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J E Van Lier

Publications and source records attributed to J E Van Lier.

At least 19 recordsLinked to original sources
PubMed2002

Optimizing pH-responsive polymeric micelles for drug delivery in a cancer photodynamic therapy model.

Different pH-sensitive, randomly- and terminally-alkylated N-isopropylacrylamide (NIPAM) copolymers were synthesized and used to prepare pH-responsive polymeric micelles (PM). These copolymers were modified from previously-studied copolymers by incorporating an additional hydrophilic monomer, N-vinyl-2-pyrrolidone (VP) to decrease uptake by the mononuclear phagocyte system (MPS) and improve localization in tumors. VP lowered the phase transition pH of the copolymers but did not affect the onset of micellization. The in vitro cytotoxicity of the copolymers was evaluated on EMT-6 mouse mammary tumor cells in comparison to Cremophor EL (CRM). The anticancer photosensitizer aluminum chloride phthalocyanine (AlClPc) was loaded into the PM with a standard dialysis procedure. Biodistribution and in vivo photodynamic activity were then evaluated in Balb/c mice bearing intradermal EMT-6 tumors. All NIPAM copolymers demonstrated substantially lower cell cytotoxicity than the control surfactant CRM. In vivo, similar AlClPc tumor uptake was observed for the PM and CRM formulations. However, the PM appeared to exhibit greater activity in vivo than CRM formulation at an AlClPc subtherapeutic dose. Therefore, NIPAM-based copolymers containing VP units represent promising alternatives for the formulation of poorly water-soluble phthalocyanines.

Animals↗
PubMed1996

New stimulation ligand of the adenovirus 2 protease.

The catalytic activity of the adenovirus cysteine peptidase is increased by a specific 11-amino-acid peptide adduct (GVQSLKRRRCF, referred to as pVIc). To identify additional peptides which might bind and alter the activity of the protease, a cysteine-constrained random peptide phage library was screened. Of 29 different phages which were isolated, 7 contained the consensus sequence VEGGS. Despite a superficial similarity to the substrate cleavage site of the protease, the peptide was not digested by the enzyme. VEGGS and pVIc altered protease activity similarly without sharing sequence similarity. To similar degrees, pVIc and VEGGS (a) stimulated the activity of the recombinant protease, (b) had no effect on viral protease, (c) increased the fluorescence emission of tryptophan residues in the protease, suggesting a conformational change, and (d) inhibited wt virus infection, but rescued ts1 infection at the nonpermissive temperature. The experiments also suggest that once the protease has been stimulated by one peptide, the other peptide has no further activity on the recombinant adenovirus cysteine protease, suggesting that the two peptides bring about the same change on the protease via different binding sites.

Adenoviruses, Human↗
PubMed1996

Serum albumin as a vehicle for zinc phthalocyanine: photodynamic activities in solid tumour models.

Zinc phthalocyanine (ZnPc) is a second-generation photosensitiser for the photodynamic therapy (PDT) of cancer. Unsubstituted ZnPc is, however, highly insoluble in most common solvents, and for clinical applications the material needs to be incorporated in liposomes. We report a simple, alternative procedure to formulate ZnPc through non-covalent binding to bovine serum albumin (BSA). Intravenous administration of ZnPc-BSA preparations, at a molar ratio of 11:1 and at a ZnPc dose equivalent to 0.5 mol kg-1, to tumour-bearing mice followed 24 h later by PDT was shown to provide tumour control in two different models, the EMT-6 tumour in Balb/c mice and the human colon T380 carcinoma in nude mice. Analysis of serum fractions from treated animals showed that ZnPc readily redistributes over the serum high-density lipoprotein (HDL) fraction. We also demonstrated the absence of hepatic toxicity of the ZnPc-BSA preparation by monitoring the hepatic cytochrome P450 activity in treated animals and the viability of human cultured hepatocytes.

Animals↗
PubMed1995

PEG-coated poly(lactic acid) nanoparticles for the delivery of hexadecafluoro zinc phthalocyanine to EMT-6 mouse mammary tumours.

