Generation Photosensitizer Research Articles

Structural, Photophysical, and Photochemical Characterization of Zinc Protoporphyrin IX in a Dimeric Variant of an Iron Storage Protein: Insights into the Mechanism of Photosensitized H2 Generation.

Some of us have previously reported the preparation of a dimeric form of the iron storage protein, bacterioferritin (Bfr), in which the native heme b is substituted with the photosensitizer, Zn(II)-protoporphyrin IX (ZnPP-Bfr dimer). We further showed that the ZnPP-Bfr dimer can serve as a photosensitizer for platinum-catalyzed H2 generation in aqueous solution without the usually added electron relay between photosensitizer and platinum ( Clark , E. R. , Inorg. Chem. 2017 , 56 , 4584 - 4593 ). We proposed reductive or oxidative quenching pathways involving the ZnPP anion radical (ZnPP•-) or the ZnPP cation radical, (ZnPP•+), respectively. The present report describes structural, photophysical, and photochemical properties of the ZnPP in the ZnPP-Bfr dimer. X-ray absorption spectroscopic studies at 10 K showed a mixture of five- and six-coordinated Zn centers with axial coordination by one long Zn-SγMet distance of ∼2.8 Å and ∼40% having an additional shorter Zn-S distance of ∼2.4 Å, in addition to the expected 4 nitrogen atom coordination from the porphyrin. The ZnPP in ZnPP-Bfr dimer was prone to photosensitized oxidation to ZnPP•+. The ZnPP•+ was rapidly reduced by ascorbic acid, which we previously determined was essential for photosensitized H2 production in this system. These results are consistent with an oxidative quenching pathway involving electron transfer from 3ZnPP* to platinum, which may be assisted by a flexible ZnPP axial coordination sphere. However, the low quantum yield for H2 production (∼1%) in this system could make reductive quenching difficult to detect, and can, therefore, not be completely ruled out. The ZnPP-Bfr dimer provides a simple but versatile framework for mechanistic assessment and optimization of porphyrin-photosensitized H2 generation without an electron relay between porphyrin and the platinum catalyst.

Comparison of Two Generation Photosensitizers of PsD-007 and Hematoporphyrin Monomethyl Ether Photodynamic Therapy for Treatment of Port-Wine Stain: A Retrospective Study

Objective: To compare the efficacy and safety of the two generation photosensitizers, PsD-007 and hematoporphyrin monomethyl ether (HMME), for photodynamic therapy (PDT) of port-wine stain (PWS). Background: Vascular-targeted PDT has shown potentially beneficial results in treating PWS; however, the efficacy and safety of various photosensitizers have not been fully investigated. Materials and methods: We retrospectively analyzed 38 patients with PWS, who were treated with one session of PsD-007-mediated (n = 21) or HMME-mediated (n = 17) PDT. Clinical efficacy was assessed by a chromameter and visual assessment of color blanching of the PWS lesion. Adverse events were evaluated. Results: Neither visual nor chromameter optical evaluations showed significant differences between the PsD-007 and HMME groups (p = 0.337 and p = 0.191, respectively). The total response rate was 76.2% (n = 16) in the PsD-007 group and 88.2% (n = 15) in the HMME group. Good or excellent clearance was achieved in 42.9% patients in the PsD-007 group and 29.4% patients in the HMME group. The average ΔE (color expressed change or improvement) and mean blanching rate measured optically were higher in the PsD-007 group than in the HMME group without statistical differences (8.51 vs. 7.39, p = 0.649; 0.37 vs. 0.29, p = 0.191). Incidences of swelling, pruritus, scab formation, and other adverse reactions were similar for the two groups. There were no blisters, scarring, or hypopigmentation in either group. Conclusions: Both PsD-007- and HMME-mediated PDTs are effective and safe for treatment of PWS. However, HMME has a shorter photosensitivity period than does PsD-007, which might be more recommended.

UV Luminescence and Light Scattering in Photoditazine Systems with Sodium Alginate, Poly-N-Vinylpyrrolidone, and Tryptophan

Fluorescence and Rayleigh light scattering in polymer systems based on the chlorine photosensitizer photoditazine (PD) for photodynamic therapy are studied upon excitation at wavelengths λex = 260, 280, 400, and 450 nm. Nontoxic water-soluble poly-N-vinylpyrrolidone (PVP) and a plant polysaccharide (sodium alginate (SA)) were used as polymers. The PD–SA double system is characterized by dependence of its characteristics on the synthesis conditions, while the PD–SA–PVP triple complex exhibits a positive combined effect of SA and PVP polymers on the PD molecule due to the formation of a local microenvironment of the active PD center with a higher polarity. It is shown that the introduction of tryptophan, which is used as a substrate in model photooxidation processes for testing the efficiency of photosensitizers in singlet-oxygen generation, does not considerably change the fluorescence parameters of the PD–SA–PVP complex.

