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Biomedical subjects

Göran Karlsson

Publications and source records attributed to Göran Karlsson.

At least 19 recordsLinked to original sources
PubMed2007

Lack of association between a cationic protein and a cationic fluorosurfactant.

Surface tension, 19F and 1H NMR spectroscopy, and cryotransmission electron microscopy are used to characterize the state of association in aqueous solutions of a fluorosurfactant CF3(CF2)nSO2NH(CH2)3-4N(CH3)3+ I- (n = 8, 6) with and without lysozyme added. In the absence of lysozyme, we find monomers, small aggregates, and large vesicles to coexist, with the individual fluorosurfactant molecules exchanging slowly (>1 ms) among those states. When both lysozyme and fluorosurfactant are present in the solution, they have no measurable influence on the physical state of the other. In contrast, a hydrogenated cationic surfactant with the same headgroup, hexadecyltrimethylammonium bromide, is shown to associate to lysozyme.

Cations↗
PubMed2007

Docosahexaenoic acid stabilizes soluble amyloid-beta protofibrils and sustains amyloid-beta-induced neurotoxicity in vitro.

Enrichment of diet and culture media with the polyunsaturated fatty acid docosahexaenoic acid has been found to reduce the amyloid burden in mice and lower amyloid-beta (Abeta) levels in both mice and cultured cells. However, the direct interaction of polyunsaturated fatty acids, such as docosahexaenoic acid, with Abeta, and their effect on Abeta aggregation has not been explored in detail. Therefore, we have investigated the effect of docosahexaenoic acid, arachidonic acid and the saturated fatty acid arachidic acid on monomer oligomerization into protofibrils and protofibril fibrillization into fibrils in vitro, using size exclusion chromatography. The polyunsaturated fatty acids docosahexaenoic acid and arachidonic acid at micellar concentrations stabilized soluble Abeta42 wild-type protofibrils, thereby hindering their conversion to insoluble fibrils. As a consequence, docosahexaenoic acid sustained amyloid-beta-induced toxicity in PC12 cells over time, whereas Abeta without docosahexaenoic acid stabilization resulted in reduced toxicity, as Abeta formed fibrils. Arachidic acid had no effect on Abeta aggregation, and neither of the fatty acids had any protofibril-stabilizing effect on Abeta42 harboring the Arctic mutation (AbetaE22G). Consequently, AbetaArctic-induced toxicity could not be sustained using docosahexaenoic acid. These results provide new insights into the toxicity of different Abeta aggregates and how endogenous lipids can affect Abeta aggregation.

Amyloid↗
PubMed2006

Transition metal-mediated liposomal encapsulation of irinotecan (CPT-11) stabilizes the drug in the therapeutically active lactone conformation.

PURPOSE: To determine whether entrapped transition metals could mediate the active encapsulation of the anticancer drug irinotecan into preformed liposomes. Further, to establish that metal complexation could stabilize liposomal irinotecan in the therapeutically active lactone conformation. MATERIALS AND METHODS: Irinotecan was added to preformed 1,2-distearoyl-sn-glycero-phosphocholine/cholesterol (DSPC/chol) liposomes prepared in CuSO4, ZnSO4, MnSO4, or CoSO4 solutions, and drug encapsulation was determined over time. The roles of the transmembrane pH gradient and internal pH were evaluated. TLC and HPLC were used to monitor drug stability and liposome morphology was assessed by cryo-TEM. RESULTS: Irinotecan was rapidly and efficiently loaded into preformed liposomes prepared in unbuffered (approximately pH 3.5) 300 mM CuSO4 or ZnSO4. For Cu-containing liposomes, results suggested that irinotecan loading occurred when the interior pH and the exterior pH were matched; however, addition of nigericin to collapse any residual transmembrane pH gradient inhibited irinotecan loading. Greater than 90% of the encapsulated drug was in its active lactone form and cryo-TEM analysis indicated dark intravesicular electron-dense spots. CONCLUSION: Irinotecan is stably entrapped in the active lactone conformation within preformed copper-containing liposomes as a result of metal-drug complexation.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Light scattering and cryo-transmission electron microscopy investigation of the self-assembling behavior of Di-C12P-nucleosides in solution.

