| 1. |
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| 2. |
- Refaat, Doaa, et al.
(författare)
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Strategies for Molecular Imprinting and the Evolution of MIP Nanoparticles as Plastic Antibodies-Synthesis and Applications
- 2019
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 20:24, s. 1-21
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Forskningsöversikt (refereegranskat)abstract
- Materials that can mimic the molecular recognition-based functions found in biology are a significant goal for science and technology. Molecular imprinting is a technology that addresses this challenge by providing polymeric materials with antibody-like recognition characteristics. Recently, significant progress has been achieved in solving many of the practical problems traditionally associated with molecularly imprinted polymers (MIPs), such as difficulties with imprinting of proteins, poor compatibility with aqueous environments, template leakage, and the presence of heterogeneous populations of binding sites in the polymers that contribute to high levels of non-specific binding. This success is closely related to the technology-driven shift in MIP research from traditional bulk polymer formats into the nanomaterial domain. The aim of this article is to throw light on recent developments in this field and to present a critical discussion of the current state of molecular imprinting and its potential in real world applications.
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| 6. |
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| 7. |
- Engberg, Anna E., et al.
(författare)
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Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma
- 2015
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612 .- 1878-5905. ; 36, s. 55-65
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Tidskriftsartikel (refereegranskat)abstract
- Inappropriate complement activation is often responsible for incompatibility reactions that occur when biomaterials are used. Complement activation is therefore a criterion included in legislation regarding biomaterials testing. However, no consensus is yet available regarding appropriate complement-activation-related test parameters. We examined protein adsorption in plasma and complement activation/cytokine release in whole blood incubated with well-characterized polymers. Strong correlations were found between the ratio of C4 to its inhibitor C4BP and generation of 10 (mainly pro-inflammatory) cytokines, including IL-17, IFN-gamma, and IL-6. The levels of complement activation products correlated weakly (C3a) or not at all (C5a, sC5b-9), confirming their poor predictive values. We have demonstrated a direct correlation between downstream biological effects and the proteins initially adhering to an artificial surface after contact with blood. Consequently, we propose the C4/C4BP ratio as a robust, predictor of biocompatibility with superior specificity and sensitivity over the current gold standard. (C) 2014 Elsevier Ltd. All rights reserved.
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| 8. |
- Karlsson, Björn C. G., et al.
(författare)
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Structure and Dynamics of Monomer-Template Complexation: An Explanation for Molecularly Imprinted Polymer Recognition Site Heterogeneity
- 2009
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 131:37, s. 13297-13304
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Tidskriftsartikel (refereegranskat)abstract
- We here present the first simulation of a complete molecularly imprinted polymer prepolymerization system. Molecular dynamics studies were performed for a system comprising a total of 1199 discrete molecules, replicating the components and concentrations employed in the corresponding polymer synthesis. The observed interactions correlate well with results obtained from (1)H NMR spectroscopic studies. Comparison with simulations performed in the absence of cross-linking agent (ethylene dimethacrylate) demonstrated its significance in the formation of ligand recognition sites. Moreover, the influence of events such as template-template (bupivacaine) and monomer-monomer (methacrylic acid) self-association, porogen-template interactions, and template conformational variability was revealed. The template recognition capacity of the modeled polymer system was verified by synthesis of imprinted and reference polymers and subsequent radioligand binding Analysis. Collectively, through a series of statistical analyses of molecular trajectories in conjunction with spectroscopic data it was demonstrated that an ensemble of complex structures is present in the prepolymerization mixture and that this diversity is the basis for the binding site heterogeneity observed in molecularly imprinted polymers (MIPs) prepared using the noncovalent strategy.
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| 9. |
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| 11. |
- Patterson, Nick, et al.
