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  • 1.
    Borro, Bruno C.
    et al.
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Bohr, Adam
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Bucciarelli, Saskia
    Univ Copenhagen, Dept Drug Design & Pharmacol, Jagtvej 162, DK-2100 Copenhagen, Denmark.
    Boetker, Johan P.
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Foged, Camilla
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Rantanen, Jukka
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Microfluidics-based self-assembly of peptide-loaded microgels: Effect of three dimensional (3D) printed micromixer design2019In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 538, p. 559-568Article in journal (Refereed)
    Abstract [en]

    In an effort to contribute to research in scalable production systems for polymeric delivery systems loaded with antimicrobial peptides (AMPS), we here investigate effects of hydrodynamic flow conditions on microfluidic particle generation. For this purpose, rapid prototyping using 3D printing was applied to prepare micromixers with three different geometric designs, which were used to prepare Ca2+-crosslinked alginate microgels loaded with the AMP polymyxin B in a continuous process. Based on fluid dynamic simulations, the hydrodynamic flow patterns in the micromixers were designed to be either (i) turbulent with chaotic disruption, (ii) laminar with convective mixing, or (iii) convective with microvortex formation. The physicochemical properties of the microgels prepared with these micromixers were characterized by photon correlation spectroscopy, laser-Doppler micro-electrophoresis, smallangle x-ray scattering, and ellipsometry. The particle size and compactness were found to depend on the micromixer geometry: From such studies, particle size and compactness were found to depend on micromixer geometry, the smallest and most compact particles were obtained by preparation involving microvortex flows, while larger and more diffuse microgels were formed upon laminar mixing. Polymyxin B was found to be localized in the particle interior and to cause particle growth with increasing peptide loading. Ca2+-induced cross-linking of alginate, in turn, results in particle contraction. The peptide encapsulation efficiency was found to be higher than 80% for all investigated micromixer designs; the highest encapsulation efficiency observed for the smallest particles generated by microvortexmediated self-assembly. Ellipsometry results for surface-immobilized microgels, as well as results on peptide encapsulation, demonstrated electrolyte-induced peptide release. Taken together, these findings demonstrate that rapid prototyping of microfluidics using 3D-printed micromixers offers promises for continuous manufacturing of AMP-loaded microgels. Although the micromixer combining turbulent flow and microvortexes was demonstrated to be the most efficient, all three micromixer designs were found to mediate self-assembly of small microgels displaying efficient peptide encapsulation. This demonstrates the robustness of employing 3D-printed micromixers for microfluidic assembly of AMP-loaded microgels during continuous production. 

  • 2.
    Braun, Katharina
    et al.
    Univ Ulm, Dept Inorgan Chem 2, D-89031 Ulm, Germany..
    Pochert, Alexander
    Univ Ulm, Dept Inorgan Chem 2, D-89031 Ulm, Germany..
    Linden, Mika
    Univ Ulm, Dept Inorgan Chem 2, D-89031 Ulm, Germany..
    Davoudi, Mina
    Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden..
    Schmidtchen, Artur
    Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden.;Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore..
    Nordström, Randi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Membrane interactions of mesoporous silica nanoparticles as carriers of antimicrobial peptides2016In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 475, p. 161-170Article in journal (Refereed)
    Abstract [en]

    Membrane interactions are critical for the successful use of mesoporous silica nanoparticles as delivery systems for antimicrobial peptides (AMPs). In order to elucidate these, we here investigate effects of nanoparticle charge and porosity on AMP loading and release, as well as consequences of this for membrane interactions and antimicrobial effects. Anionic mesoporous silica particles were found to incorporate considerable amounts of the cationic AMP LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES (LL-37), whereas loading is much lower for non-porous or positively charged silica nanoparticles. Due to preferential pore localization, anionic mesoporous particles, but not the other particles, protect LL-37 from degradation by infection-related proteases. For anionic mesoporous nanoparticles, membrane disruption is mediated almost exclusively by peptide release. In contrast, non-porous silica particles build up a resilient LL-37 surface coating due to their higher negative surface charge, and display largely particle-mediated membrane interactions and antimicrobial effects. For positively charged mesoporous silica nanoparticles, LL-37 incorporation promotes the membrane binding and disruption displayed by the particles in the absence of peptide, but also causes toxicity against human erythrocytes. Thus, the use of mesoporous silica nanoparticles as AMP delivery systems requires consideration of membrane interactions and selectivity of both free peptide and the peptide-loaded nanoparticles, the latter critically dependent on nanoparticle properties.

  • 3.
    Browning, Kathryn L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lind, T. K.
    Malmo Univ, Dept Biomed Sci & Biofilms, Malmo, Sweden..
    Maric, S.
    Malmo Univ, Dept Biomed Sci & Biofilms, Malmo, Sweden..
    Malekkhaiat Häffner, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Fredrikson, G. N.
    Lund Univ, Dept Clin Sci, Malmo, Sweden..
    Bengtsson, E.
    Lund Univ, Dept Clin Sci, Malmo, Sweden..
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, Copenhagen, Denmark..
    Cardenas, M.
    Malmo Univ, Dept Biomed Sci & Biofilms, Malmo, Sweden..
    Human Lipoproteins at Model Cell Membranes: Effect of Lipoprotein Class on Lipid Exchange2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 7478Article in journal (Refereed)
    Abstract [en]

    High and low density lipoproteins (HDL and LDL) are thought to play vital roles in the onset and development of atherosclerosis; the biggest killer in the western world. Key issues of initial lipoprotein (LP) interactions at cellular membranes need to be addressed including LP deposition and lipid exchange. Here we present a protocol for monitoring the in situ kinetics of lipoprotein deposition and lipid exchange/removal at model cellular membranes using the non-invasive, surface sensitive methods of neutron reflection and quartz crystal microbalance with dissipation. For neutron reflection, lipid exchange and lipid removal can be distinguished thanks to the combined use of hydrogenated and tail-deuterated lipids. Both HDL and LDL remove lipids from the bilayer and deposit hydrogenated material into the lipid bilayer, however, the extent of removal and exchange depends on LP type. These results support the notion of HDL acting as the 'good' cholesterol, removing lipid material from lipid-loaded cells, whereas LDL acts as the 'bad' cholesterol, depositing lipid material into the vascular wall.

