Search PubMed⌕ Search

Biomedical subjects

J E van Lier

Publications and source records attributed to J E van Lier.

At least 19 recordsLinked to original sources
PubMed2001

Internalisation enhances photo-induced cytotoxicity of monoclonal antibody-phthalocyanine conjugates.

Immunophototherapy of cancer combines the specificity of a monoclonal antibody (MAb) to an overexpressed tumor marker with the phototoxic properties of the conjugated dye. To analyze the potential role of internalisation of the dye on photo-induced cytotoxicity, we compared two target antigens, carcinoembryonic antigen (CEA) that does not internalise and ErbB2 that does. Human ovarian carcinoma SKOv3 cells that express a high level of ErbB2 were transfected with the CEA cDNA. Using FACS analysis, the resulting cell line, SKOv3-CEA-1B9, demonstrated comparable levels of expression of the two target antigens. Aluminium tetrasulfophthalocyanine (AlPcS(4)) was covalently coupled to anti-CEA MAb 35A7, anti-ErbB2 MAb FSP77 and a non-specific MAb PX, via a five-carbon sulfonamide spacer chain (A(1)) at molar ratios ranging from 6 to 9 moles of AlPcS(4) per mole of MAb. The 35A7-(AlPcS(4)A(1))(8) conjugate induced 68% growth inhibition of the SKOv3-CEA-1B9 cell line after a 20 h incubation at 2.50 microg/ml (based on AlPcS(4)A(1) content) following light exposure. However, the FSP77-(AlPcS(4)A(1))(6) conjugate gave a 51% growth inhibition for an AlPcS(4)A(1) concentration as low as 0.04 microg/ml after the same incubation time and exposure to the same light dose. At a 1.25 microg/ml AlPcS(4)A(1) concentration, the FSP77-(AlPcS(4)A(1))(6) conjugate gave a 67% growth inhibition after an incubation time as short as 1 h, reaching a 96% inhibition after an 8 h incubation time. Using an unique cell line that expresses two different target antigens, we demonstrated a clear advantage of an internalising over a non-internalising MAb-dye conjugate in terms of phototoxic efficacy. In vivo evaluation of the photodynamic properties of the conjugates is in progress.

Antibodies, Monoclonal↗
PubMed2001

In-vitro and in-vivo evaluation of pH-responsive polymeric micelles in a photodynamic cancer therapy model.

pH-sensitive polymeric micelles of randomly and terminally alkylated N-isopropylacrylamide copolymers were prepared and characterized. Aluminium chloride phthalocyanine (AlClPc), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in the micelles by dialysis. Their photodynamic activities were evaluated in-vitro against EMT-6 mouse mammary tumour cells and in-vivo against EMT-6 tumours implanted intradermally on each hind thigh of Balb/c mice. pH-sensitive polymeric micelles were found to exhibit greater cytotoxicity in-vitro than control Cremophor EL formulations. In the presence of chloroquine, a weak base that raises the internal pH of acidic organelles, in-vitro experiments demonstrated the importance of endosomalllysosomal acidity for the pH-sensitive polymeric micelles to be fully effective. Biodistribution was assessed by fluorescence of tissue extracts after intravenous injection of 2 micromol kg(-1) AlClPc. The results revealed accumulation of AlClPc polymeric micelles in the liver, spleen and lungs, with a lower tumour uptake than AlClPc Cremophor EL formulations. However, polymeric micelles exhibited similar activity in-vivo to the control Cremophor EL formulations, demonstrating the higher potency of AlClPc polymeric micelles when localized in tumour tissue. It was concluded that polymeric micelles represent a good alternative to Cremophor EL preparations for the vectorization of hydrophobic drugs.

Acrylamides↗
PubMed2000

Preparation and characterization of pH-responsive polymeric micelles for the delivery of photosensitizing anticancer drugs.

pH-responsive polymeric micelles (PM) consisting of random copolymers of N-isopropylacrylamide (NIPA), methacrylic acid (MAA), and octadecyl acrylate (ODA) were prepared and characterized. The critical aggregation concentration, as determined by a fluorescence probe technique, was approximately 10 mg/L in water and phosphate-buffered saline. Phase transition pH was estimated at 5.7. The decrease in pH was accompanied by the destruction of hydrophobic clusters. Micelle size was dependent on temperature and the nature of the aqueous medium. The micelles were successfully loaded with a substantial amount of a photoactive anticancer drug, namely, aluminum chloride phthalocyanine (AlClPc). pH-responsive PM loaded with AlClPc were found to exhibit higher cytotoxicity against EMT-6 mouse mammary cells in vitro than control Cremophor EL formulation. These results show the potential of poly(NIPA-co-MAA-co-ODA) for in vivo administration of water-insoluble, photosensitizing anticancer drugs.