(författare)
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Large-scale migration into Britain during the Middle to Late Bronze Age
- 2022
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; , s. 588-594
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Tidskriftsartikel (refereegranskat)abstract
- Present-day people from England and Wales harbour more ancestry derived from Early European Farmers (EEF) than people of the Early Bronze Age1. To understand this, we generated genome-wide data from 793 individuals, increasing data from the Middle to Late Bronze and Iron Age in Britain by 12-fold, and Western and Central Europe by 3.5-fold. Between 1000 and 875 BC, EEF ancestry increased in southern Britain (England and Wales) but not northern Britain (Scotland) due to incorporation of migrants who arrived at this time and over previous centuries, and who were genetically most similar to ancient individuals from France. These migrants contributed about half the ancestry of Iron Age people of England and Wales, thereby creating a plausible vector for the spread of early Celtic languages into Britain. These patterns are part of a broader trend of EEF ancestry becoming more similar across central and western Europe in the Middle to Late Bronze Age, coincident with archaeological evidence of intensified cultural exchange2-6. There was comparatively less gene flow from continental Europe during the Iron Age, and Britain's independent genetic trajectory is also reflected in the rise of the allele conferring lactase persistence to ~50% by this time compared to ~7% in central Europe where it rose rapidly in frequency only a millennium later. This suggests that dairy products were used in qualitatively different ways in Britain and in central Europe over this period.
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| 23. |
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| 24. |
- Anaspure, Prasad
(författare)
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Novel strategies for C-C/X bond formation
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The formation of C-C/X bonds is essential for the manufacture of a broad range of chemicals and materials used in areas critical for maintaining quality of life in modern society, e.g. pharmaceuticals, agrochemicals and polymers, and for aspects of research in organic chemistry. The use of catalysts for facilitating these reactions is highly desirable due to the improvements in energy and atom economies that can potentially be achieved.The primary objective of the thesis was to explore novel approaches for catalysis of C-C/X bond-forming reactions, both through C-H activation. In paper I, at unable cobalt catalyzed C-H activation-driven annulation of benzamides with unsymmetrical diynes was developed, where either 3- or 4-substitution of the isoquinolone could be steered by the nature of the diyne used. Anunprecedented iridium catalyzed tandem bis-arylsulfenylation of indoles was described (paper II), where an adamantoyl sacrificial directing group plays a key role in the simultaneous direction of arylsulfenylation to the 2- and 4- positions. In paper III, a flow reactor in a lab-on-a-chip device was developed for the Suzuki cross-coupling reaction. Miniaturization provides the opportunity to reduce material consumption. Polyethyleneimine (PEI)-brushes were used for the immobilization of Pd-nanoparticles, and high efficiencies were observed. Collectively, the research underpinning this thesis provides new strategies forC-C and C-X(S) bond formation.
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| 30. |
- Andersson, Håkan S
(författare)
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Towards the Rational Design of Molecularly Imprinted Polymers
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Molecular imprinting is a technique by which polymeric materials selective for a given target molecule can be created through a casting procedure. Functionalised monomers are added to a solution of molecular templates. Monomer-template complexes are formed and subsequently fixed through polymerisation, and following removal of the template species from the resultant molecularly imprinted polymer, MIP, a material containing binding sites able to specifically rebind the template is left. The objective of the present work has been to learn more about the mechanisms leading to the formation of selective binding sites in MIPs and the nature of these sites (1-3), with the goal to utilise this knowledge to develop better MIPs (4-7). 1) UV spectroscopic studies of the pre-polymerisation mixture were utilised to estimate the stabilities of monomer-template complexes under different conditions. It was observed that many templates are not fully complexed by monomers, possibly leading to different binding site populations. Such heterogeneity is indeed observed in MIPs. The method developed was found useful for rapid evaluation of different monomers or conditions for a given template. 2) Chromatographic studies were performed on polymers imprinted with various pyridyl templates. It was demonstrated that electrostatic interactions were those mainly responsible for binding in these systems. It was also demonstrated that free rotors in the template structure affected binding and selectivity negatively, and that the accessibilities of functional groups were essential for the utility of the template for molecular imprinting. 3) Load capacity studies of nicotine and 4,4´-bipyridyl MIPs revealed two different behaviours. The retention of 4,4´-bipyridyl decreased upon raising the sample load, but nicotine exhibited an increase. Two possible explanations to this unexpected effect were suggested: mobile phase related nicotine solvation effects or a type of cooperative binding. A maximum in resolution for the separation of (+/-)-nicotine at different sample loads indicated the presence of recognition sites for template-template complexes, implying the possible imprinting of template-template complexes. 4) A chiral tartaric acid based monomer was synthesised and employed for the imprinting of cinchona alkaloids. The chirality of the monomer was shown able to enhance selectivity for certain templates. Post-polymerisation debenzylation of the MIP enhanced both retention and selectivity due to a change from hydrogen bond interactions to ionic interactions. 5) Crown ethers were employed as co-templates in molecular imprinting to demonstrate a principle by which organic solvent non-solubles can be solubilised, and imprinted, in organic media. Rebinding studies in the absence of crown ether revealed imprinting related selectivity. 6) Imprinting in water was achieved through the introduction of a hydrophilic cross-linker, a highly acidic monomer, and a beta-cyclodextrin based monomer, able to interact by hydrophobic interactions with aromatic ring structures. By this approach, the enantiomers of phenylalanine were successfully imprinted. 7) A series of monomer combinations were evaluated to optimise the polymer system described in (6). Binding site hydrophobicities were examined by fluorescence spectroscopy. This thesis demonstrates that there is significant room for improving the performance of MIPs and points to some ways by which this can be achieved.