Hexadecafluoro zinc phthalocyanine (ZnPcF16), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in three vehicles: poly(D,L-lactic acid) (PLA) nanoparticles, polyethylene glycol (PEG)-coated nanoparticles and a Cremophor EL (CRM) oil-water emulsion. Nanoparticles were prepared by the salting-out procedure. Biodistribution of the dye was assessed by fluorescence in EMT-6 mammary tumour bearing mice after intravenous injection of 1 mumol kg-1 ZnPcF16. Plain nanoparticles were rapidly retained by the reticuloendothelial system (RES) as reflected by the low area under the blood concentration-time curve (AUC0-168, 57 micrograms h g-1). Little tumour uptake of the dye was observed with this formulation. In contrast, PEG-coated nanoparticles displayed a reduced RES uptake, leading to significantly higher blood levels over an extended period (t1/2 30 h; AUC 0-168 227 micrograms h g-1) and enhanced tumour uptake. At 48 h post injection, tumour to skin and tumour to muscle concentration ratios reached 3.5 and 10.8, respectively. Blood levels of ZnPcF16 after administration as a CRM emulsion decreased faster than with PEG-coated nanoparticles (t1/2 12 h), but since no early liver uptake was observed, the AUC0-168 and the tumour uptake were only slightly lower. However, with the CRM formulation, a late liver uptake was observed, reaching 51% of the injected dose after 7 days.

Animals↗
PubMed1994

Evaluation of 99mTc-labeled modified serum albumin for tumor detection.

Serum albumin (SA) modified and labeled with 131I-tyramine N-1'-desoxysorbitol (131I-TDS) has been shown to localize in tumors [Sinn et al., (1990) Nucl. Med. Biol. Part B 17, 819-827]. We prepared similar TDS complexes labeled with 99mTc and evaluated their potential for tumor imaging. Derivatization of SA with TDS was optimized using cyanuric chloride or 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDAC) as coupling agents. A high TDS loading yield of 38 mol/mol SA was obtained with the latter reagent. Modified SA (8 and 38 mol TDS/mol SA) were labeled with 99mTc via the stannous reduction method and injected i.v. into EMT-6 tumor bearing mice. 125I-TDS-SA (8 mol 125I-TDS/mol SA) revealed a high tumor uptake of 10% ID/g at 3 h post-injection. The 99mTc-labeled SA and TDS-SA complexes lacked tumor specificity, instead TDS loading of SA resulted in increased liver/spleen uptake, suggesting colloid formation. This study confirms the potential of modified SA for tumor imaging but highlights the importance of choice of radioisotope, as well as site of attachment of the radiolabel to the modified SA for optimal tumor localization.

Animals↗
PubMed1994

Photocytotoxicity and intracellular generation of free radicals by tetrasulphonated Al- and Zn-phthalocyanines.

The photosensitizing properties of tetrasulphonated Al- and Zn-phthalocyanines (AlPcS4 and ZnPcS4) in lymphoma cells were studied as a function of the pre/post-illumination incubation time. Photocytotoxicity increased with incubation time, ranging from a transient cell-cycle arrest to cell killing. Under all experimental conditions, the phototoxicity of ZnPcS4 was markedly higher than that of AlPcS4. The primary photoprocesses initiated by metallo-phthalocyanines (MePcS4) in the cells were probed with DMPO/esr spin-trapping techniques. Under all incubation conditions the intracellularly bound MePcS4 sensitized formation of three different types of DMPO spin-adducts: DMPO/OH (hydroxyl radical), DMPO/R (organic carbon-centred radical(s)) and an unidentified simple nitroxyl, referred to as DMPO/ox. The yields of trapped radicals depended on the length of the incubation with the dyes prior to illumination and the formation of spin-adducts was shown to be intracellular. The ability of DMPO to protect cells from the photocytotoxic effects of Al- and ZnPcS4, combined with the generation of carbon-centred spin-adducts is direct evidence for the involvement of free-radical-mediated damage of cellular constituents.

Cells, Cultured↗
PubMed1994

On the relationship between rate of uptake of Photofrin and cellular responses to photodynamic treatment in vitro.

The Burkitt's lymphoma cell line Namalva was used as an in vitro model to study the accumulation and photocytotoxic properties of Photofrin, the photosensitizer currently in clinical trials. Photofrin uptake and intracellular protein binding were evaluated as a function of the incubation time using fluorescence spectroscopy. The drug concentration strongly affected the intracellular distribution pattern of Photofrin, which in turn was shown to correlate with the Namalva cell response to photodynamic action. At low drug load, a gradual cell response varying from transient cell cycle arrest (predominantly S-phase) to marked photocytotoxicity modulated by incubation time and light dose was observed. High drug load resulted in lethality without cell cycle selectivity. The data suggest possible Photofrin targeting of protein factors involved in cell proliferation.

Biological Transport, Active↗
PubMed1991

Biodistribution and tumor uptake of [67Ga]chlorogallium-tetraoctadecyloxy phthalocyanine and its sulfonation products in tumor bearing C3H mice.

