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PubMed1993

Endogenous porphyrin distribution induced by 5-aminolaevulinic acid in the tissue layers of the gastrointestinal tract.

The accumulation of endogenous porphyrins in rats following systemic administration of 5-aminolaevulinic acid (ALA) has been examined to assess the photosensitization characteristics of this technique for photodynamic therapy (PDT) and chemical extraction assays with fluorescence and absorbance detection of the porphyrin content have been carried out. We compared the results obtained using quantitative microfluorimetry on normal gastric and colonic tissues in rats at 0.5, 1, 2, 4 and 6 h and chemically induced duodenal tumours 2 and 4.5 h after intravenous administration of ALA at a dose of 200 mg kg-1. With chemical extraction followed by high performance liquid chromatography analysis, protoporphyrin IX (PpIX) was found to be the predominant porphyrin present, reaching peak levels of several microgrammes per gramme at 2-4 h in each type of tissue; a small amount of coproporphyrin was detected at 0.5 and 2 h in normal gastric mucosa and duodenal tumour respectively. Both the extraction assay and quantitative microfluorimetry showed that the porphyrin fluorescence builds up rapidly in the mucosal layers of the colon and stomach, reaching a maximum at 2 h, whereas lower fluorescence levels were found with a slower rate of accumulation in the corresponding muscularis layers. A significant PpIX content was found in the duodenal tumour, with a maximum of 7.1 micrograms g-1 4.5 h after ALA administration. We conclude that systemic administration of ALA can induce effective tissue sensitization with protoporphyrin IX and appears to be a promising technique for PDT.

Aminolevulinic Acid↗
PubMed2005

Porphyrins and porphines bind strongly and specifically to tRNA, precursor tRNA and to M1 RNA and inhibit the ribonuclease P ribozyme reaction.

Porphyrins and porphines strongly inhibit the action of the RNA subunit of the Escherichia coli ribonuclease P (M1 RNA). Meso-tetrakis(N-methyl-pyridyl)porphine followed linear competitive kinetics with pre-tRNA(Gly1) from E. coli as variable substrate (Ki 0.960 microM). Protoporphyrin IX showed linear competitive inhibition versus pre-tRNA(Gly1) from E. coli (Ki 1.90 microM). Inhibition by meso-tetrakis[4-(trimethylammonio)phenyl]porphine versus pre-tRNA(Gly1) from E. coli followed non-competitive kinetics (Ki 4.1 microM). The porphyrins bound directly to E. coli tRNAVal, E. coli pre-tRNAGly1 and M1 RNA and dissociation constants for the 1:1 complexes were determined using fluorescence spectroscopy. Dissociation constants (microM) against E. coli tRNAVal and E. coli pre-tRNAGly were: meso-tetrakis(N-methyl-pyridyl)porphine 1.21 and 0.170; meso-tetrakis[4-(trimethylammonio)phenyl]porphine, 0.107 and 0.293; protoporphyrin IX, 0.138 and 0.0819. For M1 RNA, dissociation constants were 32.8 nM for meso-tetrakis(N-methyl-pyridyl)porphine and 59.8 nM for meso-tetrakis[4-(trimethylammonio)phenyl]porphine and excitation and emission spectra indicate a binding mode with strong pi-stacking of the porphine nucleus and base pairs in a rigid low-polarity environment. Part of the inhibition of ribonuclease P is from interaction with the pre-tRNA substrate, resulting from porphyrin binding to the D-loop/T-loop region which interfaces with M1 RNA during catalysis, and part from the porphyrin binding to the M1 RNA component.

Escherichia coli↗
PubMed2004

Dynamics of pH-dependent self-association and membrane binding of a dicarboxylic porphyrin: a study with small unilamellar vesicles.

