy host cells untouched, is still a great challenge faced in the field of medicine. Photodynamic therapy (PDT) seems to be a promising approach for anticancer treatment, as well as to combat various dermatologic and ophthalmic diseases and microbial infections. The application of liposomes as delivery systems for porphyrinoids has helped overcome many drawbacks of conventional photosensitizers and facilitated the development of novel effective photosensitizers that can be encapsulated in liposomes. The development, preclinical studies and future directions for liposomal delivery of conventional and novel photosensitizers are reviewed. © 2013 Elsevier Ltd. All rights reserved

Liposomal formulations of magnesium sulfanyl tribenzoporphyrazines for the photodynamic therapy of cancer

Photodynamic therapy (PDT) is a treatment that uses light to activate a photosensitizer in the presence of oxygen, leading to the damage of targeted cells by the generation of reactive oxygen species. PDT is used to treat various cancers and cardiovascular, dermatological and ophthalmic diseases as well as different microbial and viral infections. The main drawbacks of currently used photosensitizers, including porphyrinoids, are poor aqueous solubility and the tendency to form aggregates. These issues have been addressed by developing drug delivery systems of which liposomes are considered one of the best and most promising. In this study, previously synthesized dendritic magnesium tribenzoporphyrazineswere incorporatedinto four types of liposome

Liposomal formulations of magnesium sulfanyl tribenzoporphyrazines for the photodynamic therapy of cancer

Photodynamic therapy (PDT) is a treatment that uses light to activate a photosensitizer in the presence of oxygen, leading to the damage of targeted cells by the generation of reactive oxygen species. PDT is used to treat various cancers and cardiovascular, dermatological and ophthalmic diseases as well as different microbial and viral infections. The main drawbacks of currently used photosensitizers, including porphyrinoids, are poor aqueous solubility and the tendency to form aggregates. These issues have been addressed by developing drug delivery systems of which liposomes are considered one of the best and most promising. In this study, previously synthesized dendritic magnesium tribenzoporphyrazineswere incorporatedinto four types of liposome

Photocytotoxicity of liposomal zinc phthalocyanine in oral squamous cell carcinoma and pharyngeal carcinoma cells

Aim: Photodynamic therapy utilizes a light-sensitive molecule that produces reactive oxygen species following irradiation. Photodynamic activities of free Zn phthalocyanine (ZnPc) and its liposomal formulations on human oral squamous cell carcinoma and pharyngeal carcinoma cells were assessed. Materials & methods: ZnPc was incorporated in extruded and nonextruded liposomes composed of palmitoyloleoylphosphatidylglycerol (POPG):palmitoyloleoylphosphatidylcholine (POPC) or POPG:dioleoylphosphatidylethanolamine liposomes and incubated with CAL 27 or FaDu cells. Cell viability was assessed following illumination and further incubation. Results: ZnPc incorporated in extruded POPG:POPC liposomes caused extensive cytotoxicity, while ZnPc in extruded or nonextruded POPG:dioleoylphosphatidylethanolamine liposomes or in multilamellar POPG:POPC liposomes were not effective. Conclusion: Extruded POPG:POPC liposomes are a useful delivery vehicle for ZnPc in photodynamic therapy of oral and pharyngeal cancers