Acrylamides↗
PubMed2000

(17alpha,20E/Z)-iodovinyl- and 16alpha-iodP618-homoestradiol derivatives: synthesis and evaluation for estrogen receptor imaging.

Three new 125I-radioiodinated estrogens featuring a 13beta-ethyl instead of the natural 13beta-methyl group, i.e. 18-homoestradiols, were synthesized and evaluated as potential estrogen receptor imaging agents. The 16alpha-iodo-18-methylestradiol and the 125I-labeled analog were synthesized from the corresponding 16beta-bromo analog by the halogen-exchange method. The cis-bromohydrin precursor was obtained by bromination of an estrone enolacetate, followed by epimerization and reduction. The isomeric (17alpha,20E/Z)-iodovinyl-18-methylestradiols were prepared via the vinyltin intermediates. Treatment of 18-methyl-17alpha-ethynylestradiol with tri-n-butyltin hydride, in the presence of azobisisobutyronitrile as catalyst and heating at 90-100 degrees C afforded the (17alpha,20E)-tri-n-butylstannyl isomer as the major product. Changing the catalyst for triethyl borane, at room temperature, mainly gave the 20Z-isomer. The nca 125I-labeled analogs were obtained from their corresponding tin intermediates upon treatment with [125I]NaI in the presence of H2O2. The 16alpha-[125I]iodo- and isomeric (17alpha,20E/Z)-[125I]iodovinyl-18-methylestradiols were evaluated for estrogen receptor-mediated uterine uptake in immature female rats. Homologation of the C13-methyl group did improve the uterine uptake of the iodovinyl derivatives, but also increased blood retention, resulting in lower target uptake ratios. In the case of the 16alpha-iodo analog uterine retention decreased upon C13-homologation.

Animals↗
PubMed2000

Eradication of multiple myeloma and breast cancer cells by TH9402-mediated photodynamic therapy: implication for clinical ex vivo purging of autologous stem cell transplants.

High-dose chemotherapy combined with autologous transplantation using bone marrow or peripheral blood-derived stem cells (PBSC) is now widely used in the treatment of hematologic malignancies as well as some solid tumors like breast cancer (BC). However, some controversial results were recently obtained in the latter case. The presence of malignant cells in the autograft has been associated with the recurrence of the disease, and purging procedures are needed to eliminate this risk. The aim of this study was to evaluate the potential of the photosensitizer 4,5-dibromorhodamine methyl ester (TH9402), a dibrominated rhodamine derivative, to eradicate multiple myeloma (MM) and BC cell lines, while sparing more than 50% of normal pluripotential blood stem cells from healthy volunteers. The human BC MCF-7 and T-47D and MM RPMI 8226 and NCI-H929 cell lines were used to optimize the photodynamic purging process. Cell concentration and the cell suspension thickness as well as the dye and light doses were varied in order to eventually treat 1-2 L of apheresis. The light source consisted of two fluorescent scanning tubes emitting green light centered about 515 nm. The cellular uptake of TH9402 was measured during the incubation and washout periods and after photodynamic treatment (PDT) using spectrofluorometric analysis. The limiting dilution assay showed that an eradication rate of more than 5 logs is obtained when using a 40 min incubation with 5-10 microM dye followed by a 90 min washout period and a light dose of 5-10 J/cm2 (2.8 mW/cm2) in all cell lines. Agitating the 2 cm thick cell suspension containing 20 x 10(6) cells/mL during PDT was essential for maximal photoinactivation. Experiments on mobilized PBSC obtained from healthy volunteers showed that even more drastic purging conditions than those found optimal for maximal eradication of the malignant cell lines were compatible with a good recovery of hematopoietic progenitors cells. The absence of significant toxicity towards normal hematopoietic stem cells, combined with the 5 logs eradication of cancer cell lines induced by this procedure suggests that TH9402 offers an excellent potential as an ex vivo photodynamic purging agent for autologous transplantation in MM and BC treatment.

Breast Neoplasms↗
PubMed2000

Scintimammography with 11beta-methoxy-(17alpha,20Z)-[123I]iodovinylestrad iol: a complementary role to 99mTc-methoxyisobutyl isonitrile in the characterization of breast tumors.

