Martin Lundqvist | Lund University (original) (raw)
Papers by Martin Lundqvist
Small, Oct 26, 2020
This will be a more challenging task than just detect them in the corona.
Journal of Chemical Education, Jul 17, 2019
The one-hour workshop, containing both a demonstration and hands-on experiments on the topic of n... more The one-hour workshop, containing both a demonstration and hands-on experiments on the topic of nanosafety, is based on current science on a topic of general interest. The workshop aims to provide a deeper knowledge and understanding of nanoparticles. The participants get an introduction to what nanoparticles are, why nanosized materials are interesting, how nanomaterials interact with biological molecules, and potential risks associated with nanoparticles. Furthermore, by participating in the workshop the audience gains insights into how research about nanoparticles is conducted. The participants carry out experiments to demonstrate that daily-used plastic products can be disintegrated into particles in the nanometer size range, which may have important implications for the environment.
Springer eBooks, 2010
... Application as Contrast Agents Johannes Stigler, Martin Lundqvist, Tommy Cedervall, Kenneth D... more ... Application as Contrast Agents Johannes Stigler, Martin Lundqvist, Tommy Cedervall, Kenneth Dawson, and Iseult Lynch Abstract. ... Proteomics 5:35313536 14. Ong ATL, Hoye A, Aoki J, van Mieghem CAG, Rodriguez Granillo GA, Son-nenschein K, Regar E, McFadden ...
Environmental Science: Processes & Impacts, 2022
With polystyrene nanoparticles being widely used in various applications, there is a great need f... more With polystyrene nanoparticles being widely used in various applications, there is a great need for deeper knowledge on the safety, fate and biological effects of these particles on both individual living organisms and the whole ecosystems. Due to this, there is a growing interest in performing ecotoxicological studies using model plastic nanoparticles, and consequently it generates an increasing number of published papers describing the negative impact on wildlife caused by such nanoparticles. Polystyrene is the most studied nanosized plastic, therefore this review focuses on research conducted with manufactured polystyrene nanoparticles. The aim of the present article is to provide a critical methodological outline of the existing ecotoxicological studies on the effects of polystyrene nanoparticles on aquatic organisms. Going through the published articles, we noted that particle characterization especially in the test medium, can be improved. The analysis also highlights the importance of purifying the polystyrene nanoparticles before studying its toxicity. Furthermore, the size characterization of such nanoparticles is underemphasized, and in future studies, authors should consider including more techniques to achieve this goal. Finally, short-term or direct exposure scenarios do not add the most environmentally relevant knowledge in terms of the toxicity caused by polystyrene nanoparticles. Environmental signicance Today, there are many papers published regarding the toxicity caused by polystyrene nanoparticles. However, several factors are underemphasized, for example, the importance of nanoparticle solution purication before using them in the toxicity studies, as well as characterization of nanoparticles size. Therefore, we review published papers in order to highlight some common problems in the experimental set ups. We believe that emphasizing these shortcomings and suggesting different experimental routines will help to achieve the most relevant information on the toxicity caused by these nanoparticles.
Frontiers in Nanotechnology
Nanoplastics are defined as plastic particles broken down to extremely small sizes (1–100 nm) wit... more Nanoplastics are defined as plastic particles broken down to extremely small sizes (1–100 nm) with unknown effects to the human body and immune system. Air and food exposure scenarios involving blood, lungs and intestine are considered in the literature. The fact that plastics also needs to pass the nose, oral cavity, and throat is so far ignored in the literature. The tonsils are immunologically important tissue in the oral cavity in which ingested and inhaled agents are incorporated through crypts with the capacity to capture agents and start early immunologic reactions. We argue that the tonsil is a very important tissue to study in regard to micro and nanoplastic human exposure and immunologic response. Nano-sized particles are known to be able to travel through the natural barriers and have different effects on biology compared to larger particle and the bulk material. It is therefore, although difficult, important to develop experimental methods to detect and identify nanoplas...
Environmental Science: Nano
Toxic and non-toxic polystyrene particles bind different proteins during filtration by zooplankton.
