Photodynamic Efficiency Research Articles

Lipophilic phthalocyanines for their potential interest in photodynamic therapy: synthesis and photo-physical properties

Several phthalocyanines with different peripheral substituents were prepared and characterized by MALDI-TOF, 1H NMR, UV–vis, fluorescence, and singlet oxygen quantum yields and retention time in HPLC normal phase. Zinc was used as a central metal ion to increase the photodynamic therapy efficiency. Phthalonitrile or 4-nitro phthalonitriles were used as starting materials. The influence of lipophilicity on the photophysical and photochemical properties was evaluated.

Enhanced photodynamic efficacy of PLGA-encapsulated 5-ALA nanoparticles in mice bearing Ehrlich ascites carcinoma

Nanoparticles (NPs) fabricated from the biodegradable copolymer poly(lactic-co-glycolic acid) (PLGA) were investigated as a drug delivery system to enhance the photodynamic efficacy of 5-aminolevulinic acid (5-ALA) in mice bearing Ehrlich ascites carcinoma. The PLGA-encapsulated 5-ALA NPs were prepared using binary organic solvent diffusion method and characterized in terms of shape and particle size. The in vivo photodynamic efficiency in Ehrlich ascites-bearing mice was studied. The obtained particles were uniform in size with spherical shape of mean size of 249.5 nm as obtained by particle size analyzer and the in vitro release studies demonstrated a controlled release profile of 5-ALA. Tumor-bearing mice injected with PLGA-encapsulated 5-ALA NPs exhibited significantly smaller mean tumor volume, increased tumor growth delay compared with the control group and the group injected with free 5-ALA during the time course of the experiment. Histopathological examination of tumor from mice treated with PLGA-encapsulated 5-ALA NPs showed regression of tumor cells, in contrast to those obtained from mice treated with free 5-ALA. The results indicate that PLGA-encapsulated 5-ALA NPs are a successful delivery system for improving photodynamic activity in the target tissue.

PEG-functionalized iron oxide nanoclusters loaded with chlorin e6 for targeted, NIR light induced, photodynamic therapy

Magnetic targeting that utilizes a magnetic field to specifically delivery theranostic agents to targeted tumor regions can greatly improve the cancer treatment efficiency. Herein, we load chlorin e6 (Ce6), a widely used PS molecule in PDT, on polyethylene glycol (PEG) functionalized iron oxide nanoclusters (IONCs), obtaining IONC–PEG–Ce6 as a theranostic agent for dual-mode imaging guided and magnetic-targeting enhanced in vivo PDT. Interestingly, after being loaded on PEGylated IONCs, the absorbance/excitation peak of Ce6 shows an obvious red-shift from ∼650 nm to ∼700 nm, which locates in the NIR region with improved tissue penetration. Without noticeable dark toxicity, Ce6 loaded IONC–PEG (IONC–PEG–Ce6) exhibits significantly accelerated cellular uptake compared with free Ce6, and thus offers greatly improved in vitro photodynamic cancer cell killing efficiency under a low-power light exposure. After demonstrating the magnetic field (MF) enhanced PDT using IONC–PEG–Ce6, we then further test this concept in animal experiments. Owing to the strong magnetism of IONCs and the long blood-circulation time offered by the condensed PEG coating, IONC–PEG–Ce6 shows strong MF-induced tumor homing ability, as evidenced by in vivo dual modal optical and magnetic resonance (MR) imaging. In vivo PDT experiment based magnetic tumor targeting using IONC–PEG–Ce6 is finally carried out, achieving high therapeutic efficacy with dramatically delayed tumor growth after just a single injection and the MF-enhanced photodynamic treatment. Considering the biodegradability and non-toxicity of iron oxide, our IONC–PEG–Ce6 presented in this work may be a useful multifunctional agent promising in photodynamic cancer treatment under magnetic targeting.

Hypericin encapsulated in solid lipid nanoparticles: Phototoxicity and photodynamic efficiency

The hydrophobicity of some photosensitizers can induce aggregation in biological systems, which consequently reduces photodynamic activity. The conjugation of photosensitizers with nanocarrier systems can potentially be used to overcome this problem. The objective of this study was to prepare and characterise hypericin-loaded solid lipid nanoparticles (Hy-SLN) for use in photodynamic therapy (PDT). SLN were prepared using the ultrasonication technique, and their physicochemical properties were characterised. The mean particle size was found to be 153 nm, with a low polydispersity index of 0.28. One of the major advantages of the SLN formulation is its high entrapment efficiency (EE%). Hy-SLN showed greater than 80% EE and a drug loading capacity of 5.22% (w/w). To determine the photodynamic efficiency of Hy before and after encapsulation in SLN, the rate constants for the photodecomposition of two 1O2 trapping reagents, DPBF and AU, were determined. These rate constants exhibited an increase of 60% and 50% for each method, respectively, which is most likely due to an increase in the lifetime of the triplet state caused by the increase in solubility. Hy-SLN presented a 30% increase in cell uptake and a correlated improvement of 26% in cytotoxicity. Thus, all these advantages suggest that Hy-loaded SLN has potential for use in PDT.