Aggregates formed from freshly prepared and annealed samples of dilauroyl-phosphatidyl-adenosine, dilauroyl-phosphatidyl-uridine, and their 1:1 mixture have been investigated by dynamic light scattering, cryo-transmission electron microscopy (cryo-TEM) observations, and circular dichroism. The two surfactants differ only for the nucleoside at the phospholipid polar headgroup and self-assemble in solution to form supramolecular structures that behave dissimilarly. The uridine derivative forms long wormlike aggregates that are invariant with the aging of the solution, while the wormlike aggregate of the adenosine derivative undergoes, as the sample ages, a subsequent self-assembling process forming giant helicoidal aggregates that coexist with the smaller wormlike aggregates. Dynamic light scattering and cryo-TEM show that the large helicoidal structures are formed at the expense of the small wormlike micelles. The 1:1 mixture behaves as the adenosine derivative and evolves to form giant superstructures for all the lipid concentrations investigated. Circular dichroism measurements suggest that the formation of the supramolecular helicoidal structure might not be driven by a purely chiral effect, but rather stacking and hydrogen bonding, present at the phospholipid headgroups of the self-assembled nucleosides, contribute to the final supramolecular structure.

Chemistry, Physical↗
PubMed2006

Using NMR metabolomics to identify responses of an environmental estrogen in blood plasma of fish.

Nuclear magnetic resonance (NMR) based metabolomics in combination with multivariate data analysis may become valuable tools to study environmental effects of pharmaceuticals and other chemicals in aquatic organisms. To explore the usefulness of this approach in fish, we have used 1H NMR metabolomics to compare blood plasma and plasma lipid extracts from rainbow trout exposed to the synthetic contraceptive estrogen ethinylestradiol (EE2) with plasma from control fish. The plasma metabolite profile was affected in fish exposed to 10 ng/L but not 0.87 ng/L of EE2, which was in agreement with an induced vitellogenin synthesis in the high dose group only, as measured by ELISA. The main affected metabolites were vitellogenin, alanine, phospholipids and cholesterol. The responses identified by this discovery-driven method could be put in context with previous knowledge of the effects of estrogens on fish. This adds confidence to the approach of using NMR metabolomics to identify environmental effects of pharmaceuticals and other contaminants.

Animals↗
PubMed2006

Morphology of magnetically aligning DMPC/DHPC aggregates-perforated sheets, not disks.

The morphology of DMPC/DHPC mixtures at total lipid concentration cL = 5% (w/w) and DMPC/DHPC ratio q approximately 3, doped with small amounts of DMPG or CTAB, was investigated. 31P NMR was used to identify the magnetically aligning phase, and cryo-transmission electron microscopy (cryo-TEM) was employed for structural characterization. Magnetic alignment was found to occur between approximately 30 and approximately 45 degrees C, and cryo-TEM showed that the magnetically aligning phase consisted of extended sheets with a lacelike structure. The aggregates are best described as intermediates between two-dimensional networks of flattened, highly branched, cylindrical micelles and lamellar sheets perforated by large irregular holes. DHPC most likely covers the edges of the holes, while DMPC makes up the bilayer bulk of the aggregates. However, 20-43% of the DHPC takes part in the bilayer, corresponding to 6-12% of the bilayer being made up of DHPC. This fraction increases with increasing temperature. At temperatures above 45 degrees C, the aligning phase collapses.

Journal Article↗
PubMed2006

Self-assembly of beta-cyclodextrin in water. Part 1: Cryo-TEM and dynamic and static light scattering.

In this article, we report evidence of beta-cyclodextrin (beta-CD) self-aggregation in water. A critical aggregation concentration (cac) between 2 and 3 mM was determined by using dynamic (DLS) and static (SLS) light scattering to investigate the presence of beta-cyclodextrin aggregates. Transmission electron microscopy at cryogenic temperature (Cryo-TEM) was used to detect the structural features of cyclodextrin self-aggregates. The results show the occurrence of polymorphism depending on the beta-CD concentration: polydisperse nearly spherical objects with diameters of about 100 nm are present at lower concentrations, whereas micrometer planar aggregates are predominant at higher concentrations.

Microscopy, Electron, Transmission↗
PubMed2006

Unilamellar vesicles obtained by simply mixing dioctadecyldimethylammonium chloride and bromide with water.