  • 4.
    Browning, Kathryn L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Lind, Tania Kjellerup
    Malmo Univ, Res Ctr Biointerfaces, Dept Biomed Sci & Biofilms, Malmo, Sweden.
    Maric, Selma
    Malmo Univ, Res Ctr Biointerfaces, Dept Biomed Sci & Biofilms, Malmo, Sweden.
    Barker, Robert David
    Inst Laue Langevin, Grenoble, France;Univ Kent, Sch Phys Sci, Canterbury, Kent, England.
    Cardenas, Marite
    Malmo Univ, Res Ctr Biointerfaces, Dept Biomed Sci & Biofilms, Malmo, Sweden.
    Malmsten, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Effect of bilayer charge on lipoprotein lipid exchange2018In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 168, p. 117-125Article in journal (Refereed)
    Abstract [en]

    Lipoproteins play a key role in the onset and development of atherosclerosis, the formation of lipid plaques at blood vessel walls. The plaque formation, as well as subsequent calcification, involves not only endothelial cells but also connective tissue, and is closely related to a wide range of cardiovascular syndromes, that together constitute the number one cause of death in the Western World. High (HDL) and low (LDL) density lipoproteins are of particular interest in relation to atherosclerosis, due to their protective and harmful effects, respectively. In an effort to elucidate the molecular mechanisms underlying this, and to identify factors determining lipid deposition and exchange at lipid membranes, we here employ neutron reflection (NR) and quartz crystal microbalance with dissipation (QCM-D) to study the effect of membrane charge on lipoprotein deposition and lipid exchange. Dimyristoylphosphatidylcholine (DMPC) bilayers containing varying amounts of negatively charged dimyristoylphosphatidylserine (DMPS) were used to vary membrane charge. It was found that the amount of hydrogenous material deposited from either HDL or LDL to the bilayer depends only weakly on membrane charge density. In contrast, increasing membrane charge resulted in an increase in the amount of lipids removed from the supported lipid bilayer, an effect particularly pronounced for LDL. The latter effects are in line with previously reported observations on atherosclerotic plaque prone regions of long-term hyperlipidaemia and type 2 diabetic patients, and may also provide some molecular clues into the relation between oxidative stress and atherosclerosis. 

  • 5.
    Browning, Kathryn L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lind, Tania
    Malmo Univ, Dept Biomed Sci & Biofilm, Malmo, Sweden.
    Maric, Selma
    Malmoe Univ, Dept Hlth & Soc, Malmo, Sweden.
    Malekkhaiat Häffner, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Fredrikson, Gunilla
    Lund Univ, Dept Clin Sci, Lund, Sweden.
    Bengtsson, Eva
    Lund Univ, Dept Clin Sci, Rochester, Sweden.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, Copenhagen, Denmark.
    Cardenas, Marite
    Malmo Univ, Dept Biomed Sci & Biofilm, Malmo, Sweden.
    Human lipoproteins at model cell membranes: Role of the lipoprotein class on lipid dynamics2017In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 253, article id 700Article in journal (Other academic)
  • 6.
    Bysell, Helena
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Visualizing the interaction between poly-L-lysine and poly(acrylic acid) microgels using microscopy techniques: effect of electrostatics and peptide size.2006In: Langmuir, ISSN 0743-7463, Vol. 22, no 12, p. 5476-84Article in journal (Refereed)
  • 7.
    Bysell, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Månsson, Ronja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Microgels and microcapsules in peptide and protein drug delivery2011In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 63, no 13, p. 1172-1185Article, review/survey (Refereed)
    Abstract [en]

    The present review focuses on the interaction of microgels and microcapsules with biological macromolecules, particularly peptides and proteins, as well as drug delivery applications of such systems. Results from recent studies on factors affecting peptide/protein binding to, and release from, microgels and related systems are discussed, including effects of network properties, as well as protein aggregation, peptide length, hydrophobicity and charge (distributions), secondary structure, and cyclization. Effects of ambient conditions (pH, ionic strength, temperature, etc.) are also discussed, all with focus on factors of importance for the performance of microgel and microcapsule delivery systems for biomacromolecular drugs.

  • 8.
    Bysell, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Månsson, Ronja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effects of peptide cyclization on the interaction with oppositely charged microgels2011In: Colloids and Surfaces A: Physicochemical and Engineering Aspects, ISSN 0927-7757, E-ISSN 1873-4359, Vol. 391, no 1-3, p. 62-68Article in journal (Refereed)
    Abstract [en]

    The effect of peptide cyclization on the interaction between antimicrobial peptides and oppositely charged poly(acrylic acid-co-acrylamide) microgels of various charge density was investigated for linear and cyclic variants of peptide oligomers (C(ARKKAAKA)nC) (n = 1, 1.5, 2, 3). Through this, peptide length could be varied without substantially affecting peptide charge density and mean hydrophobicity. Furthermore, the peptides were demonstrated to display random coil conformation both in aqueous solution and when bound to oppositely charged microgels, allowing effects of cyclization to be monitored without interference from conformational transitions. With increasing peptide length, both cyclic and linear peptide variants displayed increased binding affinity to oppositely charged microgels. For all peptide lengths, however, the difference between cyclic and linear peptide variants was marginal at most, hence cyclization had little or no influence in peptide incorporation to oppositely charged microgels. In parallel, microgel deswelling increased with peptide length for both linear and cyclic peptide variants, while linear and cyclic peptide variants of the same length displayed very similar peptide-induced deswelling. Also electrolyte-induced peptide desorption from the microgels was similar for linear and cyclic peptide variants. Taken together, these findings demonstrate that end-to-end cyclization does not markedly affect peptide incorporation into, and release from, oppositely charged microgels. This opens up opportunities for the use of microgels as carriers for peptides which have been cyclized in order to improve their proteolytic and chemical stability, or in order to achieve other therapeutic advantages compared to the corresponding linear peptide variant.