Frontiers in Molecular Biosciences, 2021
The aggregation of the human islet amyloid polypeptide (IAPP) is associated with diabetes type II... more The aggregation of the human islet amyloid polypeptide (IAPP) is associated with diabetes type II. A quantitative understanding of this connection at the molecular level requires that the aggregation mechanism of IAPP is resolved in terms of the underlying microscopic steps. Here we have systematically studied recombinant IAPP, with amidated C-terminus in oxidised form with a disulphide bond between residues 3 and 7, using thioflavin T fluorescence to monitor the formation of amyloid fibrils as a function of time and IAPP concentration. We used global kinetic analyses to connect the macroscopic measurements of aggregation to the microscopic mechanisms, and show that the generation of new aggregates is dominated by the secondary nucleation of monomers on the fibril surface. We then exposed insulinoma cells to aliquots extracted from different time points of the aggregation process, finding the highest toxicity at the midpoint of the reaction, when the secondary nucleation rate reache...
Environmental Science: Processes & Impacts, 2022
With polystyrene nanoparticles being widely used in various applications, there is a great need f... more With polystyrene nanoparticles being widely used in various applications, there is a great need for deeper knowledge on the safety, fate and biological effects of these particles on both individual living organisms and the whole ecosystems.
Small, 2020
The research about how a nanoparticle (NP) interacts with a complex biological solution has been ... more The research about how a nanoparticle (NP) interacts with a complex biological solution has been conducted, according to the literature, for almost three decades. A significant amount of data has been generated, especially in the last one and a half decade. First, it became its own research field which was later divided into many subresearch fields. This outlook does not aim to be a comprehensive review of the field or any of its subresearch fields. There is too much data published to attempt that. Instead, here it has been tried to highlight what, in the opinion, is the main step taken during these three decades. Thereafter, the weaknesses and end are pointed out with what needs to be the main focus for the future to understand the protein corona formation in the bloodstream, which is a prerequisite for the developing of true target specific drug‐delivering nanoparticles.
Nature Structural & Molecular Biology, 2020
The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is... more The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer's disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quantitative binding measurements to address the mechanism of action of four clinical stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ. Our results reveal that, uniquely among these four antibodies, aducanumab dramatically reduces the flux of Aβ oligomers.
Frontiers in Immunology, 2019
Streptococcus pyogenes infects over 700 million people worldwide annually. Immune evasion strateg... more Streptococcus pyogenes infects over 700 million people worldwide annually. Immune evasion strategies employed by the bacteria include binding of the complement inhibitors, C4b-binding protein (C4BP) and Factor H in a human-specific manner. We recently showed that human IgG increased C4BP binding to the bacterial surface, which promoted streptococcal immune evasion and increased mortality in mice. We sought to identify how IgG promotes C4BP binding to Protein H, a member of the M protein family. Dimerization of Protein H is pivotal for enhanced binding to human C4BP. First, we illustrated that Protein H, IgG, and C4BP formed a tripartite complex. Second, surface plasmon resonance revealed that Protein H binds IgG solely through Fc, but not Fab domains, and with high affinity (IgG-Protein H: K D = 0.4 nM; IgG-Fc-Protein H: K D ≤ 1.6 nM). Each IgG binds two Protein H molecules, while up to six molecules of Protein H bind one C4BP molecule. Third, interrupting Protein H dimerization either by raising temperature to 41 • C or with a synthetic peptide prevented IgG-Protein H interactions. IgG-Fc fragments or monoclonal human IgG permitted maximal C4BP binding when used at concentrations from 0.1 to 10 mg/ml. In contrast, pooled human IgG enhanced C4BP binding at concentrations up to 1 mg/ml; decreased C4BP binding at 10 mg/ml occurred probably because of Fab-streptococcal interactions at these high IgG concentrations. Taken together, our data show how S. pyogenes exploits human IgG to evade complement and enhance its virulence. Elucidation of this mechanism could aid design of new therapeutics against S. pyogenes.