Enhanced Photodynamic Efficiency of an Aptamer‐Guided Fullerene Photosensitizer toward Tumor Cells

Fullerene-based photosensitizers exhibit great potential in photodynamic therapy (PDT). Based on the high photodynamic efficacy of trimalonic acid-modified C70 fullerene (TF70), we constructed an aptamer-guided TF70 photosensitizer and investigated its photodynamic effect. Conjugation of the novel aptamer (named R13) could effectively enhance the PDT efficiency of TF70 against A549 lung cancer cells in the presence of serum. The lysosomal location of the TF70-R13 conjugate inside cells facilitates the production of intracellular reactive oxygen species (ROS), which can efficiently kill cells, under light irradiation. The enhanced photodynamic efficiency, along with its good biocompatibility in the dark, makes TF70-R13 a highly promising photosensitizer for tumor-specific PDT.

Dendrimeric-like hexadecahydroxylated zinc phthalocyanine: Synthesis and evaluation of photodynamic efficiency

The design of a dendrimeric-like diglycerol-tetrasubstituted Zn ( II ) phthalocyanine resulted in a remarkably water-soluble compound due to the presence of 16 hydroxyls. Several parameters relevant to evaluate the photodynamic efficiency of a potentiel photosensitizer such as: aggregation behavior, fluorescence properties, singlet oxygen generation, binding to a carrier protein model (Bovine Serum Albumin) and partition coefficient have been measured. Biocompatibility was demonstrated by dark cytotoxicity in in vitro experiments. The absence of phototoxicity can be explained by an elevated hydrophilicity. All the collected data have confirmed that this new substitution pattern is promising to be used on phthalocyanines aiming at being photodynamic therapy agents.

A naphthalocyanine based near-infrared photosensitizer: Synthesis and in vitro photodynamic activities

A hydrophilic near-infrared (NIR) photosensitizer featuring a naphthalocyanine core and peripheral carboxylate acid groups was synthesized and characterized. Its photophysical and photochemical properties were studied and compared with phthalocyanine. Due to the extended π-conjugation, both the Q band and fluorescence emit of this naphthalocyanine bathochromically shift to NIR region. It also exhibits superior NIR photodynamic efficiency to phthalocyanine as evidenced by high efficiency in generating singlet oxygen (ΦΔ=0.66) and in vitro phototoxicity toward Hela human cervical cancer cells. Therefore, this novel naphthalocyanine could potentially be a NIR photosensitizer for photodynamic therapy.

Monoglycoconjugated phthalocyanines: Effect of sugar and linkage on photodynamic activity

Click chemistry can be advantageously used to graft carbohydrates on phthalocyanines which are potent photosensitisers, but the effect of the presence of triazole moieties on photodynamic efficiency was not investigated systematically to date. The nature and linkage of the sugar were investigated in order to define structure-activity relationships. Two sets of monoglycoconjugated water-soluble phthalocyanines have been designed and their photodynamic activity and uptake investigated in HT-29 human colon adenocarcinoma cells. Carbohydrates: galactose, mannose or lactose were grafted onto Zn(II) phthalocyanines either by glycosylation or by click reaction. The triazole linkage formed by click conjugation lowered the biological efficiency for mannose and galactose, compared to classical glycosylation grafting. The mannose conjugate formed by glycosylation was the most photodynamically active, without correlation with the photosensitiser cell uptake.

Estudos quimiométricos da pheo formulada em pluronics®: ação fotodinâmica Sobre Artemia salina

The self-aggregation of pheophytin, a possible photosensitizer for Photodynamic Therapy, is solved by formulation in polymeric surfactant as P-123. The photosensitizer incorporation was found to be time dependent, exhibiting two steps: a partition at the micellar interface followed by an incorporation into the micelle core. The photodynamic efficiency of the formulation was tested by the bioassays against Artemia salina. In order to evaluate how the experimental parameters: pheophytin concentration, P-123 percentage and illumination time influenced the death of artemia, the factorial design 23 was chosen. The illumination time was found to be the main factor contributing to the mortality of artemia.