Steady-state and stopped-flow measurements of the absorbance and fluorescence of aqueous solutions were performed to characterize the pH-dependent ionization and aggregation states of deuteroporphyrin. Porphyrin self-association promoted by neutralization of the carboxylic groups takes place within a few milliseconds impeding characterization of the monomer ionization states. Extrapolation at infinite dilution of the values obtained from steady-state measurements yielded the pKs of the carboxylic groups (6.6, 5.3) and inner nitrogens (4.1, 2.3). The kinetics of interactions of the porphyrin with unilamellar fluid state dioleoylphosphatidylcholine vesicles was examined in a large pH range, with focus on the entry step. From alkaline pH to a value of 6.5, the entrance rate is maximal (1.69 x 10(6) M(-1) s(-1) versus phospholipid concentration). It decreases to 2.07 x 10(5) M(-1) s(-1) at lower pH with an apparent pK of 5.39. This effect appears to be related to the formation of porphyrin dimer rather than to the protonation of inner nitrogen. In keeping with previous data, these results support the concept of a pH-mediated selectivity of carboxylic porphyrins for tumor. They also indicate that the propensity of these molecules to self-associate at low pH could yield to some retention in acidic intracellular vesicles of the endosome/lysosome compartment.

Biological Transport↗
PubMed2006

Enhanced porphyrin accumulation using dendritic derivatives of 5-aminolaevulinic acid for photodynamic therapy: an in vitro study.

Intracellular porphyrin generation following administration of 5-aminolaevulinic acid has been widely used in photodynamic therapy for a range of malignant and certain non-malignant lesions. However, cellular uptake of 5-aminolaevulinic acid is limited by its hydrophilic nature and improved means of delivery are therefore being sought. Highly branched polymeric drug carriers known as dendrimers are a promising new approach to drug delivery. The aim of this study was to investigate the efficacy of dendrimers conjugated with 5-aminolaevulinic acid for porphyrin production in the transformed PAM 212 keratinocyte cell line and skin explants. Each dendritic derivative incorporated three 5-aminolaevulinic acid residues which were conjugated as esters via methyl or propyl linkers to a central tertiary carbon whose remaining terminal bore an amino, aminobenzyloxycarbonyl or nitro group. In the cell line, all compounds were more efficient at low concentrations compared to equimolar 5-aminolaevulinic acid for porphyrin production, with the most efficient incorporating the longer propyl linker. This compound was also the most lipophilic according to partition coefficient measurements. The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure for all the compounds, together with minimal dark toxicity. Our findings indicate that the key factors influencing the efficacy of the dendritic derivatives are lipophilicity and steric hindrance within the dendritic structure which could restrict access to intracellular esterases for liberation of 5-aminolaevulinic acid. These findings should be taken into account in the design of larger dendrimers of 5-aminolaevulinic acid.

Aminolevulinic Acid↗
PubMed2004

Photodynamic effects of porphyrin and chlorin photosensitizers in human colon adenocarcinoma cells.

Photodynamic therapy (PDT) is a cancer treatment involving systemic administration of a tumor-localizing photosensitizer; this, when activated by the appropriate wavelength of light, interacts with molecular oxygen to form a toxic, short-lived species known as singlet oxygen, which is thought to mediate cellular death. Photofrin, a complex mixture of porphyrin oligomers has recently received FDA approval for the photodynamic treatment of esophageal and endobronchial carcinoma, but its photodynamic and toxicity profiles are far from ideal. In the present study we evaluated a series of porphyrin-based PSs, some of which newly synthesized by our group, with the aim to identify agents with more favorable characteristics. For the most effective compounds in the porphyrin series, chlorin analogs were also synthesized; for comparison, the screening also included Photofrin. Cytotoxicity studies were performed by the MTT assay on a cultured human colon adenocarcinoma cell line (HCT116); the results indicate that the 3,4,5-trimethoxyphenyl, 3OH- and 4OH-phenyl, and the sulfonamidophenyl derivatives are significantly more potent than Photofrin. Flow cytometric studies and fluorescence microscopy indicate that in PDT-treated HCT116 cells death occurs mainly by apoptosis. In summary, novel PSs described in the present study, belonging both to the porphyrin and chlorin series, have proven more effective than Photofrin in killing colon cancer cells in vitro; extending these observation to in vivo models, particularly regarding the deeper reaching chlorin derivatives, might lead to significant advances in the development of tumor PDT.