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| 31. |
- Ankarloo, Jonas, et al.
(författare)
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Escherichia coli mar and acrAB Mutants Display No Tolerance to Simple Alcohols
- 2010
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 11:4, s. 1403-1412
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Tidskriftsartikel (refereegranskat)abstract
- The inducible Mar phenotype of Escherichia coli is associated with increased tolerance to multiple hydrophobic antibiotics as well as some highly hydrophobic organic solvents such as cyclohexane, mediated mainly through the AcrAB/TolC efflux system. The influence of water miscible alcohols ethanol and 1-propanol on a Mar constitutive mutant and a mar deletion mutant of E. coli K-12, as well as the corresponding strains carrying the additional acrAB deletion, was investigated. In contrast to hydrophobic solvents, all strains were killed in exponential phase by 1-propanol and ethanol at rates comparable to the parent strain. Thus, the Mar phenotype does not protect E. coli from killing by these more polar solvents. Surprisingly, AcrAB does not contribute to an increased alcohol tolerance. In addition, sodium salicylate, at concentrations known to induce the mar operon, was unable to increase 1-propanol or ethanol tolerance. Rather, the toxicity of both solvents was increased in the presence of sodium salicylate. Collectively, the results imply that the resilience of E. coli to water miscible alcohols, in contrast to more hydrophobic solvents, does not depend upon the AcrAB/TolC efflux system, and suggests a lower limit for substrate molecular size and functionality. Implications for the application of microbiological systems in environments containing high contents of water miscible organic solvents, e. g., phage display screening, are discussed.
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| 32. |
- Boventi, Matteo, et al.
(författare)
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Porosity of Molecularly Imprinted Polymers Investigated by 129Xe NMR Spectroscopy
- 2022
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Ingår i: ACS Applied Polymer Materials. - : American Chemical Society (ACS). - 2637-6105. ; 4:12, s. 8740-8749
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Tidskriftsartikel (refereegranskat)abstract
- Molecularly imprinted polymers (MIPs) display intriguing recognition properties and can be used as sensor recognition elements or in separation. In this work, we investigated the formation of hierarchical porosity of compositionally varied MIPs using 129Xe Nuclear Magnetic Resonance (NMR) and 1H Time Domain Nuclear Magnetic Resonance (TD-NMR). Variable temperature 129Xe NMR established the morphological variation with respect to the degree of cross-linking, supported by 1H TDNMR determination of polymer chain mobility. Together, the results indicate that a high degree of cross-linking stabilizes the porous structure: highly cross-linked samples display a significant amount of accessible mesopores that instead collapse in less structured polymers. No significant differences can be detected due to the presence of templated pores in molecularly imprinted polymers: in the dry state, these specific shapes are too small to accommodate xenon atoms, which, instead, probe higher levels in the porous structure, allowing their study in detail. Additional resonances at a high chemical shift are detected in the 129Xe NMR spectra. Even though their chemical shifts are compatible with xenon dissolved in bulk polymers, variable temperature experiments rule out this possibility. The combination of 129Xe and TDNMR data allows attribution of these resonances to softer superficial regions probed by xenon in the NMR time scale. This can contribute to the understanding of the surface dynamics of polymers.