Folate-directed zinc (II) phthalocyanine loaded polymeric micelles engineered to generate reactive oxygen species for efficacious photodynamic therapy of cancer.

Targeted and effective drug transport is becoming an attractive option in cancer therapy since it can improve drug efficacy and reduce drugs' side effects in normal tissues. In addition to using specific surface ligand molecules, the selective drug delivery can be accomplished via enhanced permeability and retention effect. Therefore, in our studies, we entrapped zinc (II) phthalocyanine (ZnPc) - a second generation photosensitizer - in folate-functionalized micelles of the biocompatible, FDA-approved for biomedical application diblock copolymer methoxypoly(ethylene oxide)-b-poly(L-lactide) (mPEG-b-PLLA) and its derivative with folate (FA) attached to the end of PEG chain (FA-PEG-b-PLLA). Dynamic light scattering (DLS) measurements confirmed the micellar size to be <150 nm in diameter, a low polydispersity index, and good colloid stability of the studied nanocarriers, while atomic force microscopy (AFM) was used to study their morphology. The application potential of the resulting micelles was evaluated in cyto- and photocytotoxicity studies in conjunction with intracellular distribution and accumulation imaging of the photosensitizer delivered to ovarian carcinoma (SKOV-3) and metastatic melanoma (Me45) cell lines. Reactive oxygen species generation study was performed after photodynamic reaction, and cellular cytoskeleton reorganization was visualized after undergoing a photodynamic reaction. The results demonstrated that the functionalized polymeric micelles are promising nanocarriers for photodynamic therapy procedures and can be used in anticancer drug delivery.

Gold-Based Nanoparticles Systems in Phototherapy - Current Strategies.

The understanding of the action mechanism of the nanoparticles systems consisting of metallic nanoparticles and dyes or cytostatic molecule is crucial for searching and designing the ideal, novel drugs. In this review, we have considered moleculefunctionalized metallic nanoparticle systems for phototherapy. We performed a thorough search of the high-quality peer-reviewed literature on metallic nanoparticles systems in phototherapy, focusing on their biological importance and the action mechanism. 138 papers were included in the mini-review. The majority of them discussed the way of metallic nanoparticles functionalization and its impact on the biological activity of a hybrid system. In this work, we show numerous medically and chemically important development strategies of hybrid types of drugs which can be used in phototherapy. These systems have a high affinity to the tumor cells surface proteins which transport the nanoparticles directly into a cell. The application of functionalized metallic nanoparticles in phototherapy improved photophysical properties lowered cytotoxicity of commonly used photosensitizers and facilitated the development of the third generation photosensitizers. Furthermore, this type of nanoparticles could also be used as a cytostatic drug carrier in the chemo or combined anticancer therapies.

Synthesis, photochemical and in vitro cytotoxic evaluation of benzoselenazole-based aminosquaraines

Squaraine dyes have recently attracted interest as potential second generation photosensitizers for photodynamic therapy. Several cationic aminosquaraine dyes bearing benzoselenazole terminal nuclei were synthezised and their cytotoxic activity was tested against four different human tumor cell lines - breast (MCF-7), non-small cell lung (NCI-H460), cervical (HeLa) and hepatocellular (HepG2) carcinomas - and against a non-tumor porcine liver primary cell line (PLP2), both in the absence of light and under irradiation. All dyes, which displayed strong absorption within the phototherapeutic window, were found to exhibit photodynamic activity and were shown to be, in most cases, more cytotoxic, both in the dark and upon irradiation, than their benzothiazole analogues.

Empirical Modeling of Zn/ZnO Nanoparticles Decorated/Conjugated with Fotolon (Chlorine e6) Based Photodynamic Therapy towards Liver Cancer Treatment