  • 9. Carlsson, F
    et al.
    Hyltner, E
    Arnebrant, T
    Malmsten, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Linse, P
    Lysozyme adsorption to charged surfaces: A Monte Carlo Study2004In: J Phys Chem, Vol. 108, p. 9871-Article in journal (Refereed)
  • 10. Carlsson, Fredrik
    et al.
    Malmsten, Martin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Linse, Per
    Protein-polyelectrolyte cluster formation and redissolution: a Monte Carlo study.2003In: J Am Chem Soc, ISSN 0002-7863, Vol. 125, no 10, p. 3140-9Article in journal (Refereed)
  • 11. Cicuendez, Monica
    et al.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Carlos Doadrio, Juan
    Teresa Portoles, Maria
    Izquierdo-Barba, Isabel
    Vallet-Regi, Maria
    Tailoring hierarchical meso- macroporous 3D scaffolds: from nano to macro2014In: Journal of Materials Chemistry B, ISSN 2050-750X, Vol. 2, no 1, p. 49-58Article in journal (Refereed)
    Abstract [en]

    Bone tissue regeneration requires the use of 3D scaffolds which mimic the architecture of the natural extracellular matrix, creating an adequate microenvironment for bone cell growth. Such 3D scaffolds need surface properties suitable for biological recognition in the early stage of cell adhesion, necessary to ensure complete cell colonization, retained cell functionality, and subsequently bone regeneration. Herein, hierarchical 3D scaffolds based on new hydroxyapatite/mesoporous glass nanocomposite bioceramic (MGHA) exhibiting different scales of porosity have been synthesized. These 3D scaffolds possess: (i) highly ordered mesopores with diameters of 10 nm; (ii) macropores with diameters in the 30-80 mu m range with interconnections of 1-10 mu m; and (iii) large macropores of ca. 500 mu m. To improve their surface properties, 3D scaffolds were modified through direct functionalization with amine propyl groups, which notably improve preosteoblast adhesion, proliferation (2.3 fold), differentiation (4.8 fold) and further cell colonization of these scaffolds. The observed enhancement can be related to these amine groups which favour early adhesion, e. g., based on nonspecific protein adsorption as was demonstrated by ellipsometry. These results suggest that the combination of hierarchical structure design and amine surface modification of hydroxyapatite/mesoporous nanocomposite scaffolds yields a double increase in cell proliferation, as well as a quadruple increase in cell differentiation, demonstrating the potential of these nanocomposite materials for bone tissue regeneration purposes.

  • 12.
    Colombo, Stefano
    et al.
    Univ Copenhagen, Dept Pharm, Copenhagen, Denmark.
    Beck-Broichsitter, Moritz
    Philipps Univ, Dept Pharmaceut & Biopharm, Marburg, Germany.
    Becker, Johan Peter
    Univ Copenhagen, Dept Pharm, Copenhagen, Denmark.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, Copenhagen, Denmark.
    Rantanen, Jukka
    Univ Copenhagen, Dept Pharm, Copenhagen, Denmark.
    Bohr, Adam
    Univ Copenhagen, Dept Pharm, Copenhagen, Denmark.
    Transforming nanomedicine manufacturing toward Quality by Design and microfluidics2018In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 128, p. 115-131Article, review/survey (Refereed)
    Abstract [en]

    Nanopharmaceuticals aim at translating the unique features of nano-scale materials into therapeutic products and consequently their development relies critically on the progression in manufacturing technology to allow scalable processes complying with process economy and quality assurance. The relatively high failure rate in translational nanopharmaceutical research and development, with respect to new products on the market, is at least partly due to immature bottom-up manufacturing development and resulting sub-optimal control of quality attributes in nanopharmaceuticals. Recently, quality-oriented manufacturing of pharmaceuticals has undergone an unprecedented change toward process and product development interaction. In this context, Quality by Design (QbD) aims to integrate product and process development resulting in an increased number of product applications to regulatory agencies and stronger proprietary defense strategies of process-based products. Although QbD can be applied to essentially any production approach, microfluidic production offers particular opportunities for QbD-based manufacturing of nanopharmaceuticals. Microfluidics provides unique design flexibility, process control and parameter predictability, and also offers ample opportunities for modular production setups, allowing process feedback for continuously operating production and process control. The present review aims at outlining emerging opportunities in the synergistic implementation of QbD strategies and microfluidic production in contemporary development and manufacturing of nanopharmaceuticals. In doi ng so, aspects of design and development, but also technology management, are reviewed, as is the strategic role of these tools for aligning nanopharmaceutical innovation, development, and advanced industrialization in the broader pharmaceutical field. (C) 2018 Elsevier B.V. All rights reserved.