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| 33. |
- Chavan, Swapnil, et al.
(författare)
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A k-nearest neighbor classification of hERG K+ channel blockers
- 2016
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Ingår i: Journal of Computer-Aided Molecular Design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 30:3, s. 229-236
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Tidskriftsartikel (refereegranskat)abstract
- A series of 172 molecular structures that block the hERG K+ channel were used to develop a classification model where, initially, eight types of PaDEL fingerprints were used for k-nearest neighbor model development. A consensus model constructed using Extended-CDK, PubChem and Substructure count fingerprint-based models was found to be a robust predictor of hERG activity. This consensus model demonstrated sensitivity and specificity values of 0.78 and 0.61 for the internal dataset compounds and 0.63 and 0.54 for the external (PubChem) dataset compounds, respectively. This model has identified the highest number of true positives (i.e. 140) from the PubChem dataset so far, as compared to other published models, and can potentially serve as a basis for the prediction of hERG active compounds. Validating this model against FDA-withdrawn substances indicated that it may even be useful for differentiating between mechanisms underlying QT prolongation.
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| 34. |
- Chavan, Swapnil, et al.
(författare)
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Acute Toxicity-Supported Chronic Toxicity Prediction : A k-Nearest Neighbor Coupled Read-Across Strategy
- 2015
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 16:5, s. 11659-11677
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Tidskriftsartikel (refereegranskat)abstract
- A k-nearest neighbor (k-NN) classification model was constructed for 118 RDT NEDO (Repeated Dose Toxicity New Energy and industrial technology Development Organization; currently known as the Hazard Evaluation Support System (HESS)) database chemicals, employing two acute toxicity (LD50)-based classes as a response and using a series of eight PaDEL software-derived fingerprints as predictor variables. A model developed using Estate type fingerprints correctly predicted the LD50 classes for 70 of 94 training set chemicals and 19 of 24 test set chemicals. An individual category was formed for each of the chemicals by extracting its corresponding k-analogs that were identified by k-NN classification. These categories were used to perform the read-across study for prediction of the chronic toxicity, i.e., Lowest Observed Effect Levels (LOEL). We have successfully predicted the LOELs of 54 of 70 training set chemicals (77%) and 14 of 19 test set chemicals (74%) to within an order of magnitude from their experimental LOEL values. Given the success thus far, we conclude that if the k-NN model predicts LD50 classes correctly for a certain chemical, then the k-analogs of such a chemical can be successfully used for data gap filling for the LOEL. This model should support the in silico prediction of repeated dose toxicity.
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| 35. |
- Chavan, Swapnil, et al.
(författare)
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Towards Global QSAR Model Building for Acute Toxicity : Munro Database Case Study
- 2014
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 15:10, s. 18162-18174
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Tidskriftsartikel (refereegranskat)abstract
- A series of 436 Munro database chemicals were studied with respect to their corresponding experimental LD50 values to investigate the possibility of establishing a global QSAR model for acute toxicity. Dragon molecular descriptors were used for the QSAR model development and genetic algorithms were used to select descriptors better correlated with toxicity data. Toxic values were discretized in a qualitative class on the basis of the Globally Harmonized Scheme: the 436 chemicals were divided into 3 classes based on their experimental LD50 values: highly toxic, intermediate toxic and low to non-toxic. The k-nearest neighbor (k-NN) classification method was calibrated on 25 molecular descriptors and gave a non-error rate (NER) equal to 0.66 and 0.57 for internal and external prediction sets, respectively. Even if the classification performances are not optimal, the subsequent analysis of the selected descriptors and their relationship with toxicity levels constitute a step towards the development of a global QSAR model for acute toxicity.
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| 36. |
- Cleland, Dougal, et al.