Optically clear dispersions of dioctadecyldimethylammonium bromide and chloride (DODAX, X = Br-, Cl-) in water can be obtained by simply mixing the amphiphiles at low concentrations (1 mM) and at a temperature safely above the gel to liquid crystalline phase transition temperature (Tm approximately 45-48 degrees C) of DODAX in water. Under these conditions, dynamic light scattering shows that, at room temperature, the dispersions contain two well-defined populations of large vesicles with average hydrodynamic radii (R(H)) of 80 and 337 nm for DODAB and of 69 and 247 nm for DODAC. Cryo-transmission electron microscopy (cryo-TEM) micrographs show that DODAX vesicles are unilamellar and polydisperse with apparent radius up to 800 nm. The vesicles are stable for at least 1 month according to the ageing time-dependence of the turbidity and molar absorption coefficient.

Absorption↗
PubMed2006

Therapeutically optimized rates of drug release can be achieved by varying the drug-to-lipid ratio in liposomal vincristine formulations.

The anti-tumor efficacy of liposomal formulations of cell cycle dependent anticancer drugs is critically dependent on the rates at which the drugs are released from the liposomes. Previous work on liposomal formulations of vincristine have shown increasing efficacy for formulations with progressively slower release rates. Recent work has also shown that liposomal formulations of vincristine with higher drug-to-lipid (D/L) ratios exhibit reduced release rates. In this work, the effects of very high D/L ratios on vincristine release rates are investigated, and the antitumor efficacy of these formulations characterized in human xenograft tumor models. It is shown that the half-times (T(1/2)) for vincristine release from egg sphingomyelin/cholesterol liposomes in vivo can be adjusted from T(1/2) = 6.1 h for a formulation with a D/L of 0.025 (wt/wt) to T(1/2) = 117 h (extrapolated) for a formulation with a D/L ratio of 0.6 (wt/wt). The increase in drug retention at the higher D/L ratios appears to be related to the presence of drug precipitates in the liposomes. Variations in the D/L ratio did not affect the circulation lifetimes of the liposomal vincristine formulations. The relationship between drug release rates and anti-tumor efficacy was evaluated using a MX-1 human mammary tumor model. It was found that the antitumor activity of the liposomal vincristine formulations increased as D/L ratio increased from 0.025 to 0.1 (wt/wt) (T(1/2) = 6.1-15.6 h respectively) but decreased at higher D/L ratios (D/L = 0.6, wt/wt) (T(1/2) = 117 h). Free vincristine exhibited the lowest activity of all formulations examined. These results demonstrate that varying the D/L ratio provides a powerful method for regulating drug release and allows the generation of liposomal formulations of vincristine with therapeutically optimized drug release rates.

Adenocarcinoma↗
PubMed2006

Dioctadecyldimethylammonium bromide vesicles prepared by the surfactant removal method.

Dioctadecyldimethylammonium bromide (DODAB) is a double chain vesicle-forming cationic surfactant, whereas octa-ethyleneglycol mono-n-dodecyl ether (C12E8) is a single chain micelle-forming nonionic surfactant. At room temperature (ca. 22 degrees C) C12E8 molecules self-assemble in water as micelles while DODAB is insoluble. A mixture of DODAB and C12E8, however, can be soluble in water at room temperature depending on the relative amount of the compounds. We report the formation of small unilamellar vesicles (SUVs) by dialyzing at room temperature a mixture of 1.0 mM DODAB with 10 mM C12E8 in water. Extended bilayers are formed as well in equilibrium with vesicles. Such structures are viewed by a cryogenic transmission electron microscopy (cryo-TEM) image.

Journal Article↗
PubMed2006

Cryo-TEM investigation of phase behaviour and aggregate structure in dilute dispersions of monoolein and oleic acid.

Cryo-transmission electron microscopy (cryo-TEM) was used to image the microstructure in dilute sonicated dispersions of monoolein and oleic acid. The aim of the study was to explore how different experimental parameters, such as sample composition, total lipid concentration, pH, and ageing affect the phase behaviour and aggregate structure. Our investigations show that a rich variety of lamellar and non-lamellar structures, including liposomes and particles of cubic and inverted hexagonal phase, may form depending on the experimental conditions. The results are analyzed and discussed in relation to existing phase diagrams and earlier investigations concerning phase- and structural behaviour in monoolein/oleic acid/water systems.

Colloids↗
PubMed2006

Novel findings in Swedish patients with MYH-associated polyposis: mutation detection and clinical characterization.