  • 13.
    Colombo, Stefano
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Brisander, Magnus
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Sjövall, Peter
    Andersson, Per
    Østergaard, Jesper
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Matrix effects in nilotinib formulations with pH-responsive polymer produced by carbon dioxide-mediated precipitation2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 494, no 1, p. 205-217Article in journal (Refereed)
    Abstract [en]

    Factors determining the pH-controlled dissolution kinetics of nilotinib formulations with the pH-titrable polymer hydroxypropyl methylcellulose phthalate, obtained by carbon dioxide-mediated precipitation, were mechanistically examined in acid and neutral environment. The matrix effect, modulating the drug dissolution, was characterized with a battery of physicochemical methodologies, including ToF-SIMS for surface composition, SAXS/WAXS and modulated DSC for crystallization characterization, and simultaneous UV-imaging and Raman spectroscopy for monitoring the dissolution process in detail. The hybrid particle formulations investigated consisted of amorphous nilotinib embedded in a polymer matrix in single continuous phase, displaying extended retained amorphicity also under wet conditions. It was demonstrated by Raman and FTIR spectroscopy that the efficient drug dispersion and amorphization in the polymer matrix were mediated by hydrogen bonding between the drug and the phthalate groups on the polymer. Simultaneous Raman and UV-imaging studies of the effect of drug load on the swelling and dissolution of the polymer matrix revealed that high nilotinib load prevented matrix swelling on passage from acid to neutral pH, thereby preventing re-precipitation and re-crystallization of incorporated nilotinib. These findings provide a mechanistic foundation of formulation development of nilotinib and other protein kinase inhibitors, which are now witnessing an intense therapeutic and industrial attention due to the difficulty in formulating these compounds so that efficient oral bioavailability is reached.

  • 14.
    Datta, A.
    et al.
    Bose Inst, Dept Biophys, P-1-12 CIT Scheme 7 M, Kolkata 700054, India.
    Bhattacharyya, D.
    Bose Inst, Dept Biophys, P-1-12 CIT Scheme 7 M, Kolkata 700054, India.
    Singh, Shalini
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ghosh, A.
    Bose Inst, Dept Biophys, P-1-12 CIT Scheme 7 M, Kolkata 700054, India.
    Schmidtchen, A.
    Lund Univ, Div Dermatol & Venereol, Dept Clin Sci, SE-22184 Lund, Sweden.; Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore .
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bhunia, A.
    Bose Inst, Dept Biophys, P-1-12 CIT Scheme 7 M, Kolkata 700054, India.
    Role of Aromatic Amino Acids in Lipopolysaccharide and Membrane Interactions of Antimicrobial Peptides for use in Plant Disease Control2016In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 25, p. 13301-13317Article in journal (Refereed)
    Abstract [en]

    KYE28(KYEITTIHNLFRKLTHRLFRRNFGYTLR), the representative sequence  of helix D of heparin co-factor II, was demonstrated to be potent against agronomically important Gram-negative plant pathogens X. vesicatoria and X. oryzae,capable of inhibiting disease symptoms in detached tomato leaves. NMR studies in presence of lipopolysaccharide provided structural insights into the mechanisms underlying this, notably in relation to outer membrane permeabilisation. The three-dimensional solution structure of KYE28 in LPS is characterised by a N-ter helical segment, an intermediate loop and an extended C-ter. The two termini are in close proximity to each other via aromatic packing interactions, while the positively charged residues formed an exterior polar shell. To further demonstrate the importance of the aromatic residues for this, a mutant peptide KYE28A, with Ala substitutions at F11, F19, F23 and Y25 showed attenuated antimicrobial activity at high salt concentrations, as well as lower membrane disruption and LPS binding abilities compared to KYE28. In contrast to KYE28, KYE28A adopted an opened out helical structure in LPS with extended N- and C-ter and a small break in between the helical segments. Aromatic packing interactions were completely lost, although hydrophobic interaction between the side chains of hydrophobic residues were still partly retained, imparting an amphipathic character and explaining its residual antimicrobial activity and LPS binding as observed from ellipsometry and ITC. We thus present important structural aspects of KYE28, constituting an aromatic zipper, of potential importance, for the development of novel plant protection agents and therapeutic agents.

  • 15.
    Duong, Dinh Thuy
    et al.
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore.
    Singh, Shalini
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bagheri, Mojtaba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Tehran, Inst Biochem & Biophys, Peptide Chem Lab, Tehran 1417614335, Iran..
    Verma, Navin Kumar
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore..
    Schmidtchen, Artur
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore.;Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden..
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pronounced peptide selectivity for melanoma through tryptophan end-tagging2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 24952Article in journal (Refereed)
    Abstract [en]

    Effects of oligotryptophan end-tagging on the uptake of arginine-rich peptides into melanoma cells was investigated under various conditions and compared to that into non-malignant keratinocytes, fibroblasts, and erythrocytes, also monitoring resulting cell toxicity. In parallel, biophysical studies on peptide binding to, and destabilization of, model lipid membranes provided mechanistic insight into the origin of the selectivity between melanoma and non-malignant cells. Collectively, the results demonstrate that W-tagging represents a powerful way to increase selective peptide internalization in melanoma cells, resulting in toxicity against these, but not against the non-malignant cells. These effects were shown to be due to increased peptide adsorption to the outer membrane in melanoma cells, caused by the presence of anionic lipids such as phosphatidylserine and ganglioside GM1, and to peptide effects on mitochondria membranes and resulting apoptosis. In addition, the possibility of using W-tagged peptides for targeted uptake of nanoparticles/drug carriers in melanoma was demonstrated, as was the possibility to open up the outer membrane of melanoma cells in order to facilitate uptake of low Mw anticancer drugs, here demonstrated for doxorubicin.

  • 16. Edström Hagerwall, Anneli M. L.
    et al.
    Rydengard, Victoria
    Fernlund, Per
    Morgelin, Matthias
    Baumgarten, Maria
    Cole, Alexander M.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kragelund, Birthe B.
    Sorensen, Ole E.
    beta-Microseminoprotein Endows Post Coital Seminal Plasma with Potent Candidacidal Activity by a Calcium- and pH-Dependent Mechanism2012In: PLoS Pathogens, ISSN 1553-7366, Vol. 8, no 4, p. e1002625-Article in journal (Refereed)
    Abstract [en]

