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Biomedical subjects

G Jori

Publications and source records attributed to G Jori.

At least 55 records · Page 3Linked to original sources
PubMed1996

Liposome-delivered 131I-labelled Zn(II)-phthalocyanine as a radiodiagnostic agent for tumours.

131I-Zn(II)-phthalocyanine (ZnPc) incorporated into unilamellar liposomes has been systemically injected to mice bearing a transplanted MS-2 fibrosarcoma. Biodistribution studies show that the pharmacokinetic behaviour of 131I-ZnPc is very similar to that defined for the parent molecule ZnPc including a serum half-life of ca. 12 h, a high recovery from liver and spleen and minimal accumulation in kidney and brain. The most important pharmacokinetic parameter is represented by the high tumour/ muscle ratio of 131I-ZnPc concentration (ca. 9 at 24 h post-injection). These results suggest the possible use of the radiolabelled derivative for a real-time non-invasive monitoring of the ZnPc concentration in the tumour and peritumoural tissue during photodynamic therapy.

Animals↗
PubMed1996

Interaction of hydro- or lipophilic phthalocyanines with cells of different metastatic potential.

A highly metastatic (4R) and a nonmetastatic (RE4) transformed rat embryo fibroblast cell line were incubated with lipid-soluble Zn(II)-phthalocyanine (ZnPc) and its water-soluble tetrasulphonated derivative (ZnPcTS) and compared for phthalocyanine uptake. The hydrophobic liposome-delivered ZnPc showed a significantly greater uptake by both cell lines than did ZnPcTS. Moreover, the two phthalocyanines appear to interact with cells according to different pathways, as suggested by the different temperature-dependence of the binding process and the different inhibitory action exerted by selected serum proteins, such as lipoproteins and heavy proteins. Under all experimental conditions, the two cell lines exhibited similar interactions with ZnPc and ZnPcTS, suggesting that heterogeneity of the tumor cell population has a minor influence on the accumulation of photosensitizers.

Animals↗
PubMed1996

Meso-substituted cationic porphyrins as efficient photosensitizers of gram-positive and gram-negative bacteria.

Previous studies on the photosensitization of bacterial cells with different neutral or negatively charged porphyrins and phthalocyanines have demonstrated that, although Gram-positive bacteria are efficiently photoinactivated, Gram-negative bacteria become photosensitive only after modification of the permeability of their outer membrane. The results described in this paper show that two meso-substituted cationic porphyrins, namely tetra(4N-methyl-pyridyl)porphine tetraiodide and tetra(4N,N,N-trimethyl-anilinium)porphine, efficiently photosensitize the inactivation of Gram-negative bacteria, such as Vibrio anguillarum and Escherichia coli. A negatively charged meso-substituted porphyrin, tetra(4-sulphonatophenyl)porphine, has no appreciable photosensitizing activity towards Gram-negative bacteria, although all three porphyrins exhibit a similar subcellular distribution pattern, being mainly localized in the protoplasts or spheroplasts. Moreover, the three porphyrins show similar efficiency in the photoinactivation of the Gram-positive bacterium Entorecoccus seriolicida.

Dose-Response Relationship, Radiation↗
PubMed1996

Apoptosis of mouse MS-2 fibrosarcoma cells induced by photodynamic therapy with Zn (II)-phthalocyanine.

The destructive process of mouse MS-2 fibrosarcoma induced by photodynamic therapy (PDT) with liposome-administered Zn(II)-phthalocyanine (ZnPc) was studied by electron microscopy. Pronounced ultrastructural changes characteristic of apoptosis were observed for several tumour cells, including early occurrence of condensation and margination of chromatin, disappearance of nuclear pores, karyopyknosis, karyorrhexis, protuberance formation at the cell surface and cell fragmentation. The findings indicate that apoptosis was involved in the process of tumour cell death induced by ZnPc-PDT. The detailed mechanism and pathways controlling this phenomenon need to be elucidated further.

Animals↗
PubMed1996

Studies on the mechanism of bacteria photosensitization by meso-substituted cationic porphyrins.