(författare)
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Molecular dynamics approaches to the design and synthesis of PCB targeting molecularly imprinted polymers: interference to monomer-template interactions in imprinting of 1,2,3-trichlorobenzene
- 2014
-
Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 12:5, s. 844-853
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Tidskriftsartikel (refereegranskat)abstract
- The interactions between each component of the pre-polymerisation mixtures used in the synthesis of molecularly imprinted polymers (MIP) specific for 1,2,3,4,5-pentachlorobenzene (1) and 1,2,3-trichlorobenzene (2) were examined in four molecular dynamics simulations. These simulations revealed that the relative frequency of functional monomer template (FM T) interactions was consistent with results obtained by the synthesis and evaluation of the actual MIPs. The higher frequency of 1 interaction with tri-methylstyrene (TMS; 54.7%) than 1 interaction with pentafluorostyrene (PFS; 44.7%) correlated with a higher imprinting factor (IF) of 2.1 vs. 1.7 for each functional monomer respectively. The higher frequency of PFS interactions with 2 (29.6%) than TMS interactions with 2 (1.9%) also correlated well with the observed differences in IF (3.7) of 2 MIPs imprinted using PFS as the FM than the IF (2,8) of 2 MIPs imprinted using TMS as the FM. The TMS-1 interaction dominated the molecular simulation due to high interaction energies, but the weaker TMS-2 resulted in low interaction maintenance, and thus lower IF values. Examination of the other pre-polymerisation mixture components revealed that the low levels of TMS-2 interaction was, in part, due to interference caused by the cross linker (CL) ethyleneglycol dimethylacrylate (EGDMA) interactions with TMS. The main reason was, however, attributed to MeOH interactions with TMS in both a hydrogen bond and perpendicular configuration. This positioned a MeOH directly above the it-orbital of all TMS for an average of 63.8% of MD2 creating significant interference to pi-pi stacking interactions between 2 and TMS. These findings are consistent with the deviation from the 'normal' molecularly imprinted polymer synthesis ratio of 1 : 4 : 20 (T : FM : CL) of 20 : 1 : 29 and 15 : 6 : 29 observed with 2 and TMS and PFS respectively. Our molecular dynamics simulations correctly predicted the high level of interference from other MIP synthesis components. The effect on PFS-1 interaction by MeOH was significantly lower and thus this system was not adversely affected.
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| 37. |
- Dhillon, Prakriti, et al.
(författare)
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Diyne-steered switchable regioselectivity in cobalt(ii)-catalysed C(sp(2))-H activation of amides with unsymmetrical 1,3-diynes
- 2023
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry. - 1477-0520 .- 1477-0539. ; 21:9, s. 1942-1951
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Tidskriftsartikel (refereegranskat)abstract
- The regiochemical outcome of a cobalt(ii) catalysed C-H activation reaction of aminoquinoline benzamides with unsymmetrical 1,3-diynes under relatively mild reaction conditions can be steered through the choice of diyne. The choice of diyne provides access to either 3- or 4-hydroxyalkyl isoquinolinones, paving the way for the synthesis of more highly elaborate isoquinolines.
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| 38. |
- Durall, Claudia, et al.
(författare)
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Robust QCM-Based Sensing and Assay Formats in Commercialized Systems
- 2023
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Ingår i: Springer Series on Chemical Sensors and Biosensors. - : Springer.
-
Bokkapitel (refereegranskat)abstract
- Attana’s Quartz Crystal Microbalance (QCM) analytical instruments have been developed to study in vitro biological interactions, mimicking the in vivo conditions. Attana’s superior technology for kinetic interaction studies allows to perform different assays, including biochemical, crude, sera, cell, and tissue-based, in vitro diagnostic and material chemistry assays, in real time and label free. With the focus to validate, select, and optimize drug candidates prior to clinical trials, Attana has helped pharmaceutical companies to increase their efficiency and profitability. In addition, the Attana instruments and services have been used in many other applications and research as described in this chapter.
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| 39. |
- Düringer, Caroline, et al.
(författare)
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Agonist-specific patterns of beta(2)-adrenoceptor responses in human airway cells during prolonged exposure.