    The innate immune factors controlling Candida albicans are mostly unknown. Vulvovaginal candidiasis is common in women and affects approximately 70-75% of all women at least once. Despite the propensity of Candida to colonize the vagina, transmission of Candida albicans following sexual intercourse is very rare. This prompted us to investigate whether the post coital vaginal milieu contained factors active against C. albicans. By CFU assays, we found prominent candidacidal activity of post coital seminal plasma at both neutral and the acid vaginal pH. In contrast, normal seminal plasma did not display candidacidal activity prior to acidification. By antifungal gel overlay assay, one clearing zone corresponding to a protein band was found in both post coital and normal seminal plasma, which was subsequently identified as beta-microseminoprotein. At neutral pH, the fungicidal activity of beta-microseminoprotein and seminal plasma was inhibited by calcium. By NMR spectroscopy, amino acid residue E-71 was shown to be critical for the calcium coordination. The acidic vaginal milieu unleashed the fungicidal activity by decreasing the inhibitory effect of calcium. The candidacidal activity of beta-microseminoprotein was mapped to a fragment of the C-terminal domain with no structural similarity to other known proteins. A homologous fragment from porcine beta-microseminoprotein demonstrated calcium-dependent fungicidal activity in a CFU assay, suggesting this may be a common feature for members of the beta-microseminoprotein family. By electron microscopy, beta-microseminoprotein was found to cause lysis of Candida. Liposome experiments demonstrated that beta-microseminoprotein was active towards ergosterol-containing liposomes that mimic fungal membranes, offering an explanation for the selectivity against fungi. These data identify beta-microseminoprotein as an important innate immune factor active against C. albicans and may help explain the low sexual transmission rate of Candida.

  • 17. Eriksson, Jonny
    et al.
    Malmsten, Martin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Tiberg, Fredrik
    Callisen, Thomas H
    Damhus, Ture
    Johansen, Katja S
    Enzymatic degradation of model cellulose films.2005In: J Colloid Interface Sci, ISSN 0021-9797, Vol. 284, no 1, p. 99-106Article in journal (Refereed)
  • 18.
    Eriksson, Jonny
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Tiberg, Fredrik
    Callisen, Thomas H
    Damhus, Ture
    Johansen, Katja S
    Model cellulose films exposed to H. insolens glucoside hydrolase family 45 endo-cellulase--the effect of the carbohydrate-binding module.2005In: J Colloid Interface Sci, ISSN 0021-9797, Vol. 285, no 1, p. 94-9Article in journal (Refereed)
  • 19. Fadeel, B.
    et al.
    Kasemo, B.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Nanomedicine: reshaping clinical practice2010In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 267, no 1, p. 2-8Article in journal (Refereed)
  • 20. Feitosa, Eloi
    et al.
    Adati, Renata D.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Thermal and Structural Behavior of Dioctadecyldimethylammonium Bromide Dispersions Studied by Differential Scanning Calorimetry and X-Ray Scattering2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e44702-Article in journal (Refereed)
    Abstract [en]

    Dioctadecyldimethylammonium bromide (DODAB) is a double chain cationic lipid, which assembles as bilayer structures in aqueous solution. The precise structures formed depend on, e.g., lipid concentration and temperature. We here combine differential scanning calorimetry (DSC) and X-ray scattering (SAXS and WAXS) to investigate the thermal and structural behavior of up to 120 mM DODAB in water within the temperature range 1-70 degrees C. Below 1 mM, this system is dominated by unilamellar vesicles (ULVs). Between 1 and 65 mM, ULVs and multilamellar structures (MLSs) co-exist, while above 65 mM, the MLSs are the preferred structure. Depending on temperature, DSC and X-ray data show that the vesicles can be either in the subgel (SG), gel, or liquid crystalline (LC) state, while the MLSs (with lattice distance d = 36.7 angstrom) consist of interdigitated lamellae in the SG state, and ULVs in the LC state (no Bragg peak). Critical temperatures related to the thermal transitions of these bilayer structures obtained in the heating and cooling modes are reported, together with the corresponding transition enthalpies.

  • 21. Hansen, F.
    et al.
    Kalle, M.
    van der Plas, M. J.
    Stromdahl, A.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Schmidtchen, A.
    The thrombin-derived peptide GKY25 modulates endotoxin-induced responses through direct interactions with macrophages and monocytes2014In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 134, p. S81-S81Article in journal (Other academic)
  • 22.
    Hansen, F.
    et al.
    Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, Lund, Sweden..
    Kalle, M.
    Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, Lund, Sweden..
    van der Plas, M.
    Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, Lund, Sweden..
    Stromdahl, A. -C
    Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, Lund, Sweden..
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Morgelin, M.
    Lund Univ, Div Infect Med, Dept Clin Sci, Lund, Sweden..
    Schmidtchen, A.
    Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, Lund, Sweden.;Nanyang Technol Univ, LKC Med, Dermatol, Singapore 639798, Singapore..
    The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes2015In: Wound Repair and Regeneration, ISSN 1067-1927, E-ISSN 1524-475X, Vol. 23, no 4, p. A11-A11Article in journal (Other academic)
  • 23. Hansen, Finja C.
    et al.
    Kalle-Brune, Martina
    van der Plas, Mariena J. A.
    Stromdahl, Ann-Charlotte
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Morgelin, Matthias
    Schmidtchen, Artur
    The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes2015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 194, no 11, p. 5397-5406Article in journal (Refereed)
    Abstract [en]

    Host defense peptides have recently gained much interest as novel anti-infectives owing to their ability to kill bacteria and simultaneously modulate host cell responses. The cationic host defense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), derived from the C terminus of human thrombin, inhibits proinflammatory responses in vitro and in vivo, but the mode of action is unclear. In this study, we show that GKY25, apart from binding bacterial LPS, also interacts directly with monocytes and macrophages in vitro, ex vivo, and in vivo. Moreover, GKY25 inhibits TLR4-and TLR2-induced NF-kappa B activation in response to several microbe-derived agonists. Furthermore, GKY25 reduces LPS-induced phosphorylation of MAPKs p38 alpha and JNK1/2/3. FACS and electron microscopy analyses showed that GKY25 interferes with TLR4/myeloid differentiation protein-2 dimerization. The results demonstrate a previously undisclosed activity of the host defense peptide GKY25, based on combined LPS and cell interactions leading to inhibition of TLR4 dimerization and subsequent reduction of NF-kappa B activity and proinflammatory cytokine production in monocytes and macrophages.