Photodynamic Efficiency of Cationicmeso-Porphyrins at Lipid Bilayers: Insights from Molecular Dynamics Simulations

Porphyrin derivatives have applications as photoactive drugs in photodynamic therapy. However, little is known about their interactions with phospholipid membranes at the molecular level. We employed molecular dynamics simulations to model the binding between a series of cationic meso-(N-methyl-4-pyridinium)phenylporphyrins and anionic phosphatidylglycerol lipid bilayers. This was done in the presence of molecular oxygen within the membrane. The ability of various porphyrins to cause photodamage was quantified in terms of their immersion depth and degree of exposition to a higher oxygen concentration inside the membrane. Simulations showed that the photodynamic efficiency could be improved as the number of hydrophobic phenyl substituents attached to the porphyrinic ring increased. In the specific case of porphyrins containing two hydrophobic and two charged substituents, the cis isomer was significantly more efficient than the trans. These results correlate well with previous experimental observations. They highlight the importance of both the total charge and amphiphilicity of the photosensitizer for its performance in photodynamic therapy.

Susceptibility of non-enveloped DNA- and RNA-type viruses to photodynamic inactivation

The comparative susceptibility of DNA- and RNA-type viruses to photodynamic inactivation has not yet been clearly addressed. In this study the effect of the tricationic porphyrin Tri-Py(+)-Me-PF on the inactivation of four DNA and three RNA non-enveloped phages was compared. The results obtained show that the photodynamic efficiency varied with the phage type, the RNA-type phages being much more easily photoinactivated than the DNA-type ones.

Systems biology approach for in vivo photodynamic therapy optimization of ruthenium-porphyrin compounds

Two arene ruthenium porphyrin compounds showing interesting photodynamic activity in vitro, [Ru(η6-p-PriC6H4Me)(PMP)Cl2] (PMP=5-(3-pyridyl)-10,15,20-triphenylporphyrin) and [Ru4(η6-p-PriC6H4Me)4(PTP)Cl8] (PTP=5,10,15,20-tetra(3-pyridyl)porphyrin) coined Rut1 and Rut4 respectively, have been evaluated in vivo. Porphyrins alone and the arene ruthenium porphyrin derivatives (Rut1 and Rut4) showed comparable spectroscopic and photophysical properties. The in vivo study consisted in selecting the optimal arene ruthenium porphyrin photosensitizer by using an original experimental design approach on mice bearing an ectopic human oral carcinoma xenograft. The model of experimental design demonstrated to be well suited to the empirical model-building of photodynamic therapy (PDT) response. Arene ruthenium porphyrins concentration and fluence level demonstrated no statistically significant influence on the tumor growth. On the contrary, the presence of ruthenium groups improved the in vivo photodynamic efficiency. By optical fiber fluorimetry, we demonstrated that both compounds exhibited enhanced accumulation in KB tumors from 24h to 96h post-intravenous injection. These experiments were completed by inductively coupled plasma mass spectrometry quantification of ruthenium in different organs including tumor tissue. Despite a statistically significant in vivo photodynamic efficiency for Rut4, cellular localization in human oral carcinoma KB cells using fluorescence microscopy demonstrated that both conjugates Rut1 and Rut4 accumulated only in cytoplasm of KB cells but not in the nucleus.

Photodynamic Effects of Zinc(II) Phthalocyanine‐Loaded Polymeric Micelles in Human Nasopharynx KB Carcinoma Cells

A major difficulty in photodynamic therapy is the poor solubility of the photosensitizer (PS) under physiological conditions which correlates with low bioavailability. PS aggregation leads to a decrease in the photodynamic efficiency and a more limited activity in vitro and in vivo. To improve the aqueous solubility and reduce the aggregation of 2,9(10),16(17),23(24)-tetrakis[(2-dimethylamino)ethylsulfanyl]phthal-ocyaninatozinc(II) (Pc9), the encapsulation into four poloxamine polymeric micelles (T304, T904, T1107 and T1307) displaying a broad spectrum of molecular weight and hydrophilic-lipophilic balance was investigated. The aqueous solubility of Pc9 was increased up to 30 times. Morphological evaluation showed the formation of Pc9-loaded spherical micelles in the nanosize range. UV/Vis and fluorescence studies indicated that Pc9 is less aggregated upon encapsulation in comparison with Pc9 in water-DMSO 2% and remained photostable. Pc9-loaded micelles generated singlet molecular oxygen in high yields. Photocytotoxicity assays using human nasopharynx KB carcinoma cells confirmed that the encapsulation of Pc9 in T1107 and T1307 increases its photocytotoxicity by 10 times in comparison with the free form in water-DMSO. In addition, Pc9 incorporated into cells was mainly localized in lysosomes.