- 2009
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 158, s. 169-179
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: beta(2)-Adrenoceptor agonists (beta(2)-agonists) are important bronchodilators used in the treatment of asthma and chronic obstructive pulmonary disease. At the molecular level, beta(2)-adrenergic agonist stimulation induces desensitization of the beta(2)-adrenoceptor. In this study, we have examined the relationships between initial effect and subsequent reduction of responsiveness to restimulation for a panel of beta(2)-agonists in cellular and in vitro tissue models. Experimental approach: beta(2)-Adrenoceptor-induced responses and subsequent loss of receptor responsiveness were studied in primary human airway smooth muscle cells and bronchial epithelial cells by measuring cAMP production. Receptor responsiveness was compared at equi-effective concentrations, either after continuous incubation for 24 h or after a 1 h pulse exposure followed by a 23 h washout. Key findings were confirmed in guinea pig tracheal preparations in vitro. Key results: There were differences in the reduction of receptor responsiveness in human airway cells and in vitro guinea pig trachea by a panel of beta(2)-agonists. When restimulation occurred immediately after continuous incubation, loss of responsiveness correlated with initial effect for all agonists. After the 1 h pulse exposure, differences between agonists emerged, for example isoprenaline and formoterol induced the least reduction of responsiveness. High lipophilicity was, to some extent, predictive of loss of responsiveness, but other factors appeared to be involved in determining the relationships between effect and subsequent loss of responsiveness for individual agonists. Conclusions and implications: There were clear differences in the ability of different beta(2) agonists to induce loss of receptor responsiveness at equi-effective concentrations.
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| 40. |
- Elmlund, Louise, 1981-, et al.
(författare)
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A Phage Display Screening Derived Peptide with Affinity for the Adeninyl Moiety
- 2014
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Ingår i: Biosensors. - : MDPI. - 2079-6374. ; 4:2, s. 137-149
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Tidskriftsartikel (refereegranskat)abstract
- Phage display screening of a surface-immobilized adenine derivative led to the identification of a heptameric peptide with selectivity for adenine as demonstrated through quartz crystal microbalance (QCM) studies. The peptide demonstrated a concentration dependent affinity for an adeninyl moiety decorated surface (KD of 968 ± 53.3 μM), which highlights the power of piezoelectric sensing in the study of weak interactions.
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| 41. |
- Elmlund, Louise, et al.
(författare)
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Biotin selective polymer nano-films
- 2014
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Ingår i: Journal of Nanobiotechnology. - : Springer Science and Business Media LLC. - 1477-3155. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: The interaction between biotin and avidin is utilized in a wide range of assay and diagnostic systems. A robust material capable of binding biotin should offer scope in the development of reusable assay materials and biosensor recognition elements. Results: Biotin-selective thin (3-5 nm) films have been fabricated on hexadecanethiol self assembled monolayer (SAM) coated Au/quartz resonators. The films were prepared based upon a molecular imprinting strategy where N, N'-methylenebisacrylamide and 2-acrylamido-2-methylpropanesulfonic acid were copolymerized and grafted to the SAM-coated surface in the presence of biotin methyl ester using photoinitiation with physisorbed benzophenone. The biotinyl moiety selectivity of the resonators efficiently differentiated biotinylated peptidic or carbohydrate structures from their native counterparts. Conclusions: Molecularly imprinted ultra thin films can be used for the selective recognition of biotinylated structures in a quartz crystal microbalance sensing platform. These films are stable for periods of at least a month. This strategy should prove of interest for use in other sensing and assay systems.
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| 42. |
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| 43. |
- Elmlund, Louise, 1981-, et al.
(författare)
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Study of the Interaction of Trastuzumab and SKOV3 Epithelial Cancer Cells Using a Quartz Crystal Microbalance Sensor
- 2015
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Ingår i: Sensors. - : MDPI. - 1424-8220. ; 15:3, s. 5884-5894
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Tidskriftsartikel (refereegranskat)abstract
- Analytical methods founded upon whole cell-based assays are of importance in early stage drug development and in fundamental studies of biomolecular recognition. Here we have studied the binding of the monoclonal antibody trastuzumab to human epidermal growth factor receptor 2 (HER2) on human ovary adenocarcinoma epithelial cancer cells (SKOV3) using quartz crystal microbalance (QCM) technology. An optimized procedure for immobilizing the cells on the chip surface was established with respect to fixation procedure and seeding density. Trastuzumab binding to the cell decorated sensor surface was studied, revealing a mean dissociation constant, K-D, value of 7 +/- 1 nM (standard error of the mean). This study provides a new perspective on the affinity of the antibody-receptor complex presented a more natural context compared to purified receptors. These results demonstrate the potential for using whole cell-based QCM assay in drug development, the screening of HER2 selective antibody-based drug candidates, and for the study of biomolecular recognition. This real time, label free approach for studying interactions with target receptors present in their natural environment afforded sensitive and detailed kinetic information about the binding of the analyte to the target.