Nanomedicine, May 1, 2014
This article discusses the role of the protein corona in delivery systems with tagged nanoparticl... more This article discusses the role of the protein corona in delivery systems with tagged nanoparticles and how knowledge of the protein corona can help in optimizing delivery. The basic question is whether and how the binding of proteins and other biomolecules at the nanoparticle surface interfere with the interaction between a tag and its receptor. This is an interesting problem in many respects, but most intriguing are the observed differences in delivery efficiency in vivo compared with protein-free in vitro conditions. In order to understand possible situations that the nanoparticle will face in a protein-rich biological environment, we will first describe the formation of a protein corona and thereafter discuss potential perturbations of the delivery systems when moving from in vitro testing to in vivo applications. We emphasize the role of mathematical modeling in optimizing the design of functionalized nanoparticles to achieve high success of delivery.
Biochemistry, Jul 8, 2005
It is well-known that adsorption of proteins on interfaces often induces substantial alterations ... more It is well-known that adsorption of proteins on interfaces often induces substantial alterations of the protein structure. However, very little is known about whether these conformational changes have any consequence for the protein conformation after desorption from the interface. To investigate this matter, we have selected a protein-particle system in which the enzyme human carbonic anhydrase I (HCAI) alternates between the adsorbed and free state upon interaction with the silica nanoparticles. High-resolution NMR analysis of the protein with the particles present in the sample shows a spectrum that indicates a molten globular-like structure. Removal of particles results in refolding of virtually all HCAI molecules to a fully active form. However, the two-dimensional NMR analysis shows that refolding does not result in a single well-defined protein structure but rather provides an ensemble of protein molecules with near-native conformations. A detailed comparative chemical shift analysis of 108 amide signals in 1 H-15 N HSQC spectra of native and desorbed HCAI reveals that the most profound effects are located at-strands in the center of the molecule. The observation of very slow H-D exchange in the central-strands of HCAI [Kjellsson, A., Sethson, I., and Jonsson, B. H. (2003) Biochemistry 42, 363-374] in conjunction with our results indicates that the kinetic barriers for conformational rearrangements in the central core of the protein are low in the presence of nanoparticles but are very high under native conditions.
Advances in Colloid and Interface Science, Oct 1, 2007
The major aim of our current work is to develop a deep understanding of biological effects of nan... more The major aim of our current work is to develop a deep understanding of biological effects of nanoparticles and how these effects are mediated by proteins that are adsorbed on the nanoparticles under different biological circumstances. Due to their small size, nanoparticles have distinct properties compared to the bulk form of the same materials, and these properties are rapidly revolutionizing many areas of medicine and technology. However, relatively little is known about the interaction of nanoscale objects with biological systems, as this requires quite different concepts from more established nanoscience. Thus, we have argued that in a biological fluid, proteins associate with nanoparticles, and it is the amount and presentation of the proteins on the surface rather than the particles themselves that are the cause of numerous biological responses. It is this outer layer of proteins that is seen by the biological cells, and leads to their responses. We are developing novel techniques to identify and quantify the proteins that are consistently associated with nanoparticles, as a function of the nanoparticle size, shape, and surface properties, and to correlate the adsorbed protein identities with their association and dissociation rates to and from the nanoparticles. We also seek to understand the degree of conformational change that they undergo upon adsorption to the nanoparticles. In essence, we wish to create "epitope maps" of the protein corona that surrounds nanoparticles in biological solutions, as it is the particle-protein complex that is the biologically active entity.
PLOS ONE, Apr 17, 2017
The protein corona formed around nanoparticles in protein-rich fluids plays an important role for... more The protein corona formed around nanoparticles in protein-rich fluids plays an important role for nanoparticle biocompatibility, as found in several studies during the last decade. Biological fluids have complex compositions and the molecular components interact and function together in intricate networks. Therefore, the process to isolate blood or the preparation of blood derivatives may lead to differences in the composition of the identified protein corona around nanoparticles. Here, we show distinct differences in the protein corona formed in whole blood, whole blood with EDTA, plasma, or serum. Furthermore, the ratio between particle surface area to protein concentration influences the detected corona. We also show that the nanoparticle size per se influences the formed protein corona due to curvature effects. These results emphasize the need of investigating the formation and biological importance of the protein corona in the same environment as the nanoparticles are intended for or released into.