Liquid Crystal Nanodispersions Enable the Cutaneous Delivery of Photosensitizer for Topical PDT: Fluorescence Microscopy Study of Skin Penetration

Topical photodynamic therapy (PDT) has been applied to almost all types of nonmelanoma skin cancer and numerous superficial benign skin disorders. Strategies to improve the accumulation of photosensitizer in the skin have been studied in recent years. Although the hydrophilic phthalocyanine zinc compound, zinc phthalocyanine tetrasulfonate (ZnPcSO4) has shown high photodynamic efficiency and reduced phototoxic side effects in the treatment of brain tumors and eye conditions, its use in topical skin treatment is currently limited by its poor skin penetration. In this study, nanodispersions of monoolein (MO)-based liquid crystalline phases were studied for their ability to increase ZnPcSO4 uptake by the skin. Lamellar, hexagonal and cubic crystalline phases were prepared and identified by polarizing light microscopy, and the nanodispersions were analyzed by dynamic light scattering. In vitro skin penetration studies were performed using a Franz's cell apparatus, and the skin uptake was evaluated in vivo in hairless mice. Aqueous dispersions of cubic and hexagonal phases showed particles of nanometer size, approximately 224 ±10 nm and 188 ± 10 nm, respectively. In vitro skin retention experiments revealed higher fluorescence from the ZnPcSO4 in deeper skin layers when this photosensitizer was loaded in the hexagonal nanodispersion system when compared to both the cubic phase nanoparticles and the bulk crystalline phases (lamellar, cubic and hexagonal). The hexagonal nanodispersion showed a similar penetration behavior in animal tests. These results are important findings, suggesting the development of MO liquid crystal nanodispersions as potential delivery systems to enhance the efficacy of topical PDT. Keywords: Liquid crystalline phases, nanodispersion, skin cancer, skin penetration, photodynamic therapy, zinc phthalocyanine

Global sensitivity analysis and estimation of photophysical parameters from in vivo data in photodynamic therapy

Photodynamic therapy (PDT) is an alternative treatment for cancer that involves the administration of a photosensitizing agent, which is activated by light at a specific wavelength. In this project, we aim at developing a model-based approach to compare the in vivo photodynamic efficiencies of different photosentizers. Unfortunately, constraints of in vivo experiments are such that it is impossible to estimate all the photophysical parameters. However in this paper, a feasibility study is performed to (i) select the most relevant model parameters and (ii) estimate their value and their confidence interval. Despite the previously mentioned difficulties, the results obtained in practice from in vivo experiments have shown promising results.

Photodynamic efficacy of photosensitizers under an attenuated light dose via lipid nano-carrier-mediated nuclear targeting

Photodynamic therapy (PDT) has emerged as a treatment for certain malignant-like skin, head and neck, gastrointestinal, and gynecological cancers. The broader acceptance of PDT treatment for large or deep-seated tumors is still hindered, at least in part, by the low photodynamic efficiency of photosensitizers (PS) in the deep-seated tumor environment where the light energy fluency rate is severely attenuated after propagation via skin and/or tissue barriers. In this report, efficient nuclear-targeted intracellular delivery of PS is achieved using an easily fabricated yet entirely biocompatible and inexpensive polysaccharide-functionalized nanoscale lipid carrier, which triggers the intracellular release of photosensitizers inside cancer cells and targets cell nuclear to achieve a significantly enhanced photocytotoxicity. Cancer cells are killed efficiently even under an extremely low light fluency of 1 mW/cm2 attenuated via an interval meat layer with a thickness of 3 mm. Therefore, this nuclei-targeting system may contribute to the development of a new generation of PS carriers that fight against deep-seated tumors and that exhibit excellent photodynamic efficiency under faint light irradiation.

Comparative characterization of the cellular uptake and photodynamic efficiency of Foscan® and Fospeg in a human prostate cancer cell line