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| 44. |
- Engberg, Anna E., et al.
(författare)
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Blood protein-polymer adsorption : Implications for understanding complement-mediated hemoincompatibility
- 2011
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Ingår i: Journal of Biomedical Materials Research - Part A. - : Wiley. - 1549-3296. ; 97A:1, s. 74-84
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to create polymeric materials with known properties to study the preconditions for complement activation. Initially, 22 polymers were screened for complement activating capacity. Based on these results, six polymers (P1-P6) were characterized regarding physico-chemical parameters, for example, composition, surface area, pore size, and protein adsorption from human EDTA-plasma. P2, P4, and reference particles of polystyrene and polyvinyl chloride, were hydrophobic, bound low levels of protein and were poor complement activators. Their accessible surface was limited to protein adsorption in that they had pore diameters smaller than most plasma proteins. P1 and P3 were negatively charged and adsorbed IgG and C1q. A 10-fold difference in complement activation was attributed to the fact that P3 but not P1 bound high amounts of C1-inhibitor. The hydrophobic P5 and P6 were low complement activators. They selectively bound apolipoproteins AI and AIV (and vitronectin), which probably limited the binding of complement activators to the surface. We demonstrate the usefulness of the modus operandi to use a high-throughput procedure to synthesize a great number of novel substances, assay their physico-chemical properties with the aim to study the relationship between the initial protein coat on a surface and subsequent biological events. Data obtained from the six polymers characterized here, suggest that a complement-resistant surface should be hydrophobic, uncharged, and have a small available surface, accomplished by nanostructured topography. Additional attenuation of complement can be achieved by selective enrichment of inert proteins and inhibitors.
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| 45. |
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| 46. |
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| 47. |
- Engberg, Anna E., 1982-, et al.
(författare)
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EVALUATION OF THE HEMOCOMPATIBILITY OF NOVEL POLYMERIC MATERIALS
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- When a biomaterial surface comes in contact with blood an immediate adsorption of plasma proteins to the surface will occur, and the cascade systems in the blood, such as the complement, coagulation and contact system, will be activated to various degrees. The intensity of this reaction will determine the hemocompatibility of the materials. Here we present an evaluation of the link between the composition, the physico-chemical properties and the protein adsorption properties of six newly synthesized polymers (P1-P6) and the hemocompatibility.The hemocompatibility of the polymeric surfaces was evaluated in human blood plasma and whole blood. Commercially available polyvinylchloride (PVC) was used as reference material. The hemocompatibility of the polymeric surfaces was evaluated with regard to complement activation (C3a and sC5-9 generation) and coagulation activation (platelet loss and TAT-formation) and cytokine productions (27 analytes in multiplex assay) after contact with whole blood. Contact activation was quantified by analyses of FXIIa-C1INH, FXIa-C1INH, and kallikrein-C1INH complexes.Polymers P2 (p<0.05 for C3a), P3, P5 and P6 showed less complement activation, and polymers P1 and P4 (p<0.05 for platelet loss), as well as P5 and P6 showed less coagulation activation compared with reference PVC. Polymers P1-P3 induced activation of the contact system, P3 being the most potent. Secretion of 17 cytokines including chemokines and growth factors were differentially influenced by the polymers, P1 and P3 being significantly (p<0.05) more compatible for five of the analytes.Collectively these data demonstrate that the composition of the polymers clearly leads to different biological properties as a consequence of distinctive physico-chemical properties and protein adsorption patterns.1
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