UNLABELLED: The aim of this study was to investigate a possible relationship between 99mTc-methoxyisobutyl isonitrile (MIBI) uptake and the estrogen receptor (ER) status of breast tumors as determined by 11beta-methoxy-(17alpha,20Z)-[123I]iodovinylestradi ol (MIVE) scintimammography. METHODS: Thirteen patients referred for MIVE scintimammography after abnormal mammography or finding of a suspect mass on physical examination were injected intravenously with MIVE. Planar images of the breasts and axillary region were taken with both radiopharmaceuticals and compared with pathologic examination of the tumor tissue and in vitro ER quantification. RESULTS: The presence of cancerous tissue, as indicated by MIBI uptake, is a prerequisite for the accumulation of MIVE by the breast tumors. There was no statistically significant correlation between the MIBI and MIVE tumor uptake ratios. However, the latter correlate well with the presence of ER, as determined by an in vitro assay. CONCLUSION: MIVE scans add unique information concerning the tumor ER status in breast cancer patients, which could contribute to a better characterization of the tumor and aid in the selection of the most appropriate treatment protocol.

Adult↗
PubMed1999

Binding interactions and conformational changes induced by sulfonated aluminum phthalocyanines in human serum albumin.

Phthalocyanines (Pc), which are extensively studied as tumor localizing photosensitizers for photodynamic therapy, are transported by the blood circulatory system to target tissues. Binding interactions between human serum albumin and differently sulfonated aluminum phthalocyanines (AlPcSn; n = 1-4) were studied using optical and ESR spectroscopy. AlPcSn (n = 1-3) occupy one strong binding site and eight weaker sites. The high affinity binding site interactions differ with respect to the degree of sulfonation and isomeric composition of the Pc. Phthalocyanines without SO-3 groups on adjacent iso-indole rings exhibit a high affinity binding site constant of K approximately 3-4 x 10(7) M-1, while Pc with two or three adjacent SO-3 groups show binding for this high affinity site that is no longer independent, but cooperative (alpha = 2), with K approximately 2-6 x 10(6) M-1. Binding isotherms for AlPcS4 and its close analog, tempoyl spin-labeled SL-AlPcS3, do not approach saturation at high ligand concentrations. Competition analyses between AlPcSn and spin-labeled fatty acids (5- and 16-doxyl stearate isomers) reveal that all compounds participate in cooperative (allosteric) interactions with the high affinity binding site of 16-DS, while extruding 5-DS isomer from certain sites and increasing the binding affinity for the remaining. Protein conformational dynamics was studied by ESR spectroscopy using covalent (alkylation of Cys34 residue) and noncovalent spin labeling (employing SL-AlPcS3). Phthalocyanines perturb conformational dynamics parameters (tauc and S) depending on the degree of sulfonation and isomeric composition corresponding to the type of sites, i.e., independent or cooperative, occupied on the HSA molecule.

Allosteric Regulation↗
PubMed1999

Water-soluble aluminium phthalocyanine-polymer conjugates for PDT: photodynamic activities and pharmacokinetics in tumour-bearing mice.

The potential use of unsubstituted aluminium phthalocyanine (AlClPc) as a sensitizer for photodynamic therapy (PDT) of cancer has not been fully exploited in spite of its higher efficiency as compared to the sulphonated derivatives. This is largely due to the strong hydrophobic character of AlClPc which renders the material difficult to formulate for in vivo administration. We prepared two water-soluble derivatives of AlClPc by axial coordination of polyethyleneglycol (PEG, MW 2000) or polyvinylalcohol (PVA, MW 13,000-23,000) to the central aluminium ion. Their photodynamic activities were evaluated in vitro against the EMT-6 mouse mammary tumour cells and in vivo against the EMT-6 and the colon carcinoma Colo-26 tumours implanted intradermally in Balb/c mice. Pharmacokinetics were studied in the EMT-6 tumour-bearing mice. After 1 h incubation, the light dose required to kill 90% of cells (LD90) was at least three times less for AlClPc (Cremophor emulsion) as compared to AlPc-PEG and AlPc-PVA, while after 24 h incubation all three preparations were highly phototoxic. All three dye preparations induced complete EMT-6 tumour regression in 75-100% of animals at a low drug dose (0.25 micromol kg(-1)) following PDT (400 J cm(-2), 650-700 nm) at 24 h pi. Complete tumour regression in the Colo-26 tumour model was obtained in 30% of mice at a dose of 2 micromol kg(-1). In the non-cured animals, AlPc-PVA induced the most significant tumour growth delay. This dye showed a prolonged plasma half-life (6.8 h) as compared to AlClPc (2.6 h) and AlPc-PEG (23 min), lower retention by liver and spleen and higher tumour-to-skin and tumour-to-muscle ratios. Our data demonstrate that addition of hydrophilic axial ligands to AlPc, while modifying in vitro and in vivo kinetics, does not reduce the PDT efficiency of the parent molecule. Moreover, in the case of the polyvinylalcohol derivative, axial coordination confers advantageous pharmacokinetics to AlPc, which makes this photosensitizer a valuable, water soluble candidate drug for clinical PDT of cancer.