The work presented in this thesis deals with the structural and functional properties of peptides... more The work presented in this thesis deals with the structural and functional properties of peptides at surfaces. The interaction of peptides with surfaces is an ever so common occurrence in our every day life, from the bug squashed on the windshield of our car to the barnacle on our boat, and from the blood plasma used in the hospital to the proteins in our cells. The effect these occurrences has on our lives is diverse, the bug is annoying whereas the barnacle settlement of ship hull is costly for marine transportation, the blood plasma contains components of vital importance for our immunological defense system and the proteins in our cells are crucial for regulatory processes and life.One part of this thesis, performed as a part of the EU-founded project AMBIO, deals with the concept of marine biofouling. A number of short peptides have been designed, synthesized, and used to investigate their effect on the settlement on marine biofoulers, such as the Ulva linza algae and the Navicula diatom, on template surfaces coated with thin layers of these molecules. The surfaces have been thoroughly investigated with respect of their physio-chemical properties before and after submersion in artificial seawater and ultimately in suspensions containing the organisms. The most interesting results were obtained with an arginine-rich peptide coating that when introduced to Ulva linza zoospores, displayed extensive settlement, compared to reference surfaces. In addition, a large fraction of the settled spores had an abnormal morphology.The other part of this thesis is focused on designed peptides that when adsorbed on a negatively charged surface adopts a well-defined secondary structure, either α-helical or β-sheet. Precisely placed amino acids in the peptides will strongly disfavor structure in solution, primarily due to electrostatic repulsion, but when the peptides are adsorbed on the negatively charged surfaces, they adopt a well-defined secondary structure due to ion pair bonding. These interactions have been thoroughly investigated by systematic variations of the side-chains. In order to determine the factors contributing to the induced structure, several peptides with different amino acid sequences have been synthesized. Factors that have been investigated include 1) the positive charge density, 2) distribution of positive charges, 3) negative charge density, 4) increasing hydrophobicity, and 5) incorporating amino acids with different helix propensities. Moreover, pH dependence and the effect of different interaction partners have also been investigated. It has also been shown that the system can be modified to incorporate a catalytic site that is only active when the helix is formed. This research will increase our understanding of peptide-surface interactions and might be of importance for both bionanotechnology and medicine.
A catalytic example 1 Aim A His15-Lys19 pair forms a catalytic site for ester hydrolysis which is... more A catalytic example 1 Aim A His15-Lys19 pair forms a catalytic site for ester hydrolysis which is active only when the peptide is helical.
The ability to create surfaces with well-defined chemical properties is a major research field. O... more The ability to create surfaces with well-defined chemical properties is a major research field. One possibility to do this is to design peptides that bind with a specific secondary structure to silica nanoparticles. The peptides discussed in this thesis are constructed to be random coil in solution, but are “forced” to become helical when adsorbed to the particles. The positively charged side-chains on the peptides strongly disfavor an ordered structure in solution due to electrostatic repulsion. When the peptides are introduced to the particles these charges will strongly favor the structure because of ion pair bonding between the peptide and the negatively charged nanoparticles. The peptide-nanoparticle system has been thoroughly investigated by systematic variations of the side-chains. In order to determine which factors that contributes to the induced structure, several peptides with different amino acid sequences have been synthesized. Factors that have been investigated include 1) the positive charge density, 2) distribution of positive charges, 3) negative charge density, 4) increasing hydrophobicity, 5) peptide length, and 6) by incorporating amino acids with different helix propensities. Moreover, pH dependence and the effect of different nanoparticle curvature have also been investigated. It will also be shown that the system can be modified to incorporate a catalytic site that is only active when the helix is formed. This research will increase our understanding of peptide-surface interactions and might be of importance for both nanotechnology and medicine.
Design of Functional Peptide-Nanoparticle Complexes with Potential Applications in Targeted Drug ... more Design of Functional Peptide-Nanoparticle Complexes with Potential Applications in Targeted Drug Delivery
Small, Oct 26, 2020
This will be a more challenging task than just detect them in the corona.