  • 24.
    Hansson, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bysell, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Månsson, Ronja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Peptide-Microgel Interactions in the Strong Coupling Regime2012In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, no 35, p. 10964-10975Article in journal (Refereed)
    Abstract [en]

    The interaction between lightly cross-linked poly(acrylic acid) microgels and oppositely charged peptides was investigated as a function of peptide length, charge density, pH, and salt concentration, with emphasis on the strong coupling regime at high charge contrast. By micromanipulator-assisted light microscopy, the equilibrium volume response of single microgel particles upon oligolysine and oligo(lysine/alanine) absorption could be monitored in a controlled fashion. Results show that microgel deswelling, caused by peptide binding and network neutralization, increases with peptide length (3 < 5 < 10) and charge density (30% < 50% < 100%). Furthermore, oligomer-induced microgel deswelling was more pronounced at pH 5 than at pH 8, reflecting the lower network charge density in the former case (pK(a) for the isolated acrylic acid approximate to 4.7). In order to describe these highly coupled systems, a model was developed, in which counterion/peptide-mediated electrostatic attraction between the network chains is described using an exponential force law, and the network elasticity by the inverse Langevin theory. The model was used to calculate the composition of microgels in contact with reservoir solutions of peptides and simple electrolytes. At high electrostatic coupling, the calculated swelling curves were found to display first-order phase transition behavior. The model was demonstrated to capture pH- and electrolyte-dependent microgel swelling, as well as effects of peptide length and charge density on microgel deswelling. The analysis demonstrated that the peptide charge (length), rather than the peptide charge density, determines microgel deswelling. Furthermore, a transition between continuous and discrete network collapse was identified, consistent with experimental results in the present investigations, as well as with results from the literature on microgel deswelling caused by multivalent cations.

  • 25.
    Holdbrook, Daniel A.
    et al.
    ASTAR, Bioinforrnat Inst, 30 Biopolis St,07-01 Matrix, Singapore 138671, Singapore.
    Singh, Shalini
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Choong, Yeu Khai
    Nanyang Technol Univ Singapore, Lee Kong Chian Sch Med, 59 Nanyang Dr, Singapore 636921, Singapore.
    Petrlova, Jitka
    Lund Univ, Div Dermatol & Venereol, Dept Clin Sci, SE-22184 Lund, Sweden.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Bond, Peter J.
    ASTAR, Bioinforrnat Inst, 30 Biopolis St,07-01 Matrix, Singapore 138671, Singapore;Natl Univ Singapore, Dept Biol Sci, 14 Sci Dr, Singapore 117543, Singapore.
    Verma, Navin Kumar
    Nanyang Technol Univ Singapore, Lee Kong Chian Sch Med, 59 Nanyang Dr, Singapore 636921, Singapore.
    Schmidtchen, Artur
    Nanyang Technol Univ Singapore, Lee Kong Chian Sch Med, 59 Nanyang Dr, Singapore 636921, Singapore;Lund Univ, Div Dermatol & Venereol, Dept Clin Sci, SE-22184 Lund, Sweden;Bispebjerg Hosp, Wound Healing Ctr, Copenhagen, Denmark.
    Saravanan, Rathi
    Nanyang Technol Univ Singapore, Lee Kong Chian Sch Med, 59 Nanyang Dr, Singapore 636921, Singapore.
    Influence of pH on the activity of thrombin-derived antimicrobial peptides2018In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1860, no 11, p. 2374-2384Article in journal (Refereed)
    Abstract [en]

    The wound environment is characterized by physiological pH changes. Proteolysis of thrombin by wound-derived proteases, such as neutrophil elastase, generates antimicrobial thrombin-derived C-terminal peptides (TCPs), such as HVF18 (HVFRLKKWIQKVIDQFGE). Presence of such TCPs in human wound fluids in vivo, as well as the occurrence of an evolutionarily conserved His residue in the primary amino acid sequence of TCPs, prompted us to investigate the pH-dependent antibacterial action of HVF18, as well as of the prototypic GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE). We show that protonation of this His residue at pH 5.5 increases the antibacterial activity of both TCPs against Gram-negative Escherichia coil by membrane disruption. Physiological salt level (150 mM NaCI) augments antibacterial activity of GKY25 but diminishes for the shorter HVF18. Replacing His with Leu or Ser in GKY25 abolishes the His protonation-dependent increase in antibacterial activity at pH 5.5, whereas substitution with Lys maintains activity at neutral (pH 7.4) and acidic pH. Interestingly, both TCPs display decreased binding affinities to human CD14 with decreasing pH, suggesting a likely switch in mode-of-action, from anti-inflammatory at neutral pH to antibacterial at acidic pH. Together, the results demonstrate that apart from structural prerequisites such as peptide length, charge, and hydrophobicity, the evolutionarily conserved His residue of TCPs influences their antibacterial effects and reveals a previously unknown aspect of TCPs biological action.