Adenocarcinoma↗
PubMed2005

Stabilization of guanine quadruplex DNA by the binding of porphyrins with cationic side arms.

Many aromatic ligands, including tetra-(N-methyl-4-pyridyl)porphyrin (TMPyP4), have been reported to bind and stabilize quadruplex structure of telomeric DNA. We synthesized novel quadruplex-interacting porphyrins with cationic pyridinium and trimethylammonium arms at para- or meta-position of all phenyl groups of tetratolyl porphyrin. An antiparallel quadruplex structure was found to be stabilized more greatly by the meta-isomers than by the para-isomers and well-studied TMPyP4, as revealed by the increase in melting temperature of the quadruplex. One mole equivalent of the isomers was sufficient to stabilize the quadruplex. From the results of absorption, induced circular dichroism, and fluorescence resonance energy transfer spectroscopic methods, the unique site for the porphyrin binding is suggested to be the external guanine tetrad or groove of the quadruplex. The cationic side arms played a key role in the stabilization of the quadruplex structure.

Cations↗
PubMed2005

Development and optimization of porphyrin gas sensing LB films.

A series of meso-substituted metal-free porphyrins has been developed which show high sensitivity to NO2 gas in the sub-5 ppm concentration range. By selecting different substituents, it has been possible to improve in a systematic manner the response time and sensitivity of the porphyrin LB film to NO2. Initially, a sulphonamino substituent yielded a fairly long response time of around 450 s but this was shortened considerably when this substituent was changed for a stearamido group. Further modifications resulted in achieving a porphyrin LB film which exhibited a t50 response time of only 11 s. By using an optically inert calixarene host material in which the porphyrin guest was incorporated, it was possible to obtain t50 values as low as 5 s.

Biosensing Techniques↗
PubMed2004

Incorporation of hydrophobic porphyrins into liposomes: characterization and structural requirements.

The ability of photosensitisers to give reactive oxygenated products is considered decisive for photodynamic applications, but the hydrophobic nature of many porphyrins makes necessary to obtain suitable pharmaceutical formulations. This paper reports the structural photosensitiser features that allow the preparation of stable liposomal formulations. Metallated and non-metallated TPPs and TPyPs and different lipid/porphyrin ratios were considered in order to procure liposomal preparations containing porphyrin concentrations adequate to necessary doses. The results show that the incorporation of porphyrins into liposomes can be related with their ability to form aggregates in a watery media. Thus, ZnTPP, which structural properties avoid the formation of aggregates, was efficiently incorporated into stable liposomes. Moreover, the efficient generation of singlet oxygen by ZnTPP liposomal suspensions has been shown. Because of this, the synthesis of hydrophobic porphyrin derived structures or other sensitisers, which do not aggregate in a watery media and with Q-bands shifted to higher lambda values than ZnTPP, will be efficiently incorporated into liposomes and useful for clinical applications.

Calorimetry, Differential Scanning↗
PubMed2004

Improved photodynamic activity of porphyrin loaded into nanoparticles: an in vivo evaluation using chick embryos.

Hydrophobic porphyrins are potentially interesting molecules for the photodynamic therapy (PDT) of solid cancers or ocular vascularization diseases. Their pharmaceutical development is, however, hampered by their lipophilicity, which renders formulation difficult especially when intravenous administration is needed. Encapsulation of a lipophilic derivative of porphyrin, the meso-tetra(p-hydroxyphenyl)porphyrin (p-THPP), into polymeric biodegradable poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles proved to enhance its photodynamic activity against mammary tumour cells when compared to free drug. In order to further investigate these carriers, the efficacy of the encapsulated drug was assessed on the chick embryo chorioallantoic membrane (CAM) model. First, we identified a suitable solvent for the drug in terms of p-THPP solubility and tolerability by chick embryos. This solution was used as a reference. Then, the fluorescence pharmacokinetics and the photodynamic effects of the porphyrin on CAM vessels were evaluated after intravenous administration of either a p-THPP solution (free drug) or the drug loaded into nanoparticles. The results showed that: (i) the drug remained longer in the vascular compartment when incorporated into nanoparticles and (ii) vascular effects of p-THPP after light irradiation were enhanced with nanoparticle carriers. These results are discussed taking into account the extravasation of intravascular circulating photosensitizers and its influence on PDT performance.