Cationic porphyrins have been shown to photoinduce the direct inactivation of Gram-positive (G+) and Gram-negative (G-) bacteria, thereby differing from anionic or neutral porphyrins which can photosensitize the G- bacteria only after permeabilization of their outer membrane. The present data show that the differences between these positively and negatively charged porphyrins are not related by a difference in the intrinsic photosensitizing efficiency, as determined by the photo-oxidation of model substrates or the yield of 1O2 generation; moreover, there are only minor differences in the quantum yield of porphyrin photobleaching. Rather, it appears that the positive charge promotes an electrostatic binding of the porphyrin to the outer cell surface inducing an initial limited damage which favours the penetration of the photosensitizer. Actually, the overall photoprocess is inhibited by the preincorporation of the porphyrin into liposomes, while it is enhanced by using amphiphilic dicationic porphyrins which bind to endocellular sites in larger amounts and in a more stable form.

Cell Survival↗
PubMed1996

Tumour photosensitizers: approaches to enhance the selectivity and efficiency of photodynamic therapy.

While Photofrin, the photosensitizer currently in clinical use for photodynamic therapy (PDT) of tumours, has been shown to be both efficacious and safe in the treatment of a variety of human cancers, its chemical heterogeneity and low absorbance in the phototherapeutically useful wavelength range (600-850 nm) make the development of new photosensitizers with improved characteristics desirable. A suitable manipulation of the molecular structure of porphyrins offers several interesting possibilities for controlling the optical and photophysical properties of the photosensitizer, as well as its biodistribution between tumour and peritumoural tissues or at the subtissular and subcellular level. The achievement of these goals may also be facilitated by the association of the photosensitizer with selected delivery systems, opening the way to a qualitative and quantitative improvement of PDT.

Antineoplastic Agents↗
PubMed1996

Tumour-localising and -photosensitising properties of a novel zinc(II) octadecylphthalocyanine.

1,4,8,11,15,18,22,25-Octadecylphthalocyaninato zinc(II), ZnODPc, incorporated into a Cremophor emulsion, was assayed for its pharmacokinetic and phototherapeutic properties in Balb/c mice bearing an intramuscularly transplanted MS-2 fibrosarcoma. The phthalocyanine was injected intravenously (i.v.) in three doses, i.e. 1.46, 0.73 and 0.37 mumol kg-1 body weight. In all cases, the octadecyl-substituted phthalocyanine showed an unusually high affinity for serum low-density lipoproteins (LDLs) and a high efficiency and selectivity of tumour targeting: the maximum accumulation in the tumour occurred at 24 h after injection, whereas no detectable amount of phthalocyanine was recovered from the muscle, i.e. the peritumoral tissue, between 1 h and 1 week after injection. At the same time, low amounts of phthalocyanine were recovered from skin and then only at short times after injection, with skin photosensitivity rapidly disappearing and the phthalocyanine present in the serum only. Tumour photosensitisation studies were carried out at 24 h after administration of 1.46 mumol kg-1 ZnODPc and showed that this phthalocyanine has a very high phototherapeutic efficiency; this is probably a consequence of the multiple mechanisms by which the phthalocyanine induces tumour damage, involving both direct modification of malignant cells and impairment of blood flow, as well as the alteration of a variety of subcellular components, such as mitochondria, the rough endoplasmic reticulum, the perinuclear membrane and, occasionally, cell nuclei. Tumour necrosis appears to be the consequence of both random cell death and apoptosis.

Animals↗
PubMed1996

The bronze baby syndrome: evidence of increased tissue concentration of copper porphyrins.

A case regarding a newborn infant with severe Rh haemolytic disease, who presented with the bronze baby syndrome and eventually died, is reported. The postmortem examination showed marked extramedullary haematopoiesis in the liver and spleen, heavy hepatic haemosiderosis and mild intralobular cholestasis. The porphyrin content, which was assayed in different tissues, was very high in the liver, suggesting that the increased erythropoiesis seen in Rh haemolytic disease leads to an increased synthesis of porphyrins as by-products of haem synthesis. Phototherapy causes photodestruction, sensitized by bilirubin, of porphyrins (mainly copper porphyrins), yielding brown photoproducts.