The current study is based on Zn/ZnO nanoparticles photodynamic therapy (PDT) mediated effects on healthy liver cells and cancerous cells. The synthesis of Zn/ZnO nanoparticles was accomplished using chemical and hydrothermal methods. The characterization of the synthesized nanoparticles was carried out using manifold techniques (e.g., transmission electron microscopy (TEM), X-ray diffraction (XRD), and energy dispersive X-ray spectroscopy (EDS)). In order to study the biotoxicity of the grown nanoparticles, they were applied individually and in conjunction with the third generation photosensitiser Fotolon (Chlorine e6) in the in vivo model of the normal liver of the Wister rat, and in the in vitro cancerous liver (HepG2) model both in the dark and under a variety of laser exposures (630 nm, Ultraviolet (UV) light). The localization of ZnO nanoparticles was observed by applying fluorescence spectroscopy on a 1 cm2 selected area of normal liver, whereas the in vitro cytotoxicity and reactive oxygen species (ROS) detection were carried out by calculating the loss in the cell viability of the hepatocellular model by applying a neutral red assay (NRA). Furthermore, a statistical analysis is carried out and it is ensured that the p value is less than 0.05. Thus, the current study has highlighted the potential for applying Zn/ZnO nanoparticles in photodynamic therapy that would lead to wider medical applications to improve the efficiency of cancer treatment and its biological aspect study.

Phospholipid multilamellar vesicles entrapping phenothiazine photosensitizers. Preparation, characterization and evaluation of their photodynamic properties

The aim of the present paper was to optimize the properties of phenothiazine photosensitizers (PSs), Azure B and its monobrominated derivative. They were entrapped in multilamellar liposomes of egg phosphatidylcholine (EPC) and dipalmitoylphosphatidylcholine (dpPC). The higher partition coefficient of both PSs in the EPC/water system compared with that of both PSs in the dpPC/water system allowed the selection of EPC to be used for the development of third generation photosensitizers. The optimal phospholipid/phenothiazine ratio and the location of these dyes in the lipid bilayer systems were established. These dyes were found to be located within the polar head group region of the lipid bilayer, which would enhance the effectiveness of the irradiation procedure. In addition, the encapsulation of both photosensitizers in liposomes led to a decrease in the aggregation of these compounds, and consequently to an increase in their singlet oxygen quantum yield (ϕΔ). The encapsulation of the PSs in lipid vesicles significantly increased their photochemical reactivity, doubling the ϕΔ value of AzBBr and increasing that of AzB by 60%. The results obtained demonstrate that the vehiculization of these PSs in liposomes allowed the development of third generation photosensitizers with better photochemical properties to be used in potential therapeutic applications.

“Wax‐Sealed” Theranostic Nanoplatform for Enhanced Afterglow Imaging–Guided Photothermally Triggered Photodynamic Therapy

AbstractHerein, persistent luminescence nanoparticles (PLNPs) and photosensitizer are integrated for cancer theranostics with high specificity and without the need of continuous illumination. Specifically, ZnGa1.996O4:Cr0.004 (PLNPs) and IR780 (photosensitizer) are encapsulated by a temperature‐responsive “wax‐seal” composed of oleic acid and hexadecanol. The seal prevents luminescence quenching and premature initiation of photodynamic therapy (PDT), until it is melted down by heat stimulus. After photothermal activation, the near‐infrared afterglow offered by PLNPs provides imaging with high signal‐to‐background ratio because of the absence of tissue autofluorescence, as well as continuously excited photosensitizer for reactive oxygen species generation. Such theranostic nanoplatform offers multimodal imaging–guided localized cancer PDT.

Immobilization of Photoditazine on Vaterite Porous Particles and Analysis of the System Stability in Model Media

In this paper, we present the results on immobilization of Photoditazine, the photosensitizer of the second generation, on vaterite (metastable modification of calcium carbonate) porous particles of two different sizes. The adsorption efficiency is found to be 3.0 and 3.2 wt % Photoditazine on vaterite particles with average diameters of 5 and 0.5 μm, respectively. The curves of Photoditazine desorption from vaterite particles are determined depending on the composition of the dispersion medium (water and bovine serum albumin solution). It is found that vaterite particles in water are subjected to recrystallization in accordance with the dissolution–precipitation mechanism. The presence of albumin molecules at a physiological concentration allows stabilizing metastable vaterite particles of micron and submicron size for at least 17 days.

Optical and Photosensitizing Properties of Spiro(dipyridinogermole)(dithienogermole)s with Eletron‐Donating Amino and Electron‐Withdrawing Pyridinothiadiazole Substituents

AbstractThree spiro(dipyridinogermole)(dithienogermole) (sDPyG) derivatives with conjugated substituents on the dithienogermole system were synthesized. sDPyG with highly conjugated dithienylbenzothiadiazole substituents (4) showed moderate photoluminescence (PL) behavior with quantum yields of 15–17%, regardless of the solvent (chloroform, THF, or 1,4‐dioxane). In contrast, PL quantum yields of sDPyGs with relatively less conjugated triphenylamine and phenylcarbazole substituents, respectively (5 and 6), were decreased in polar solvents without significant solvatochromic shifts of the PL bands. This seems to indicate that the photo‐induced electron transfer took place in 5 and 6. The sDPyGs were also examined as photosensitizers for singlet oxygen (1O2) generation. The first‐order rate constant for the 1O2 generation of 6 was kobs=0.048/min, comparable to that of tetraphenylporphyrin (TPP, 0.056/min), a typical photosensitizer for 1O2 generation. The quantum yield of the 4‐sensitized 1O2 generation was also determined to be 0.37.