Animals↗
PubMed1999

Receptor-mediated targeting of phthalocyanines to macrophages via covalent coupling to native or maleylated bovine serum albumin.

Targeted delivery of aluminum tetrasulfophthalocyanine (AlPcS4) to the scavenger receptor of macrophages, via coupling to maleylated bovine serum albumin (mal-BSA), was explored as a means to improve photodynamic efficacy. The AlPcS4 was covalently coupled to BSA (9:1 molar ratio) via one or two sulfonamide-hexanoic-amide spacer chains, followed by treatment with maleic anhydride to yield the mal-BSA-phthalocyanine conjugates. The latter were tested for singlet oxygen production, receptor-mediated cell uptake and phototoxicity toward J774 cells of macrophage origin and nonphagocytic EMT-6 cells. Cell uptake of 125I-mal-BSA showed specific binding for J774 cells but not for EMT-6 cells. Competition studies of the conjugates with 125I-mal-BSA showed that coupling of AlPcS4 to BSA resulted in recognition of the conjugate by the scavenger receptor, whereas coupling to mal-BSA further enhanced its binding affinity. This suggests that affinity for the scavenger receptor is related to the overall negative charge of the protein. Phototoxicity of the conjugates toward J774 cells paralleled their relative affinity, with mal-BSA-AlPcS4 coupled via two spacer chains showing the highest activity. The conjugates were less phototoxic toward the EMT-6 cell line. The activities in both cell lines of all conjugated AlPcS4 preparations were, however, lower than that of the free disulfonated AlPcS2. Possible implications for the in vivo use of protein-photosensitizer conjugates to target selectively various macrophage-associated disorders is discussed.

Animals↗
PubMed1999

High-resolution PET imaging for in vivo monitoring of tumor response after photodynamic therapy in mice.

UNLABELLED: The aim of this study was to investigate the use of [18F]fluoro-2-deoxy-D-glucose (FDG) and a small-animal PET scanner to assess early tumor response after photodynamic therapy (PDT) in mice. PDT consists of intravenous administration of a photosensitizer that accumulates preferentially in tumor tissue, followed by local illumination of the tumor with red light. Two different photosensitizers were used: Photofrin (PII), which has been approved for clinical use, and disulfonated aluminum phthalocyanine (AIPcS), which is a second-generation drug. These drugs have been shown to induce tumor necrosis through different action mechanisms, i.e., mainly initial vascular stasis (PII) or direct tumor cell kill (AIPcS). FDG PET was used to follow both perfusion and metabolic activity in the tumor tissue. METHODS: The study was performed using a mouse model implanted with two contralateral murine mammary tumors (5 mm diameter x 2.5 mm thickness) on the back. Only one tumor was subjected to PDT, whereas the other tumor served as a control. A total of 13 mice were studied, 1 without illumination, 3 at 30 min and 3 at 2 h after PDT with both PII-PDT and AIPcS-PDT. Dynamic PET imaging of the mice, which were placed in pairs in a prostate position parallel to the transaxial planes of the Sherbrooke animal PET scanner, was performed after a bolus injection of 11 MBq (300 microCi) FDG. Blood samples were collected concurrently from 1 mouse during each study using an automated microvolumetric blood sampler. RESULTS: Analysis of the tumor time-activity curves showed that (a) scans during the first 3 min provided an estimate of tumor perfusion, as confirmed by the blood samples; (b) the tumor FDG uptake after 15 min was a direct measurement of tumor metabolism clearly demonstrating the relative efficacy of the two PDT drugs; and (c) the tumor tracer concentration in the interval 3-15 min after FDG injection is an appropriate indicator of the different mechanisms of tumor necrosis through indirect vascular stasis (PII) or direct cell kill (AIPcS). CONCLUSION: This pilot study confirmed the feasibility of using dynamic in vivo PET imaging for assessing early tumor response to PDT in mice.