Erythroblastosis, Fetal↗
PubMed1996

Effect of photosensitizer delivery system and irradiation parameters on the efficiency of photodynamic therapy of B16 pigmented melanoma in mice.

Previous studies (Biolo et al., Photochem. Photobiol. 59, 362-365, 1994) showed that liposome-delivered Si(IV)-naphthalocyanine (SiNc) photosensitizes B16 pigmented melanoma subcutaneously transplanted in C57 mice to the action of 776 nm light. However, the efficacy of the phototreatment was limited by a lack of selectivity of tumor targeting by SiNc as well as by incomplete necrosis of the neoplastic mass. The present investigations show that the use of a different delivery system (Cremophor emulsion vs liposomes of dipalmitoylphosphatidylcholine) causes no significant increase in the selectivity of tumor targeting for three injected doses of SiNc (0.5, 1, 2 mg/kg). However, upon 776 nm light irradiation (300 mW/cm2; 520 J/cm2), the delay in the rate of tumor growth was maximal (7-8 days) for the highest naphthalocyanine dose. On the other hand, a remarkable improvement in the tumor response was obtained by inducing an intratumoral temperature increase to 44 degrees C immediately after PDT. The thermal effect appeared to be due to photoexcitation of melanin by 776 nm light (550 mW/cm2; 520 J/cm2) and subsequent partial conversion of absorbed energy into heat.

Animals↗
PubMed1996

Liposome-mediated delivery of photosensitizers: localization of zinc (II)-phthalocyanine within implanted tumors after intravenous administration.

CGP55847, liposomal zinc(II)-phthalocyanine (Zn-Pc), was administered by the intravenous route to Swiss mice bearing intramuscularly implanted Ehrlich carcinomas or to C57/BL6 mice bearing subcutaneously implanted B16 melanomas. Tumors were removed 3 h or 24 h after dosing the intratumoral distribution determined by fluorescence microscopy. Localization of the photosensitizer occurred more rapidly in the Ehrlich carcinoma than in the B16 melanoma; this difference in photosensitizer uptake may be related to a higher degree of vascularization of the carcinoma. The photosensitizer was found in association with blood vessels at 3 h but not 24 h after dosing and appeared to have a greater affinity for areas of tissue necrosis within the tumor compared to viable tumor tissue. Little or no Zn-Pc was detected in the muscle tissue invaded by the Ehrlich carcinoma and was associated with the membranes and the cytosol, but not the nucleus, of cells in both tumors.

Animals↗
PubMed1995

Temperature-induced changes in fluorescence properties as a probe of porphyrin microenvironment in lipid membranes. 1. The partition of hematoporphyrin and protoporphyrin in liposomes.

Temperature-induced fluorescence changes were studied for hematoporphyrin and protoporphyrin, incorporated into liposomes of dipalmitoylphosphoglycerocholine (Pam2GroPCho) or dimiristoylphosphoglycerocholine (Myr2GroPCho). In some cases, cholesterol or cardiolipin were added to the vesicles for better mimicking the lipid composition of biological membranes. The experimental conditions were appropriately chosen in order to reproduce different possible configurations of the porphyrin molecule in lipid membranes: namely, at the polar water/headgroups, headgroups/lipid and lipid/lipid interfaces. A peculiar feature observed in some of the above liposomal systems was the appearance of discontinuities in the Arrhenius plots of the fluorescence quantum yields, with relevant changes of the values of activation energies. These discontinuities were due to an increase of the fluorescence signal in a temperature range corresponding to the transition of the different lipids from the gel-to-liquid crystal state. The observed phenomena are consistent with the formation of non-covalent linear dimers or linear higher aggregates of the porphyrin molecules. The intermolecular contacts required for the formation of these species are favoured by at least three situations: disruption of the ordered lipid structure during the gel-to-liquid crystal phase transition; competition of other polar groups (e.g., the -OH group of cholesterol) with the porphyrin carboxylate groups for the polar phospholipid headgroups; and steric constraints due to overcrowding of porphyrin molecules in a restricted space.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1995

Temperature-induced changes in fluorescence properties as a probe of porphyrin microenvironment in lipid membranes. 2. The partition of hematoporphyrin and protoporphyrin in mitochondria.