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.

478 Comparison of two generation photosensitizers of PsD-007 and HMME photodynamic therapy for treatment of port-wine stain: A retrospective study

478 Comparison of two generation photosensitizers of PsD-007 and HMME photodynamic therapy for treatment of port-wine stain: A retrospective study

Iodinated zinc phthalocyanine – The novel visible-light activated photosensitizer for efficient generation of singlet oxygen

Phthalocyanines are promising photosensitizers for photodynamic therapy (PDT). A novel zinc 1,8(11),15(18),22(25)-tetraiodo-3,10(9),17(16),24(23)-tetra-tert-butylphthalocyanine has been synthesized and characterized. The synthesis of iodinated phthalocyanine was achieved through templated cyclotetramerization of 6-tert-butyl-4-iodo-1,3-diiminoisoindoline around zinc ions (Zn2+). A six step route leading to 6-tert-butyl-4-iodo-1,3-diiminoisoindoline was proposed. The synthesis started with a regiospecific iodination of 4-tert-butyl-o-xylene to 5-tert-butyl-2,3-dimethyl-iodobenzene, followed by oxidation of the methyl groups to phthalic acid, conversion of phthalic acid to phthalimide, hydrolysis of phthalimide to phthalamide, conversion of phthalamide to phthalonitrile, followed by conversion of phthalonitrile to a more reactive 6-tert-butyl-4-iodo-1,3-diiminoisoindoline. Highly desirable photophysical and photochemical properties were induced in zinc phthalocyanine by iodination of the aromatic rings, while the presence of tert-butyl groups rendered the compound non-aggregating in solution. The photosensitizer studied exhibits absorption band within the so-called “therapeutic window”, with λmax at 689 nm and very high molar absorption coefficient of 295 000 [M−1 cm−1] in DMF. Transient absorption experiment revealed T1 → Tn absorption spanning from ca. 400 nm to ca. 600 nm and allowed determination of the excited triplet state lifetime (τT). The estimated τT in THF equaled 3.3 μs. The phosphorescence maximum was found to be located at λP 1103 nm and the excited triplet state energy (ET) equaled 1.12 eV in 2-methyltetrahydrofuran at 77 K. The photosensitizer studied is characterized by a high value of singlet oxygen quantum yield (ΦΔ) of ca. 0.76 and the photooxygenation process proceeds via Type II mechanism under the experimental conditions applied. The photodegradation studies revealed that the iodinated phthalocyanine was moderately stable in the presence of oxygen with quantum yield of photodegradation (Φd) equaled 4.01 × 10−4. Moderate photostability of photosensitizer is advantageous from a PDT point of view where rapid breakdown and fast clearance from the patient’s system is necessary to avoid prolonged skin photosensitivity following treatment.

One-Pot Synthetic Approach toward Porphyrinatozinc and Heavy-Atom Involved Zr-NMOF and Its Application in Photodynamic Therapy.

Herein, we report an iodine-attached Zn(II)-porphyrinic dicarboxylic building block (ZnDTPP-I2-2H, 1) that can be introduced into UiO-66 NMOF via one-pot synthetic approach to generate a new ZnDTPP-I2 doped UiO-66 type nano metal-organic framework (NMOF) of ZnDTPP-I2⊂UiO-66 (2). Compared to its homologous iodine-free NMOF of ZnDTPP⊂UiO-66 (4), ZnDTPP-I2⊂UiO-66 (2) with heavy iodine atoms is a more effective nanosized photosensitizer for singlet oxygen generation under physiological conditions. As expected, 2 displayed a high photodynamic therapy efficacy for treatment of liver cancer cells in vitro.