Journal of Chemical Education, Jul 17, 2019
The one-hour workshop, containing both a demonstration and hands-on experiments on the topic of n... more The one-hour workshop, containing both a demonstration and hands-on experiments on the topic of nanosafety, is based on current science on a topic of general interest. The workshop aims to provide a deeper knowledge and understanding of nanoparticles. The participants get an introduction to what nanoparticles are, why nanosized materials are interesting, how nanomaterials interact with biological molecules, and potential risks associated with nanoparticles. Furthermore, by participating in the workshop the audience gains insights into how research about nanoparticles is conducted. The participants carry out experiments to demonstrate that daily-used plastic products can be disintegrated into particles in the nanometer size range, which may have important implications for the environment.
Springer eBooks, 2010
... Application as Contrast Agents Johannes Stigler, Martin Lundqvist, Tommy Cedervall, Kenneth D... more ... Application as Contrast Agents Johannes Stigler, Martin Lundqvist, Tommy Cedervall, Kenneth Dawson, and Iseult Lynch Abstract. ... Proteomics 5:35313536 14. Ong ATL, Hoye A, Aoki J, van Mieghem CAG, Rodriguez Granillo GA, Son-nenschein K, Regar E, McFadden ...
Environmental Science: Processes & Impacts, 2022
With polystyrene nanoparticles being widely used in various applications, there is a great need f... more With polystyrene nanoparticles being widely used in various applications, there is a great need for deeper knowledge on the safety, fate and biological effects of these particles on both individual living organisms and the whole ecosystems. Due to this, there is a growing interest in performing ecotoxicological studies using model plastic nanoparticles, and consequently it generates an increasing number of published papers describing the negative impact on wildlife caused by such nanoparticles. Polystyrene is the most studied nanosized plastic, therefore this review focuses on research conducted with manufactured polystyrene nanoparticles. The aim of the present article is to provide a critical methodological outline of the existing ecotoxicological studies on the effects of polystyrene nanoparticles on aquatic organisms. Going through the published articles, we noted that particle characterization especially in the test medium, can be improved. The analysis also highlights the importance of purifying the polystyrene nanoparticles before studying its toxicity. Furthermore, the size characterization of such nanoparticles is underemphasized, and in future studies, authors should consider including more techniques to achieve this goal. Finally, short-term or direct exposure scenarios do not add the most environmentally relevant knowledge in terms of the toxicity caused by polystyrene nanoparticles. Environmental signicance Today, there are many papers published regarding the toxicity caused by polystyrene nanoparticles. However, several factors are underemphasized, for example, the importance of nanoparticle solution purication before using them in the toxicity studies, as well as characterization of nanoparticles size. Therefore, we review published papers in order to highlight some common problems in the experimental set ups. We believe that emphasizing these shortcomings and suggesting different experimental routines will help to achieve the most relevant information on the toxicity caused by these nanoparticles.
Frontiers in Nanotechnology
Nanoplastics are defined as plastic particles broken down to extremely small sizes (1–100 nm) wit... more Nanoplastics are defined as plastic particles broken down to extremely small sizes (1–100 nm) with unknown effects to the human body and immune system. Air and food exposure scenarios involving blood, lungs and intestine are considered in the literature. The fact that plastics also needs to pass the nose, oral cavity, and throat is so far ignored in the literature. The tonsils are immunologically important tissue in the oral cavity in which ingested and inhaled agents are incorporated through crypts with the capacity to capture agents and start early immunologic reactions. We argue that the tonsil is a very important tissue to study in regard to micro and nanoplastic human exposure and immunologic response. Nano-sized particles are known to be able to travel through the natural barriers and have different effects on biology compared to larger particle and the bulk material. It is therefore, although difficult, important to develop experimental methods to detect and identify nanoplas...
Environmental Science: Nano
Toxic and non-toxic polystyrene particles bind different proteins during filtration by zooplankton.