  • 26.
    Häffner, Sara Malekkhaiat
    et al.
    Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Influence of self-assembly on the performance of antimicrobial peptides2018In: Current Opinion in Colloid & Interface Science, ISSN 1359-0294, E-ISSN 1879-0399, Vol. 38, p. 56-79Article, review/survey (Refereed)
    Abstract [en]

    With a rapidly growing number of bacterial strains displaying resistance against conventional antibiotics, the development of novel types of antimicrobial agents represents an important health challenge. Antimicrobial peptides (AMPs) has attracted interest in this context, as these can be designed to display potent broad-spectrum antimicrobial as well as antiinflammatory effects, but simultaneously low toxicity against human cells. Much of the work on AMPs has been focused on membrane interactions of monomeric AMPs, and how these can be controlled by peptide design to obtain selective disruption of bacterial membranes. However, a growing body of research has demonstrated that AMPs offer opportunities as antimicrobials beyond this through their self-assembly. An overview is therefore provided of the current understanding of the interplay between AMP aggregation and antimicrobial effects, including the role of oligomerization and self-assembly on membrane interactions and antimicrobial effects, AMP interactions with amyloid-forming peptides/proteins, AMP self assemblies as antimicrobial biomaterials, and AMP-induced flocculation of bacteria and bacterial lipopolysaccharides as a novel pathway for confinement of infection and inflammation.

  • 27.
    Häffner, Sara Malekkhaiat
    et al.
    Univ Copenhagen, Dept Pharm, Wound Healing Ctr, Bispebjerg Hosp, DK-2100 Copenhagen, Denmark.
    Nyström, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Browning, Kathryn L.
    Univ Copenhagen, Dept Pharm, Wound Healing Ctr, Bispebjerg Hosp, DK-2100 Copenhagen, Denmark.
    Nielsen, Hanne Mörck
    Univ Copenhagen, Dept Pharm, Wound Healing Ctr, Bispebjerg Hosp, DK-2100 Copenhagen, Denmark.
    Strömstedt, Adam A.
    Univ Copenhagen, Dept Med Chem, Wound Healing Ctr, Bispebjerg Hosp,Pharmacognosy, DK-2100 Copenhagen, Denmark.
    van der Plas, Mariena J. A.
    Univ Copenhagen, Dept Pharm, Wound Healing Ctr, Bispebjerg Hosp, DK-2100 Copenhagen, Denmark;Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden.
    Schmidtchen, Artur
    Univ Copenhagen, Dept Biomed Sci, Wound Healing Ctr, Bispebjerg Hosp, DK-2100 Copenhagen, Denmark;Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, Wound Healing Ctr, Bispebjerg Hosp, DK-2100 Copenhagen, Denmark.
    Interaction of Laponite with Membrane Components - Consequences for Bacterial Aggregation and Infection Confinement2019In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 11, no 17, p. 15389-15400Article in journal (Refereed)
    Abstract [en]

    The antimicrobial effects of Laponite nano particles with or without loading of the antimicrobial peptide LL-37 was investigated along with their membrane interactions. The study combines data from ellipsometry, circular dichroism, fluorescence spectroscopy, particle size/zeta potential measurements, and confocal microscopy. As a result of the net negative charge of Laponite, loading of net positively charged LL-37 increases with increasing pH. The peptide was found to bind primarily to the outer surface of the Laponite nanoparticles in a predominantly helical conformation, leading to charge reversal. Despite their net positive charge, peptide-loaded Laponite nanoparticles did not kill Gram-negative Escherichia coli bacteria or disrupt anionic model liposomes. They did however cause bacteria flocculation, originating from the interaction of Laponite and bacterial lipopolysaccharide (LPS). Free LL-37, in contrast, is potently antimicrobial through membrane disruption but does not induce bacterial aggregation in the concentration range investigated. Through LL-37 loading of Laponite nanoparticles, the combined effects of bacterial flocculation and membrane lysis are observed. However, bacteria aggregation seems to be limited to Gram-negative bacteria as Laponite did not cause flocculation of Gram-positive Bacillus subtilis bacteria nor did it bind to lipoteichoic acid from bacterial envelopes. Taken together, the present investigation reports several novel phenomena by demonstrating that nanoparticle charge does not invariably control membrane destabilization and by identifying the ability of anionic Laponite nanoparticles to effectively flocculate Gram-negative bacteria through LPS binding. As demonstrated in cell experiments, such aggregation results in diminished LPS-induced cell activation, thus outlining a promising approach for confinement of infection and inflammation caused by such pathogens.

  • 28. Jesson, Gerald
    et al.
    Brisander, Magnus
    Andersson, Per
    Demirbuker, Mustafa
    Derand, Helene
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Carbon Dioxide-Mediated Generation of Hybrid Nanoparticles for Improved Bioavailability of Protein Kinase Inhibitors2014In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 31, no 3, p. 694-705Article in journal (Refereed)
    Abstract [en]

    A versatile methodology is demonstrated for improving dissolution kinetics, gastrointestinal (GI) absorption, and bioavailability of protein kinase inhibitors (PKIs). The approach is based on nanoparticle precipitation by sub- or supercritical CO2 together with a matrix-forming polymer, incorporating surfactants either during or after nanoparticle formation. Notably, striking synergistic effects between hybrid PKI/polymer nanoparticles and surfactant added after particle formation is investigated. The hybrid nanoparticles, consisting of amorphous PKI embedded in a polymer matrix (also after 12 months), display dramatically increased release rate of nilotinib in both simulated gastric fluid and simulated intestinal fluid, particularly when surfactants are present on the hybrid nanoparticle surface. Similar results indicated flexibility of the approach regarding polymer identity, drug load, and choice of surfactant. The translation of the increased dissolution rate found in vitro into improved GI absorption and bioavalilability in vivo was demonstrated for male beagle dogs, where a 730% increase in the AUC(0-24h) was observed compared to the benchmark formulation. Finally, the generality of the formulation approach taken was demonstrated for a range of PKIs. Hybrid nanoparticles combined with surfactant represent a promising approach for improving PKI dissolution rate, providing increased GI absorption and bioavailability following oral administration.