Aluminum↗
PubMed1999

Biodistribution, dosimetry and metabolism of 11beta-methoxy-(17alpha,20E/Z)-[123I]iodovinylestradiol in healthy women and breast cancer patients.

UNLABELLED: The biodistribution and dosimetry of the 20E and 20Z stereoisomers of 11 beta-methoxy-(17alpha,20)-[123I]iodovinylestradiol (MIVE) were evaluated in six healthy women. Tumor uptake and metabolism of the 20Z isomer were evaluated in 13 women referred after abnormal mammography or after discovery of a suspect mass at physical examination. METHODS: The radiopharmaceuticals were prepared from their corresponding stannyl intermediates and administrated intravenously. Blood samples were drawn at different time intervals and urine was collected for up to 24 h. Metabolites were detected by radiochromatography. Tissue distribution was followed for up to 24 h by scintigraphic imaging. The dosimetry was computed according to the Medical Internal Radiation Dose scheme. RESULTS: The 20E and 20Z isomers exhibit similar biodistribution and dosimetry patterns. Chromatographic analysis of plasma samples of healthy volunteers and cancer patients, as well as in vitro plasma incubations, confirmed the in vivo stability of (20Z)-[123I]MIVE. Radioactivity was rapidly cleared from the blood by the liver and excreted through the gut, which received the highest radiation dose (0.211 mGy/MBq). The effective doses for the adult female and male phantom were 0.054 and 0.046 mSv/MBq, respectively. Among the 13 patients imaged with (20Z)-[123I]MIVE, 3 had fibrocystic disease with no focal uptake, 8 had good agreement with in vitro estrogen receptor determination and 2 were false-positive. CONCLUSION: The radiation dose after intravenous administration of 20E- or (20Z)-[123I]MIVE at imaging dose levels is within acceptable limits. There was a good correlation between uptake of (20Z)-[123I]MIVE and the presence of estrogen receptors in breast cancer patients.

Adult↗
PubMed1999

Photodynamic therapy: tumor targeting with adenoviral proteins.

A brief summary of the mechanisms involved in photodynamic therapy (PDT) and the role of delivery vehicles for photosensitizer targeting is addressed. Phthalocyanines (Pc) have been coupled to adenovirus type 2 capsid proteins including the hexon, the penton base and the fiber to enhance their target selectivity. Adenovirus penton base proteins contain the arginine-glycine-aspartic acid peptidic sequence (RGD) motif known to bind with great affinity and high specificity to integrin receptors, expressed by several types of cancer. Tetrasulfonated aluminum phthalocyanine (AlPcS4) was covalently coupled to the various capsid proteins via one or two caproic acid spacer chains (A1 or A2) in 7:1 up to 66:1 molar ratios. The capacity of the bioconjugates for singlet oxygen production, as measured by an L-tryptophan oxidation assay, was strongly reduced, likely reflecting scavenging by the carrier. Cell adsorption and in vitro photocytotoxicity assays were carried out using the A549 and HEp2 human cell lines expressing integrin receptors, and one murine, the EMT-6 cell line, which lacks receptors for the RGD sequence. The AlPcS4A2-protein complexes induced greater cytotoxicity as compared to the analogous AlPcS4A1 preparations. The penton base-AlPcS4A2 derivative was the more phototoxic for all cell lines tested. Tumor response studies using Balb/c mice with EMT-6 tumor implants demonstrated that the free AlPcS4A2 induced complete tumor regression at a dose of 1 mumol/kg and 400 J/cm2, which is comparable to the activity of the known AlPcS2adj. A mixture of adenovirus type 2 soluble proteins covalently labeled with AlPcS4A2 required 0.5 mumol/kg to induce the same response with the same light dose, suggesting that the high affinity RGD/receptor complex is able to target Pc for PDT.

Animals↗
PubMed1999

Preparation, phototoxicity and biodistribution studies of anti-carcinoembryonic antigen monoclonal antibody-phthalocyanine conjugates.