Frontiers in Molecular Biosciences, 2021
The aggregation of the human islet amyloid polypeptide (IAPP) is associated with diabetes type II... more The aggregation of the human islet amyloid polypeptide (IAPP) is associated with diabetes type II. A quantitative understanding of this connection at the molecular level requires that the aggregation mechanism of IAPP is resolved in terms of the underlying microscopic steps. Here we have systematically studied recombinant IAPP, with amidated C-terminus in oxidised form with a disulphide bond between residues 3 and 7, using thioflavin T fluorescence to monitor the formation of amyloid fibrils as a function of time and IAPP concentration. We used global kinetic analyses to connect the macroscopic measurements of aggregation to the microscopic mechanisms, and show that the generation of new aggregates is dominated by the secondary nucleation of monomers on the fibril surface. We then exposed insulinoma cells to aliquots extracted from different time points of the aggregation process, finding the highest toxicity at the midpoint of the reaction, when the secondary nucleation rate reache...
Environmental Science: Processes & Impacts, 2022
With polystyrene nanoparticles being widely used in various applications, there is a great need f... more With polystyrene nanoparticles being widely used in various applications, there is a great need for deeper knowledge on the safety, fate and biological effects of these particles on both individual living organisms and the whole ecosystems.
Small, 2020
The research about how a nanoparticle (NP) interacts with a complex biological solution has been ... more The research about how a nanoparticle (NP) interacts with a complex biological solution has been conducted, according to the literature, for almost three decades. A significant amount of data has been generated, especially in the last one and a half decade. First, it became its own research field which was later divided into many subresearch fields. This outlook does not aim to be a comprehensive review of the field or any of its subresearch fields. There is too much data published to attempt that. Instead, here it has been tried to highlight what, in the opinion, is the main step taken during these three decades. Thereafter, the weaknesses and end are pointed out with what needs to be the main focus for the future to understand the protein corona formation in the bloodstream, which is a prerequisite for the developing of true target specific drug‐delivering nanoparticles.
Nature Structural & Molecular Biology, 2020
The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is... more The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer's disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quantitative binding measurements to address the mechanism of action of four clinical stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ. Our results reveal that, uniquely among these four antibodies, aducanumab dramatically reduces the flux of Aβ oligomers.
Frontiers in Immunology, 2019
Streptococcus pyogenes infects over 700 million people worldwide annually. Immune evasion strateg... more Streptococcus pyogenes infects over 700 million people worldwide annually. Immune evasion strategies employed by the bacteria include binding of the complement inhibitors, C4b-binding protein (C4BP) and Factor H in a human-specific manner. We recently showed that human IgG increased C4BP binding to the bacterial surface, which promoted streptococcal immune evasion and increased mortality in mice. We sought to identify how IgG promotes C4BP binding to Protein H, a member of the M protein family. Dimerization of Protein H is pivotal for enhanced binding to human C4BP. First, we illustrated that Protein H, IgG, and C4BP formed a tripartite complex. Second, surface plasmon resonance revealed that Protein H binds IgG solely through Fc, but not Fab domains, and with high affinity (IgG-Protein H: K D = 0.4 nM; IgG-Fc-Protein H: K D ≤ 1.6 nM). Each IgG binds two Protein H molecules, while up to six molecules of Protein H bind one C4BP molecule. Third, interrupting Protein H dimerization either by raising temperature to 41 • C or with a synthetic peptide prevented IgG-Protein H interactions. IgG-Fc fragments or monoclonal human IgG permitted maximal C4BP binding when used at concentrations from 0.1 to 10 mg/ml. In contrast, pooled human IgG enhanced C4BP binding at concentrations up to 1 mg/ml; decreased C4BP binding at 10 mg/ml occurred probably because of Fab-streptococcal interactions at these high IgG concentrations. Taken together, our data show how S. pyogenes exploits human IgG to evade complement and enhance its virulence. Elucidation of this mechanism could aid design of new therapeutics against S. pyogenes.