Animals↗
PubMed2005

Photophysical properties of glucoconjugated chlorins and porphyrins and their associations with cyclodextrins.

Glucoconjugated analogues of the meta-hydroxyphenyl porphyrin (m-THPP) and meta-hydroxyphenyl chlorin (m-THPC) has been recently synthesized. The characteristics of their triplet states have been determined with regard to their involvement in the photodynamic (PDT) efficiency. In the case of porphyrin derivatives, triplet quantum yields (Phi(T)) were ranging from 0.42 to 0.55 and triplet life times (tau(T)) from 1 to 5 micros. High reaction rate constants (k(q)) with molecular oxygen (k(q): 1.2-1.6 x 10(9)s(-1)) have been found. The triplet lifetimes of chlorin derivatives were about four times higher than those of porphyrins whereas the Phi(T) and k(q) values remained quite similar. Singlet oxygen yields of glucosylated and non-glucosylated porphyrins and chlorins were not significantly different within experimental errors (Phi(Delta)((1)O(2)): 0.41-0.58). Furthermore, it has been shown that glucoconjugated photosensitizers could undergo associations with the methyl-beta-cyclodextrin (Me-beta-CD) which exhibit high triplet lifetimes and singlet oxygen yields ranging from 0.27 to 0.48.

Circular Dichroism↗
PubMed2004

Inhibitory effects of water-soluble cationic manganese porphyrins on peroxynitrite-induced SOS response in Salmonella typhimurium TA4107/pSK1002.

We have investigated the protective effects of water-soluble cationic Mn(III) porphyrins against peroxynitrite (ONOO-)-induced DNA damage in the cells of Salmonella typhimurium TA4107/pSK1002 and lipid peroxidation of red blood cell membranes. Mn(III) tetrakis (N-methylpyridinium-4-yl) porphine (TMPyP) and the brominated form, Mn(III) octabromo-tetrakis (N-methylpyridinium-4-yl) porphine (OBTMPyP) effectively reduced the damage and peroxidation induced by N-morpholino sydnonimine (SIN-1), which gradually generates ONOO- from O2*- and *NO produced through hydrolysis. Mn(III)OBTMPyP became 10-fold more active than the non-brominated form. In the presence of authentic ONOO-, the Mn(III) porphyrins were ineffective against damage and strongly enhanced lipid peroxidation, while the coexistence of ascorbic acid inhibited peroxidation. Using a diode array spectrophotometry, the reactions of Mn(III)TMPyP with authentic ONOO- and SIN-1 were measured. Mn(III)TMPyP is known to be catalytic for ONOO- decomposition in the presence of antioxidants. OxoMn(IV)TMPyP with SIN-1 was rapidly reduced back to Mn(III) without adding any oxidants. Further, in the SIN-1 system, the concentration of NO2- and NO3- were colorimetrically determined by Griess reaction based on the two-step diazotization. NO2- increased by addition of Mn(III) porphyrin and the ratio of NO2- to NO3- was 4-7 times higher than that (1.05) of SIN-1 alone. This result suggests that O2*- from SIN-1 acts as a reductant and *NO cogenerated is oxidized to NO2-, a primarily decomposition product of *NO. Under the pathological conditions where biological antioxidants are depleted and ONOO- and O2*- are extensively generated, the Mn(III) porphyrins will effectively cycle ONOO- decomposition using O2*-.

Cations↗
PubMed2004

Infrared spectra of metal-free, N',N-dideuterio, and magnesium porphyrins: density functional calculations.