Primary screening of substances-photosensibilizers of the bacteriochlorin range for photodynamic therapy of malignant neoplasms

This paper presents a primary screening of bacteriochlorin-type compounds with aminoamide, propyl and carbohydrate substituents aimed for development a new generation photosensitizers (PS) for photodynamic therapy of malignant tumors. Absorption and fluorescence spectral characteristics of the compounds, their storage stability in solutions under dark conditions and light exposure, photo-induced and dark cytotoxicity against human HEp2 tumor cells have been studied. It has been shown that the dyes with aminoamide substituents have an absorbtion maximum at 754±2 nm in the long wavelength region and they are not stable during storage (the specific fluorescence intensity decreased by 33-56% during 24 hours). The long wavelength region absorption of the propyl and carbohydrate substituted compounds varied in the range 780-831 nm, they were stable in solutions during storage and under light irradiation. Except the dye with a carbohydrate residue in the exocycle E, all PS exhibited the high photo-induced activity and low level of the dark cytotoxicity. The highest photo-induced cytotoxicity was observed for compounds with aminoamide substituents inthe macrocyclic ring (IC 50 values ranged from 17 nM to49 nM after 2 hour incubation with PS followed by exposure to the 10 J/cm 2 dose of red light). Taking into account the totality of the physico-chemical and biological properties, as well as manufacturability of production, O-propyloxime-N-propoxybacteriopurinimide methyl ester was chosen as the most promising candidate compound for further investigations.

Spiropyran in nanoassemblies as a photosensitizer for photoswitchable ROS generation in living cells.

Reversibly controlled generation of singlet oxygen from photosensitizing nanosystems has the benefits of selective cell killing and controllable effect time, but is a challenging option for photodynamic therapies. We report a strategy for integrating photochromic spiropyrans into biocompatible cationic polymers, which involved assembling nucleic acids into functional nanoparticles without introducing additional photosensitizers and imaging agents. We found that spiropyran-containing nanoparticles have photoswitching properties for both fluorescence (with a quantum yield of up to 0.27) and singlet oxygen generation (with a quantum yield of up to 0.22) in aqueous solutions and cells, and demonstrated that spiropyrans in nanoassemblies featuring aggregation-induced enhanced photosensitization and emission could be potentially applied in photodynamic therapy studies on tumor cells.

New Generation of Photosensitizers: The Conjugate of Folic Acid with Nanoparticles and Chlorine E6

Synthesis of chlorine e6 conjugates with diamond nanoparticles and folic acid. was developed. In the result of the conducted experimental investigations it was shown that chlorine e6 in a composition of chlorine e6-diamond nanoparticles-folic acid nanocomplex posess photodynamic activity, conjugated Che6 is capable of effective photosensitizing of necrotic death of tumor Hela cells in vitro at relatively low concentration and folic acid provides binding of the nanocomplex with cells expressing the folate receptor.

A heterogeneous photocatalytic system based on a nickel complex over a CdS nanorod photosensitizer for H2 generation from water under visible light

In this paper, we present a nickel complex, [BzPyN(CH3)2]2[Ni(mnt)2] 1 (mnt2−=maleonitriledithiolate), a cocatalyst for building a photocatalytic system for H2 generation from water. Under photoirradiation with blue light (λmax=469nm), 1, together with CdS nanorods (CdS NRs) as a photosensitizer, and ascorbic acid (H2A) as a sacrificial electron donor in a pH2.5 aqueous solution, produces hydrogen with a turnover number (TON) of 70,970mol of H2 per mol of catalyst during 70h irradiation and the average value of AQY is ~18% during 10h of irradiation.

Bovine serum albumin-capped gold nanoclusters conjugating with methylene blue for efficient 1O2 generation via energy transfer

Bovine serum albumin (BSA)-capped gold nanoclusters (BSA-Au NCs) are attractive photosensitizers for efficient singlet oxygen 1O2 generation owing to their high-water solubility, low toxicity, and the broad absorption from UV to visible wavelengths, and the long lifetime of the electronic excitations (of the order of microseconds). However, the 1O2 generation efficiency of BSA-Au NCs is relatively low. In the present study, a conjugate of BSA-Au NCs and methylene blue (MB) (BSA-Au NC-MB conjugate) has been developed to improve 1O2 generation for antimicrobial photodynamic therapy (aPDT). The BSA-Au NC-MB conjugate demonstrated enhanced 1O2 generation compared to the case of BSA-Au NCs and effective aPDT ability under white-light LED illumination for only 1min due to the resonance energy transfer from the Au NCs to the MB in the conjugate. To the best of my knowledge, this is first report of Au NCs on the resonance energy transfer application for efficient 1O2 generation. Therefore, the BSA-Au NC-MB conjugate is a novel photosensitizer for 1O2 generation that shows great potential for aPDT, and the present study also develops a very simple strategy to fabricate albumin-based nanoparticles for PDT.