Nanomedicine, May 1, 2014
This article discusses the role of the protein corona in delivery systems with tagged nanoparticl... more This article discusses the role of the protein corona in delivery systems with tagged nanoparticles and how knowledge of the protein corona can help in optimizing delivery. The basic question is whether and how the binding of proteins and other biomolecules at the nanoparticle surface interfere with the interaction between a tag and its receptor. This is an interesting problem in many respects, but most intriguing are the observed differences in delivery efficiency in vivo compared with protein-free in vitro conditions. In order to understand possible situations that the nanoparticle will face in a protein-rich biological environment, we will first describe the formation of a protein corona and thereafter discuss potential perturbations of the delivery systems when moving from in vitro testing to in vivo applications. We emphasize the role of mathematical modeling in optimizing the design of functionalized nanoparticles to achieve high success of delivery.
Biochemistry, Jul 8, 2005
It is well-known that adsorption of proteins on interfaces often induces substantial alterations ... more It is well-known that adsorption of proteins on interfaces often induces substantial alterations of the protein structure. However, very little is known about whether these conformational changes have any consequence for the protein conformation after desorption from the interface. To investigate this matter, we have selected a protein-particle system in which the enzyme human carbonic anhydrase I (HCAI) alternates between the adsorbed and free state upon interaction with the silica nanoparticles. High-resolution NMR analysis of the protein with the particles present in the sample shows a spectrum that indicates a molten globular-like structure. Removal of particles results in refolding of virtually all HCAI molecules to a fully active form. However, the two-dimensional NMR analysis shows that refolding does not result in a single well-defined protein structure but rather provides an ensemble of protein molecules with near-native conformations. A detailed comparative chemical shift analysis of 108 amide signals in 1 H-15 N HSQC spectra of native and desorbed HCAI reveals that the most profound effects are located at-strands in the center of the molecule. The observation of very slow H-D exchange in the central-strands of HCAI [Kjellsson, A., Sethson, I., and Jonsson, B. H. (2003) Biochemistry 42, 363-374] in conjunction with our results indicates that the kinetic barriers for conformational rearrangements in the central core of the protein are low in the presence of nanoparticles but are very high under native conditions.
Advances in Colloid and Interface Science, Oct 1, 2007
The major aim of our current work is to develop a deep understanding of biological effects of nan... more The major aim of our current work is to develop a deep understanding of biological effects of nanoparticles and how these effects are mediated by proteins that are adsorbed on the nanoparticles under different biological circumstances. Due to their small size, nanoparticles have distinct properties compared to the bulk form of the same materials, and these properties are rapidly revolutionizing many areas of medicine and technology. However, relatively little is known about the interaction of nanoscale objects with biological systems, as this requires quite different concepts from more established nanoscience. Thus, we have argued that in a biological fluid, proteins associate with nanoparticles, and it is the amount and presentation of the proteins on the surface rather than the particles themselves that are the cause of numerous biological responses. It is this outer layer of proteins that is seen by the biological cells, and leads to their responses. We are developing novel techniques to identify and quantify the proteins that are consistently associated with nanoparticles, as a function of the nanoparticle size, shape, and surface properties, and to correlate the adsorbed protein identities with their association and dissociation rates to and from the nanoparticles. We also seek to understand the degree of conformational change that they undergo upon adsorption to the nanoparticles. In essence, we wish to create "epitope maps" of the protein corona that surrounds nanoparticles in biological solutions, as it is the particle-protein complex that is the biologically active entity.
PLOS ONE, Apr 17, 2017
The protein corona formed around nanoparticles in protein-rich fluids plays an important role for... more The protein corona formed around nanoparticles in protein-rich fluids plays an important role for nanoparticle biocompatibility, as found in several studies during the last decade. Biological fluids have complex compositions and the molecular components interact and function together in intricate networks. Therefore, the process to isolate blood or the preparation of blood derivatives may lead to differences in the composition of the identified protein corona around nanoparticles. Here, we show distinct differences in the protein corona formed in whole blood, whole blood with EDTA, plasma, or serum. Furthermore, the ratio between particle surface area to protein concentration influences the detected corona. We also show that the nanoparticle size per se influences the formed protein corona due to curvature effects. These results emphasize the need of investigating the formation and biological importance of the protein corona in the same environment as the nanoparticles are intended for or released into.