The temperature dependence of hematoporphyrin and protoporphyrin fluorescence quantum yields (phi F) was studied after delivery to whole mitochondria or isolated inner (IMM) and outer (OMM) mitochondrial membranes, obtained from liver of Wistar rats. These studies are very sensitive to variations of the porphyrin lipid environment. Before incorporation, the porphyrins were dissolved in 0.01 M sodium phosphate, 0.15 M NaCl, pH 7.4) NaCl/Pi (only hematoporphyrin) or dispersed into liposomes of dipalmitoylphosphoglycerocholine (Pam2GroPCho), sometimes enriched with cholesterol or cardiolipin. Whole mitochondria show higher incorporation capacity of hematoporphyrin and protoporphyrin than isolated IMM and OMM, probably because additional, energy-sensitive transport mechanisms for the porphyrin uptake occur in intact organelles. A small decrease in protoporphyrin uptake is observed in OMM in comparison with IMM; in contrast, the decrease in hematoporphyrin uptake by OMM is rather significant. A comparison between the results obtained with IMM, OMM and whole mitochondria show that both porphyrins, when released to the intact organelles, preferentially localize in the IMM, irrespective of the lipid carrier used. NaCl/Pi-dissolved hematoporphyrin probably interacts with some membrane proteins, due to the similarity of the Arrhenius plots with those obtained for liposome-entrapped human serum albumin/hematoporphyrin complexes which were used as models to mimic hematoporphyrin-membrane protein binding sites. Liposomal hematoporphyrin and protoporphyrin bind to lipid domains. Hematoporphyrin accumulates in specific, localized lipid regions, perhaps in the boundary lipids area surrounding some inner-mitochondrial carriers; protoporphyrin accomodates in more rigid, lipid areas. On these bases, the higher photoactivity of hematoporphyrin, previously observed in mitochondria, in comparison with protoporphyrin, can be easily explained. Formation of linear dimers/aggregates, endowed with higher phi F than that of the monomers, are postulated to occur for both porphyrins only in the inner mitochondrial membrane.

Animals↗
PubMed1995

Effect of the delivery system on the biodistribution of Ge(IV) octabutoxy-phthalocyanines in tumour-bearing mice.

The pharmacokinetic properties of the Ge(IV)-octabutoxy-phthalocyanines (GePc) with two axially ligated triethylsiloxy (GePcEt) or trihexyl-siloxy (GePcHex) chains were studied in BALB/C mice bearing a transplanted MS-2 fibrosarcoma. The GePcs were delivered to mice after incorporation into unilamellar liposomes of dipalmitoyl phosphatidylcholine (DPPC) or in an emulsion of Cremophor-EL. The Cremophor delivered GePcs were cleared from the blood circulation at a much slower rate than the liposome-delivered GePcs. At the same time, Cremophor induced a slower and reduced uptake of the GePcs in the liver and spleen while it greatly enhanced the uptake in the tumour as compared to liposomes. Maximum tumour uptake was observed at 24 h post-injection and was equivalent to 0.67 and 0.50 nmol/g, respectively, for the Cremophor delivered GePcHex and GePcEt. The corresponding values for the liposome-delivered drugs were approximately one fourth of that observed with Cremophor.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1995

Effect of axial ligation and delivery system on the tumour-localising and -photosensitising properties of Ge(IV)-octabutoxy-phthalocyanines.