To evaluate the biodistribution and tumor uptake of chlorogallium tetraoctadecycloxy phthalocyanine, a potential new drug for the photodynamic therapy of cancer, we prepared the radioactive 67Ga-labeled complex and its water soluble sulfonated derivative. The non-sulfonated dye was obtained by condensation of octadecyloxyphthalonitrile in the presence of a mixture of 67Ga and 69Ga chloride. The sulfonated derivative was obtained by treatment of the condensation product with oleum. As singlet molecular oxygen has been implicated in the photodynamic action of phthalocyanines (Pcs), the quantum yield of singlet oxygen (phi delta) was evaluated for chlorogallium tetraoctadecyloxy Pc, and also its zinc, aluminum and metal free analogues. After intraperitoneal administration of the non-sulfonated dye into RIF tumor bearing C3H mice, a very high 67Ga-uptake was observed in the spleen, while tumor radioactivity remained low during the 3 day study. The in vivo stability of the 67Ga-phthalocyanine complex was confirmed by comparing the distribution pattern with that of 67Ga-citrate, which proved to be significantly different. Intravenous injection of the sulfonated dye resulted in an overall lowering of 67Ga-uptake by most tissues, particularly in the spleen, while tumor radioactivities were slightly higher. These data suggest that amphiphilic photosensitizers, containing both polar sulfonate groups and long aliphatic substituents, exhibit the best distribution pattern for both imaging and photodynamic therapy of tumors.

Animals↗
PubMed1987

Effect of cholesterol alpha and beta epoxides on cell killing and transformation.

V-79 Chinese hamster lung fibroblasts and C3H-10T1/2 mouse embryo cells were used to study the toxicity and transformation effects of the 5 alpha,6 alpha, and 5 beta,6 beta-epoxy derivatives of cholesterol. Both epoxides were found to be carcinogenic, and the transformation frequency increased with epoxide concentration and exposure time. The 5 beta,6 beta-epoxide caused a higher level of transformation than the alpha-isomer, and this is consistent with its greater toxicity.

Animals↗
PubMed1977

Mechanism of cholesterol side-chain cleavage. II. The enzymic hydroperoxide-glycol rearrangement of the epimeric 20-hydroperxycholesterols in 18O-enriched water.

Incubation of 20 alpha-hydroperoxycholesterol (I) and its 20 beta-isomer, 20 beta-hydroperoxy-20 isocholesterol (II) with adrenocortical mitochondrial preparations in the absence of molecular oxygen, in normal and 18O-enriched water, gave 20 alpha, 22R-dihydroxycholesterol (III) from I and 20 beta,21-dihydroxy-20-iso-cholesterol (IV) from II. Mass spectral analysis of the persilylated glycol products III and IV showed no uptake of 18O, indicating that the oxygen atoms of the C20-, C22- and C21-hydroxyl groups originated from the 20-hydroperoxy atomic oxygen complex is the intermediate in the enzymic oxidative reactions of cholesterol side-chain cleavage.

Adrenal Cortex↗
PubMed1976

Tracer studies of cholesterol degradation induced by ionized gases.

Multiple molecular layers of cholesterol-4-C14 were bombarded in an ultra high vacuum system with various excited molecular, ionic and atomic species derived from oxygen, methane and carbon monoxide. The degradation products were analyzed by thin layer chromatography followed by autoradiography and the decomposition patterns were compared with those obtained from the autoxidation of cholesterol. Bombardment with excited and ionized species derived from both molecular oxygen and carbon monoxide leads to a number of known polar cholesterol oxidation products, similar to those formed during the natural oxidation of cholesterol. In contrast, species derived from methane lead only to the formation of products less polar than cholesterol with none of the established autoxidation products at detectable levels.

Carbon Monoxide↗
PubMed1975

Cholesterol autoxidation: identification of the volatile fragments.

The volatile fragments of air-aged cholesterol were analysed by means of gas chromatography-mass spectrometry; The following fourteen compounds were identified: ethanol, acetic acid, acetone, 2-methylpropene, 2-methyl-1-propanol, 2-methyl-2-propanol, 2-butanone, 2-methylpropionic acid, 2-methyl-2-butanol, 2-pentanone, 3-methyl-2-butanone, 2-methyl-1-pentene, 2-methyl-2-pentanol, and 2-methyl-4-penten-2-ol. Their formation via decomposition of initially formed sterol hydroperoxides is discussed.

Chemical Phenomena↗