m-THPC (Foscan(®)) is one of the most potent second generation photosensitizers used in photodynamic therapy, photoactivated at higher wavelengths (652 nm). However, its strongly hydrophobic nature causes aggregation of the molecules and prevents its unbiased bioavailability in the biological media, resulting in lower accumulation in the tumor cells. Several strategies have been adopted to improve the photodynamic characteristics of the photosensitizer. Among them, very promising seems to be the encapsulation of the molecule into liposomes, due to the superior properties of liposomes as drug carriers. In this paper the photodynamic characteristics of the PEGylated liposomal formulation of m-THPC, Fospeg, using the human prostate cancer cell line LNCaP, as an in vitro model, were investigated. In addition the spectral characteristics, cellular uptake and localization, dark and light induced cytotoxicity and photodynamic efficacy of Foscan(®) and Fospeg were compared. Fospeg, compared with Foscan, showed higher intracellular uptake at any concentration and incubation time. Regarding PDT efficacy, Fospeg produced more severe cytotoxicity than Foscan(®) at any concentration and energy dose. Using Fospeg, the lowest concentration (0.22 μM) and energy dose (180 mJ/cm(2)) was adequate to result in the death of 50% of the cells 24h post PDT while an approximately 10 times higher Foscan(®) concentration (1.8 μM) was needed to result in the same cytotoxicity. The use of the PEGylated liposomal formulation of m-THPC resulted in the improvement of its intracellular uptake and the enhancement of its photodynamic activity. Fospeg, compared to Foscan(®), proved to be a more advantageous photosensitizer for photodynamic therapy.

Drug Targeting Strategies for Photodynamic Therapy

In human pathologies, therapeutic treatments are often limited by the lack of selectivity of drugs and their elevated effective concentrations. Targeting these agents to a defined tissue could enhance their selectivity and then diminish their side effects when compared to drugs that accumulate in the entire body. Targeting could also improve treatment efficiency by allowing a localized high concentration of the agents. Based on the different behaviors and patterns of expression between diseased and normal cells, strategies for targeting can be explored. For example, receptors, proteases or trans-membrane carriers could be different or differently expressed. Many therapeutic procedures rely on this fact, including photodynamic therapy (PDT). PDT is already used in the treatment of some cancers, of inflammatory diseases and others diseases such as age-related macular degeneration or acne. PDT relies on the activation of a photosensitizer (PS) by visible light which results in the production of cytotoxic reactive oxygen species. In PDT, the general distribution of PS to the whole body leads to generalized photosensitization and poor acceptance of treatments by patients. One way to avoid these effects is to improve the targeting of PSs to diseased tissues using modification of PS with peptides or proteins that will target specific receptors or enzymes. PSs could also be functionalized with non-proteic ligands such as organometalics to achieve targeted and/or combined therapies. Alternatively, PSs could be encapsulated in nanoparticles bearing targeting agents which will decrease concentration of free circulating PS and improve photodynamic efficiency. These different approaches will be discussed in the present review with an emphasis on the use of peptides and proteins.

국내 태양광자원의 성분 및 파장별 분석에 관한 연구

Knowledge of the solar radiation components and classified wavelength data are essential for modeling many solar photovoltaic systems. This is particularly the case for applications that concentrate the incident energy to attain high photo-dynamic efficiency achievable only at the higher intensities. In order to estimate the performance of concentrating PV systems, it is necessary to know the intensity of the beam radiation, as only this components can be concentrated, and The new PV cell can generate electricity from ultraviolet and infrared light as well as visible light. The Korea Institute of Energy Research(KIER) has began collecting solar radiation components data since January, 1988, and solar radiation classified wavelength data since November, 2008. KIER's solar radiation components and classified wavelength data will be extensively used by concentrating PV system users or designers as well as by research institutes. It is essential to utilize the solar radiation data as application and development of solar energy system increase. Consider able efforts have been made constructing a standard data base system from measure data.

Singlet oxygen dosimetry using uric acid as a chemical probe: Systematic evaluation

Abstract The singlet oxygen generation of a photosensitizer compound (PS) is an important property for photodynamic treatments. The PS quantum yield of 1 O 2 ( Φ Δ ) is usually obtained by the time-resolved measurement of 1 O 2 phosphorescence emission. However, the equipment employed is quite expensive. In the present study, the methodology previously proposed by us for Φ Δ dosimetry using uric acid (UA) as a chemical-probe was systematically evaluated. The PS photo-excitation was achieved with a polychromatic light source (LED) that generates 1 O 2 which attacks the UA. The level of UA oxidation is proportional to a parameter called chemical photodynamic efficiency, which is correlated to Φ Δ by comparing it to a standard compound. The photobleaching reaction of the PS is considered in the calculation. Several parameters that influence this measurement have been investigated with different PS (phenothiazines, xanthenes, chlorins, and benzoporphyrin dyes) in water, ethanol, and aqueous P-123 polymeric surfactant. Excellent results were obtained when standard compounds belonging to the same class of the photosensitizer and the same solvent were used. The chemical method of 1 O 2 evaluation with UA is reliable, exact, precise, easy to perform and low cost, although limited by the standard compound employed as Φ Δ Std .