Four Ge(IV)-octabutoxy-phthalocyanines (GePcs) bearing two alkyl-type axial ligands were assayed for their pharmacokinetic properties and phototherapeutic efficiency in Balb/c mice bearing an intramuscularly transplanted MS-2 fibrosarcoma. The GePcs were i.v. injected at a dose of 0.35 mumol kg-1 body weight after incorporation into either Cremophor emulsions or small unilamellar liposomes of dipalmitoyl-phosphatidylcholine (DPPC). Both the nature of the delivery system and the chemical structure of the phthalocyanine were found to affect the behaviour of the GePcs in vivo. Thus, Cremophor-administered GePcs invariably yielded a more prolonged serum retention and a larger association with low-density lipoproteins (LDLs) as compared with the corresponding liposome-delivered phthalocyanines. This led to a greater efficiency and selectivity of tumour targeting. These effects were more pronounced for those GePcs having relatively long alkyl chains (hexyl to decyl) in the axial ligands. Maximal tumour accumulation (0.67 nmol per g of tissue) was found for Ge-Pc(hexyl)2 at 24 h after injection. Consistently, the Ge-Pc(hexyl)2, administered via Cremophor, showed the highest phototherapeutic activity towards MS-2 fibrosarcoma.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1995

On the source of the oscillations observed during in vivo zinc phthalocyanine fluorescence pharmacokinetic measurements in mice.

Surface-detected fluorescence spectroscopy can be used to monitor the pharmacokinetics of uptake and clearance of red-absorbing fluorophores such as zinc(II) phthalocyanine (ZnPc) in vivo. When this technique is applied to mice that have been fed on a normal chlorophyll-based diet, and particularly when measurements are performed in the abdominal region, oscillations are sometimes observed superimposed on the pharmacokinetic curve of the ZnPc. An oscillatory signal has also been observed arising from the abdominal region of control mice fed a normal diet but not injected with the ZnPc photosensitizer; this oscillatory component to the signal is reduced when mice are fed a chlorophyll-free diet. The oscillatory signal component has been attributed to fluorescence arising from chlorophyll derivatives (pheophorbide/pheophytin) contained in the rodent food, whose concentration in the measured abdominal region changes substantially with time, presumably due to digestive processes. Thus it is important to be aware of the possibility of such artifactual contributions to in vivo fluorescence pharmacokinetic measurements.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1995

Unusually high affinity of Zn(II)-tetradibenzobarrelenooctabutoxy-phthalocyanine for low-density lipoproteins in a tumor-bearing mouse.

An important factor in determining the efficacy of photosensitizing compounds in photodynamic therapy of tumors is the level to which tumors take up the photosensitizers after systemic injection. This parameter seems to be related to the transport modalities of the photosensitizer in the bloodstream. In this work the photosensitizer Zn(II)-tetradibenzobarrelenooctabutoxyphthalocyanine was shown to have an unprecedentedly high association with low-density lipoproteins (71% of the phthalocyanine in the plasma) when delivered in Cremophor micelles to tumor-bearing mice. This was accompanied by a particularly high tumor uptake at 24 h post-injection.

Animals↗
PubMed1994

Interaction of phthalocyanines with lipid membranes: a spectroscopic and functional study on isolated rat liver mitochondria.

Absorption and emission spectroscopic studies on Zn(II)-phthalocyanine (ZnPc) incorporated into unilamellar liposomes of dipalmitoylphosphatidylcholine, sometimes added with cholesterol or cardiolipin, and released to rat liver mitochondria via the three types of liposomal vesicles indicated that: (a) ZnPc predominantly dissolves in all lipid domains of biological membranes with the exception of cardiolipin-containing regions; a partial localization of ZnPc in protein binding sites is also postulated; (b) the spectroscopic properties of ZnPc, although mainly determined by the aggregation state of the dye, are somewhat influenced by the physico-chemical characteristics of the lipid environment; (c) ZnPc-binding lipid domains in mitochondria are mainly localized in the outer membrane; this conclusion is clearly deduced from the trends of Arrhenius plots of the ZnPc fluorescence quantum yield in whole mitochondria and isolated inner or outer membrane in the temperature range -10 degrees C-(+)45 degrees C; (d) the nature of the ZnPc-binding site in mitochondria is not dependent on the chemical composition of the liposome carrier, contrary to what observed for other hydrophobic dyes, such as porphyrins. This has been also confirmed by photosensitization experiments. Actually, illumination of ZnPc-loaded mitochondria by 600-700 nm light causes a decline of the respiratory control ratio, which is essentially dependent on the amount of incorporated photosensitizer, irrespective of the composition of the carrier.

Animals↗