Immunophototherapy of cancer combines the specificity of a monoclonal antibody (MAb) to an overexpressed tumor marker with the phototoxic properties of a conjugated dye. Aluminum tetrasulfophthalocyanine (AlPcS4) was covalently coupled to a 35A7 MAb directed against carcinoembryonic antigen (CEA) via a five-carbon spacer chain (A1) to yield conjugates with a molar ratio ranging from 5 to 16 mol of AlPcS4 per mol of 35A7 MAb. Conjugates were labeled with radioiodine for characterization. The immunoreactivity of the conjugates, determined in a direct binding assay on CEA coupled to sepharose, was not modified by the coupled AlPcS4A1 molecules. In vivo, these conjugates were evaluated in nude mice bearing human colon carcinoma xenografts (T380). 35A7 MAb-(AlPcS4A1)5, 35A7 MAb-(AlPcS4A1)12 and 35A7 MAb-(AlPcS4A1)16 conjugates displayed a tumor uptake of 35 +/- 5.0%, 40 +/- 5.7% and 32 +/- 3.3% of the injected dose per gram of tumor tissue, respectively, corresponding to an uptake of 97%, 104% and 91% as compared to that of the unconjugated 35A7 MAb. In each experimental group, the tumor-to-normal tissue ratios obtained with the conjugates were almost identical to those obtained with unconjugated 35A7 MAb. Average values of 1.8, 7 and about 30 were obtained for blood, liver and muscle, respectively. Phototoxic efficacy of the 35A7 MAb-(AlPcS4A1)12 conjugate was demonstrated in vitro on the LoVo cell line giving a 91% growth inhibition for a 2.50 micrograms/mL AlPcS4A1 concentration. We conclude that these conjugates demonstrate clear in vivo tumor-seeking capacity and in vitro photocytotoxic properties. Such conjugates could thus be promising candidate drugs for clinical photodynamic therapy of cancers expressing CEA.

Animals↗
PubMed1998

Hydroxyphthalocyanines as potential photodynamic agents for cancer therapy.

A series of benzyl-substituted phthalonitriles, substituted at the 3-, 4-, and 4,5-positions, underwent varied condensations with phthalonitrile to give a series of protected (monohydroxy- and polyhydroxyphthalocyaninato)zinc(II) derivatives which were readily cleaved to give several hydroxyphthalocyanines (ZnPc) (phthalocyanine phenol analogues). Their efficacy as sensitizers for the photodynamic therapy (PDT) of cancer was evaluated on the EMT-6 mammary tumor cell line. In vitro, the 2-hydroxy ZnPc (32) was the most active, followed by the 2,3- and 2,9-dihydroxy ZnPc (39 and 45), with the 2,9,16-trihydroxy ZnPc (33) exhibiting the least activity. In vivo, the monohydroxy derivative 32 and the 2,3-dihydroxy derivative 39 were both efficient in inducing tumor necrosis at 1 micromol kg-1, but complete tumor regression was poor, even at 2 micromol/kg. In contrast, the 2,9-dihydroxy isomer 45, at 2 micromol kg-1, induced tumor necrosis in all animals treated, with 75% complete regression. These results underline the importance of the position of the substituents on the Pc macrocycle to optimize tumor response and confirm the PDT potential of the unsymmetrical Pcs bearing functional groups on adjacent benzene rings.

Animals↗
PubMed1997

Syntheses and photodynamic activities of novel trisulfonated zinc phthalocyanine derivatives.

The synthesis of water-soluble, unsymmetrical, trisulfonated zinc phthalocyanines (ZnPcS3) as single products of the ring expansion of boron tri(4-sulfo)subphthalocyanine (SubPc) is reported. The novel, water-soluble trisulfo-SubPcB(OH) was prepared via hydrolysis of the tris(4-chlorosulfonyl)SubPcB(Br) which in turn was obtained from the condensation of 4-(chlorosulfonyl)phthalonitrile with BBr3 in 1-chlorobenzene. A number of ZnPcS3 analogues were prepared via the reaction of S3SubPcB (OH) with different diiminoisoindoline derivatives of increasing hydrophobicity. The reaction proceeds at relative low temperature with acceptable yields. Metalation of free base Pc's with zinc acetate dihydrate afforded the corresponding zinc complexes. Photodynamic activities were measured against the EMT-6 mouse mammary tumor cell line and compared to those of the known ZnPcS3 and ZnPcS4. Added (t-Bu)benzo and (t-Bu)naphtho groups increased the in vitro cell photoinactivation efficacy of the ZnPcS3, whereas addition of a fourth sulfobenzo or bulky diphenylpyrazino group decreased the activity of the parent molecule. The (t-Bu)naphthotrisulfobenzoporphyrazine induced the best in vivo photodynamic tumor control which, combined with its good solubility and broad absorption spectrum, renders this compound an interesting dye for photodynamic applications in medicine.

Animals↗