Infrared frequencies and intensities for the metal-free porphyrin (H2Por), N',N-dideuterio porphyrin (D2Por), and magnesium porphyrin complex (MgPor) have been calculated at density functional B3LYP level using the 6-31G(d) basis set. Detailed assignments of the NH and NM vibrational bands in the IR spectra have been made on the basis of comparison between the calculated data and the experimental results. The previous empirical controversial assignments for the bands at 1224, 1110 and 771 cm(-1) for metal-free porphyrin are also clearly interpreted.

Magnesium↗
PubMed2002

Rotation of periphery methylpyridine of meso-tetrakis(n-N-methylpyridiniumyl)porphyrin (n = 2, 3, 4) and its selective binding to native and synthetic DNAs.

By utilizing circular and linear dichroism, the binding mode of meso-tetrakis(n-N-methylpyridiniumyl)porphyrin (n = 2, 3, 4) to various DNAs was studied in this work. 2-N-(methylpyridiniumyl)porphyrin(o-TMPyP), in which rotation of the periphery pyridinium ring is prevented, exhibits similar spectral properties when bound to DNA, poly[d(G-C)(2)] and poly[d(A-T)(2)], suggesting a similar binding mode. Close analysis of the spectral properties led us to conclude that o-TMPyP sits in the major groove. However, both 3-N- and 4-N-(methylpyridiniumyl)porphyrin (m- and p-TMPyP), of which the periphery pyridinium ring is free to rotate, intercalate between the basepairs of DNA and poly[d(G-C)(2)]. In the presence of poly[d(A-T)(2)], m-TMPyP exhibits a typical bisignate excitonic CD spectrum in the Soret band, while p-TMPyP shows two positive CD bands. The excitonic CD spectrum of the m-TMPyP-poly[d(A-T)(2)] complex and the positive CD band of the o-TMPyP-poly[d(A-T)(2)] complex were not affected by the presence of the minor groove binding drug, 4',6-diamidino-2-phenylindole (DAPI), indicating that this porphyrin is bound in the major groove. In contrast, two positive CD bands of the p-TMPyP-poly[d(A-T)(2)] complex altered in the presence of DAPI. From the changes in CD spectrum and other spectral properties, a few possible binding modes for p-TMPyP to poly[d(A-T)(2)] are suggested.

Binding Sites↗
PubMed2003

Small angle X-ray scattering study of meso-tetrakis (4-sulfonatophenyl) porphyrin in aqueous solution: a self-aggregation model.

The aggregate morphology of meso-tetrakis(4-sulfonatophenyl) porphyrin (TPPS(4)) in aqueous solution is investigated by using small angle x-ray scattering (SAXS) technique. Measurements were performed at pH 4.0 and 9.0 to monitor the pH influence on the structural parameters of the aggregates. Radii of gyration were obtained from distance distribution functions p(r) analysis. The experimental data of TPPS(4) at pH 4.0 showed well-defined oscillations characteristic of large aggregates in contrast to the SAXS curve of 5 mM TPPS(4) at pH 9.0, where both a significant decrease in the intensity and the disappearance of the oscillation peaks suggest the dissociation of the aggregate. A 340-A long "hollow" cylinder with shell thickness of 20 A, compatible to the porphyrin molecule dimension, represents well the scattering curve of the aggregates at pH 4.0. According to the fitting parameters, 26 porphyrin molecules self-associate into a ringlike configuration in the plane of the cylinder cross-section. The total number of porphyrin molecules in the whole aggregate was also estimated as approximately 3000. The model compatible to SAXS data of a hollow cylinder with J-aggregation in the cross-section and H-aggregation (columnar stacking) between the cylinder layers is consistent with optical absorption spectroscopic data both in the literature and obtained in this work.

Computer Simulation↗
PubMed1981

Analysis of free stool porphyrins by high-performance liquid chromatography.