BACKGROUND & AIMS: Biallelic mutations in the base-excision repair gene MYH have recently been associated with recessive inheritance of multiple colorectal adenomas. An investigation and characterization of MYH mutations in Swedish patients were therefore carried out. METHODS: A set of 15 unrelated adenomatous polyposis coli (APC)-mutation negative patients from the Swedish Polyposis Registry was screened for germline mutations in the MYH gene. The patients were clinically characterized and compared with 43 APC-mutation positive probands diagnosed during the same period. RESULTS: Disease-causing biallelic MYH mutations were identified in 6 patients (40%). The mean age at diagnosis was 47.8 years versus 34.1 years in APC-mutation positive patients (P = .015). Colorectal cancer at diagnosis of polyposis was present in 67% (4/6) of the patients, and all were right-sided, compared with only 19% versus 12.5% right-sided cancer in APC-mutation positive patients. Upper gastrointestinal manifestations were diagnosed in 1 of 5 compared with 23 of 27 in APC-mutation positive patients (odds ratio, 23; 95% confidence interval, 2-263; P = .0086). One family exhibited apparent dominant inheritance of colorectal adenomatous polyposis. Two new pathogenic mutations, MYH p.G175E and p.P391L, were identified. The mutations are argued to introduce profound changes in substrate-recognizing domains of the protein. CONCLUSIONS: Biallelic MYH mutations, including 2 novel mutations, were found in a substantial number of the patients with multiple colorectal adenomas who were negative for APC-mutation. The examined MYH-mutation positive patients were found to have higher risks of colorectal cancer at diagnosis, right-sided location of cancers, and a significantly lower incidence of upper gastrointestinal manifestations, compared with APC-mutation positive patients.

Adenomatous Polyposis Coli↗
PubMed2006

Physiochemical characterization of the Alzheimer's disease-related peptides A beta 1-42Arctic and A beta 1-42wt.

The amyloid beta peptide (A beta) is crucial for the pathogenesis of Alzheimer's disease. Aggregation of monomeric A beta into insoluble amyloid fibrils proceeds through several soluble A beta intermediates, including protofibrils, which are believed to be central in the disease process. The main reason for this is their implication in familial Alzheimer's disease with the Arctic amyloid precursor protein mutation (E693G). This mutation gives rise to early onset Alzheimer's disease, and synthetic A beta 1-40Arctic displays an enhanced rate of protofibril formation in vitro[Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Naslund J & Lannfelt L. (2001) Nat Neurosci4, 887-893]. To increase our understanding of the mechanisms involved in A beta aggregation, especially A beta monomer oligomerization into protofibrils and protofibril fibrillization into fibrils, the kinetics of A beta 1-42wt and A beta 1-42Arctic aggregation were examined under different physiochemical conditions, such as concentration, temperature, ionic strength and pH. We used size exclusion chromatography for this purpose, where monomers are separated from protofibrils, and fibrils are separated from protofibrils in a centrifugation step. The Arctic mutation significantly accelerated both A beta 1-42wt protofibril formation and protofibril fibrillization. In addition, we demonstrated that two distinct chemical processes - monomer oligomerization and protofibril fibrillization - were affected differently by changes in the micro-environment and that the Arctic mutation alters the peptide response to such changes.

Alzheimer Disease↗
PubMed2005

Formation of drug-arylsulfonate complexes inside liposomes: a novel approach to improve drug retention.

The development of procedures to enhance drug retention in liposomes is important in order to achieve therapeutically optimized rates of drug release from liposomal carriers. In this study, the ability of lipophilic weak base drugs to complex with arylsulfonates resulting in formation of intravesicular precipitates is investigated as a means to enhance drug retention. It is shown that the arylsulfonates benzenesulfonate and hydroxybenzenesulfonate (HBS) induce precipitation of ciprofloxacin and vinorelbine, two representative weak base drugs that are difficult to retain in liposomal systems. The most complete precipitation was observed at pH values corresponding to charge neutralization of the drug-arylsulfonate complex. HBS is shown to be a much more effective precipitating agent than benzenesulfonate. It is also shown that vinorelbine and ciprofloxacin can be loaded into large unilamellar vesicles (LUV) containing the calcium salt of HBS using an ionophore-based loading method. Following drug loading, the formation of intravesicular drug-arylsulfonate precipitates of vinorelbine and ciprofloxacin was observed by cryo-electron microscopy. In vitro release experiments showed substantial improvements in drug retention for both vinorelbine and ciprofloxacin when HBS was present as compared to standard loading procedures employing MgSO4 as the entrapped solute. In vivo release experiments for vinorelbine in NuNu mice indicated a half-time for release for HBS-containing LUV of approximately 30 h, compared to 6.4 h for LUV loaded employing MgSO4. It is suggested that encapsulation procedures employing HBS in the internal medium can improve the retention of drugs that are difficult to retain in liposomes, possibly leading to enhanced therapeutic properties.