The work presented in this thesis deals with the structural and functional properties of peptides... more The work presented in this thesis deals with the structural and functional properties of peptides at surfaces. The interaction of peptides with surfaces is an ever so common occurrence in our every day life, from the bug squashed on the windshield of our car to the barnacle on our boat, and from the blood plasma used in the hospital to the proteins in our cells. The effect these occurrences has on our lives is diverse, the bug is annoying whereas the barnacle settlement of ship hull is costly for marine transportation, the blood plasma contains components of vital importance for our immunological defense system and the proteins in our cells are crucial for regulatory processes and life.One part of this thesis, performed as a part of the EU-founded project AMBIO, deals with the concept of marine biofouling. A number of short peptides have been designed, synthesized, and used to investigate their effect on the settlement on marine biofoulers, such as the Ulva linza algae and the Navicula diatom, on template surfaces coated with thin layers of these molecules. The surfaces have been thoroughly investigated with respect of their physio-chemical properties before and after submersion in artificial seawater and ultimately in suspensions containing the organisms. The most interesting results were obtained with an arginine-rich peptide coating that when introduced to Ulva linza zoospores, displayed extensive settlement, compared to reference surfaces. In addition, a large fraction of the settled spores had an abnormal morphology.The other part of this thesis is focused on designed peptides that when adsorbed on a negatively charged surface adopts a well-defined secondary structure, either α-helical or β-sheet. Precisely placed amino acids in the peptides will strongly disfavor structure in solution, primarily due to electrostatic repulsion, but when the peptides are adsorbed on the negatively charged surfaces, they adopt a well-defined secondary structure due to ion pair bonding. These interactions have been thoroughly investigated by systematic variations of the side-chains. In order to determine the factors contributing to the induced structure, several peptides with different amino acid sequences have been synthesized. Factors that have been investigated include 1) the positive charge density, 2) distribution of positive charges, 3) negative charge density, 4) increasing hydrophobicity, and 5) incorporating amino acids with different helix propensities. Moreover, pH dependence and the effect of different interaction partners have also been investigated. It has also been shown that the system can be modified to incorporate a catalytic site that is only active when the helix is formed. This research will increase our understanding of peptide-surface interactions and might be of importance for both bionanotechnology and medicine.
A catalytic example 1 Aim A His15-Lys19 pair forms a catalytic site for ester hydrolysis which is... more A catalytic example 1 Aim A His15-Lys19 pair forms a catalytic site for ester hydrolysis which is active only when the peptide is helical.
The ability to create surfaces with well-defined chemical properties is a major research field. O... more The ability to create surfaces with well-defined chemical properties is a major research field. One possibility to do this is to design peptides that bind with a specific secondary structure to silica nanoparticles. The peptides discussed in this thesis are constructed to be random coil in solution, but are “forced” to become helical when adsorbed to the particles. The positively charged side-chains on the peptides strongly disfavor an ordered structure in solution due to electrostatic repulsion. When the peptides are introduced to the particles these charges will strongly favor the structure because of ion pair bonding between the peptide and the negatively charged nanoparticles. The peptide-nanoparticle system has been thoroughly investigated by systematic variations of the side-chains. In order to determine which factors that contributes to the induced structure, several peptides with different amino acid sequences have been synthesized. Factors that have been investigated include 1) the positive charge density, 2) distribution of positive charges, 3) negative charge density, 4) increasing hydrophobicity, 5) peptide length, and 6) by incorporating amino acids with different helix propensities. Moreover, pH dependence and the effect of different nanoparticle curvature have also been investigated. It will also be shown that the system can be modified to incorporate a catalytic site that is only active when the helix is formed. This research will increase our understanding of peptide-surface interactions and might be of importance for both nanotechnology and medicine.
Design of Functional Peptide-Nanoparticle Complexes with Potential Applications in Targeted Drug ... more Design of Functional Peptide-Nanoparticle Complexes with Potential Applications in Targeted Drug Delivery