The determination of stool porphyrins is necessary for the diagnosis of some porphyrias in clinical laboratories. Quantitative methods for the analysis of faeces for porphyrins are unpleasant and difficult to perform. An extraction and ion-pair reversed-phase high-performance liquid chromatographic procedure is described for the separation and determination of individual free stool porphyrins. The within-assay coefficients of variation range from 2 to 6%. A linear response curve is observed between 38 and 380 nmol/g for coproporphyrin I in dry stool The method can be applied to the routine analysis of free stool porphyrins in the clinical laboratory.

Chromatography, High Pressure Liquid↗
PubMed1988

Intratumor injection as a more effective means of porphyrin administration for photodynamic therapy.

Photodynamic therapy (PDT) with hematoporphyrin derivative (HpD) as the photosensitizer is a promising new cancer treatment. The major drawback of this procedure is the resulting skin photosensitivity. Patients must remain in subdued light for four to six weeks to avoid cutaneous phototoxicity. In this study, we examine the possibility of reducing the skin photosensitization while maintaining the tumor phototoxic effect by administering the drug directly into the tumor. A subcutaneously implanted mouse bladder tumor (MBT-2) was used. HpD was administered either intraperitoneally (I.P.; 20 mg./kg. b.w.) or by intratumor injection (I.T.; 0.4 mg./cc tumor). The concentrations of HpD in tumor and various tissues (skin, muscle, liver, spleen, kidney, bladder and whole blood) were analyzed at various times after the injection, by 3H-HpD method and by a fluorometric method. Results indicated that at three to 96 hours after the administration, porphyrin levels in tumor were about three to 15 times higher by I.T. than by I.P. injection, while the concentrations in skin and other tissues were 1.3 to 10 times lower. Consequently, at 24 hours after injection ratios between tumor to skin porphyrin were 14 to 92 times higher for I.T. than I.P. injection. Higher porphyrin levels in tumor and lower in normal tissues would indicate lower skin photosensitivity, systemic cytotoxicity and possible greater tumor photosensitivity. This method of porphyrin administration may be useful for the PDT of certain single lesions that are accessible for direct injection.

Animals↗
PubMed1978

Location of iron and porphyrin in the liver in porphyria cutanea tarda.

Porphyrin and iron distributions in the liver biopsies of patients with Porphyria cutanea tarda (PCT) were investigated by comparison of composite photographs from fluorescence microscope and after iron stain. Three distinct areas are visible: 1. red fluorescent areas with porphyrins; 2. blue areas corresponding to iron; 3. areas with neither iron nor porphyrin. The areas with iron or porphyrin do not overlap, therefore, this experiment indicates lack of direct correlation between iron and prophyrin distribution in livers of PCT patients.

Humans↗
PubMed2004

Interaction of sulfonated anionic porphyrins with HIV glycoprotein gp120: photodamages revealed by inhibition of antibody binding to V3 and C5 domains.

The key role of gp120 in the cellular entry of HIV makes this glycoprotein an attractive target for new drugs. Various polyanions bind to the positively charged V3 loop of gp120. Here, we consider a series of anionic porphyrins bearing two sulfonate groups and two carboxylic chains with various degree of esterification. These molecules carry an overall negative charge between 4 and 2. Upon activation by light, these compounds, known as photosensitizers, produce highly reactive oxygen species able to damage amino acid chains. The interactions of these molecules with the V3 loop and a positively charged area in the C5 region were investigated in the dark by using specific antibodies and ELISA protocols. Competitive inhibition of the anti-V3 antibody was observed with an increased efficiency for the esterified compounds. No evidence for binding to the C5 region was found. In contrast, when gp120 was irradiated with light in presence of the porphyrin prior to the addition of the antibody, strong inhibition of the anti-C5 antibody was observed revealing irreversible photo-damages in this region. No effect on the V3 loop was observed. Irradiations at two wavelengths made it possible to identify porphyrin monomers as the photoactive forms despite the presence of large excess of dimers in the incubation solution. It is suggested that porphyrins bound to the V3 loop could produce photo-damages at some distance, in particular within the C5 region that contains several photosensitive amino acids.

Antigen-Antibody Reactions↗