Animals↗
PubMed2005

Separation of monosaccharides by hydrophilic interaction chromatography with evaporative light scattering detection.

Hydrophilic interaction liquid chromatography (HILIC) was used to separate monosaccharides that are common in N-linked oligosaccharides in glycoproteins and other compounds. A TSKgel Amide-80 column was eluted with 82% acetonitrile, in 5 mM ammonium formate (pH 5.5). Column temperature was 60 degrees C and evaporative light scattering was used for detection (ELSD). With this method, L-fucose, D-galactose, D-mannose, N-acetyl-D-glucosamine, N-acetylneuraminic acid, and D-glucuronic acid were separated, with detection limits of 0.3-0.5 microg for each monosaccharide, and intermediate precisions were 3-6% RSD (n=6).

Chromatography, Liquid↗
PubMed2005

Wormlike micelles mediated by polyelectrolyte.

Aqueous solutions of the anionic surfactant potassium oleate (K-oleate) were studied using small-angle neutron scattering (SANS), steady-state rheology, and cryogenic transmission electron microscopy (cryo-TEM). The micellar structural changes induced by the addition of potassium chloride (KCl) and sodium polystyrenesulfonate (PSS) of different molecular weights were investigated. Upon addition of KCl, a transition from spherical to wormlike micelles was detected from the SANS data and confirmed by the cryo-TEM pictures. The rheological measurements revealed a strong dependence of the low-shear viscosity on the concentration of salt: a broad maximum in the viscosity curve was observed upon addition of KCl, characteristic of the growth of micelles into long worms, followed by branching. The addition of PSS to salt-free solutions of K-oleate had a significant effect on the scattering patterns, revealing partial growth of the spherical micelles into rodlike micelles. In contrast, in the presence of high salt concentrations, addition of PSS to solutions of wormlike micelles did not bring any noticeable modifications in the scattering. However, in the same salt conditions, a clear effect was observed on the low shear viscosity upon addition of PSS, which was found to depend significantly on molecular weight. This suggests a novel way of impacting the viscosity of solutions of wormlike micelles.

Micelles↗
PubMed2005

Substantial increases in idarubicin plasma concentration by liposome encapsulation mediates improved antitumor activity.

Idarubicin has been successfully encapsulated in cholesterol-free liposomes, however, little is known about how the rate of drug release from circulating liposomes influences therapeutic activity. The studies described herein assess the attributes of a liposome formulation required to significantly increase the plasma levels of idarubicin and further establish whether increases in the circulation longevity of the drug mediate improved antitumor activity. Pharmacokinetic assessments of 6 different 3[H]-labelled liposome formulations were compared to free idarubicin. The highest idarubicin plasma concentrations were observed with DSPC/DSPE-PEG2000 liposomes formulated with 2 mol% DSPE-PEG2000 and 150 mM (iso-osmotic) internal citrate concentration. It was shown that increased levels of PEG-lipid incorporation augmented IDA release and the optimal liposomal formulation needed to be prepared under iso-osmotic conditions. For efficacy studies in a murine leukemia model, groups of 12-14 mice were treated i.v. with saline or equivalent doses (1, 2, 3 mg/kg) of free or liposomal IDA. Liposomal treatment groups exhibited a higher % increase in life span (ILS) as compared to equivalent doses of free drug. Efficacy studies completed in two drug resistant models, P388/ADR and MDA435LCC6/MDR1, demonstrated that neither the free nor liposomal formulation of idarubicin was therapeutically active. Encapsulation of IDA in liposomes increased antitumor activity in an IDA sensitive model, however, the significant increase in plasma drug levels was not sufficient to overcome multidrug resistance.

Animals↗