  • 29.
    Jing, Xiaona
    et al.
    Univ Copenhagen, Dept Pharm, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen O, Denmark..
    Foged, Camilla
    Univ Copenhagen, Dept Pharm, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen O, Denmark..
    Martin-Bertelsen, Birte
    Univ Copenhagen, Dept Pharm, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen O, Denmark..
    Yaghmur, Anan
    Univ Copenhagen, Dept Pharm, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen O, Denmark..
    Knapp, Kolja M.
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen O, Denmark..
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Franzyk, Henrik
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen O, Denmark..
    Nielsen, Hanne M.
    Univ Copenhagen, Dept Pharm, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen O, Denmark..
    Delivery of siRNA Complexed with Palmitoylated alpha-Peptide/beta-Peptoid Cell-Penetrating Peptidomimetics: Membrane Interaction and Structural Characterization of a Lipid-Based Nanocarrier System2016In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 6, p. 1739-1749Article in journal (Refereed)
    Abstract [en]

    Proteolytically stable alpha-peptide/beta-peptoid peptidomimetics constitute promising cell-penetrating carrier candidates exhibiting superior cellular uptake as compared to commonly used cell-penetrating peptides (CPPs). The aim of the present study was to explore the potential of these peptidomimetics for delivery of small interfering RNA (siRNA) to the cytosol by incorporation of a palmitoylated peptidomimetic construct into a cationic lipid-based nanocarrier system. The optimal construct was selected on the basis of the effect of palmitoylation and the influence of the length of the peptidomimetic on the interaction with model membranes and the cellular uptake. Palmitoylation enhanced the peptidomimetic adsorption to supported lipid bilayers as studied by ellipsometry. However, both palmitoylation and increased peptidomimetic chain length were found to be beneficial in the cellular uptake studies using fluorophore-labeled analogues. Thus, the longer palmitoylated peptidomimetic was chosen for further formulation of siRNA in a dioleoylphosphatidylethanolamine/cholesteryl hemisuccinate (DOPE/CHEMS) nanocarrier system, and the resulting nanoparticles were found to mediate efficient gene silencing in vitro. Cryo-transmission electron microscopy (cryo-TEM) revealed multilamellar, onion-like spherical vesicles, and small-angle X-ray scattering (SAXS) analysis confirmed that the majority of the lipids in the nanocarriers were organized in lamellar structures, yet coexisted with a hexagonal phase, which is important for efficient nanocarrier-mediated endosomal escape of siRNA ensuring cytosolic delivery. The present work is a proof-of-concept for the use of alpha-peptides/beta-peptoid peptidomimetics in an efficient delivery system that may be more generally exploited for the intracellular delivery of biomacromolecular drugs.

  • 30. Jing, Xiaona
    et al.
    Kasimova, Marina R.
    Simonsen, Anders H.
    Jorgensen, Lene
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Franzyk, Henrik
    Foged, Camilla
    Nielsen, Hanne M.
    Interaction of Peptidomimetics with Bilayer Membranes: Biophysical Characterization and Cellular Uptake2012In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 28, no 11, p. 5167-5175Article in journal (Refereed)
    Abstract [en]

    Enzymatically stable cell-penetrating alpha-peptide/beta-peptoid peptidomimetics constitute promising drug delivery vehicles for the transport of therapeutic biomacromolecules across membrane barriers. The aim of the present study was to elucidate the mechanism of peptidomimetic-lipid bilayer interactions. A series of peptidomimetics consisting of alternating cationic and hydrophobic residues displaying variation in length and N-terminal end group were applied to fluid-phase, anionic lipid bilayers, and their interaction was investigated using isothermal titration calorimetry (ITC) and ellipsometry. Titration of lipid vesicles into solutions of peptidomimetics resulted in exothermic adsorption processes, and the interaction of all studied peptidomimetics with anionic lipid membranes was found to be enthalpy-driven. The enthalpy and Gibbs free energy (Delta G) proved more favorable with increasing chain length. However, not all charges contribute equally to the interaction, as evidenced by the charge-normalized Delta G being inversely correlated to the sequence length. Ellipsometry data suggested that the hydrophobic residues also played an important role in the interaction process. Furthermore, Delta G extracted from ellipsometry data showed good agreement with that obtained with ITC. To further elucidate their interaction with biological membranes, quantitative uptake and cellular distribution were studied in proliferating HeLa cells by flow cytometry and confocal microscopy. The cellular uptake of carboxyfluorescein-labeled peptidomimetics showed a similar ranking as that obtained from the adsorbed amount, and binding energy to model membranes demonstrated that the initial interaction with the membrane is of key importance for the cellular uptake.

  • 31. Jing, Xiaona
    et al.
    Yang, Mingjun
    Kasimova, Marina R.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Franzyk, Henrik
    Jorgensen, Lene
    Foged, Camilla
    Nielsen, Hanne M.
    Membrane adsorption and binding, cellular uptake and cytotoxicity of cell-penetrating peptidomimetics with alpha-peptide/beta-peptoid backbone: Effects of hydrogen bonding and alpha-chirality in the beta-peptoid residues2012In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1818, no 11, p. 2660-2668Article in journal (Refereed)
    Abstract [en]

    Cell-penetrating peptides (CPPs) provide a promising approach for enhancing intracellular delivery of therapeutic biomacromolecules by increasing transport through membrane barriers. Here, proteolytically stable cell-penetrating peptidomimetics with alpha-peptide/beta-peptoid backbone were studied to evaluate the effect of alpha-chirality in the beta-peptoid residues and the presence of guanidinium groups in the alpha-amino acid residues on membrane interaction. The molecular properties of the peptidomimetics in solution (surface and intramolecular hydrogen bonding, aqueous diffusion rate and molecular size) were studied along with their adsorption to lipid bilayers, cellular uptake, and toxicity. The surface hydrogen bonding ability of the peptidomimetics reflected their adsorbed amounts onto lipid bilayers as well as with their cellular uptake, indicating the importance of hydrogen bonding for their membrane interaction and cellular uptake. Ellipsometry studies further demonstrated that the presence of chiral centers in the beta-peptoid residues promotes a higher adsorption to anionic lipid bilayers, whereas circular dichroism results showed that alpha-chirality influences their overall mean residue ellipticity. The presence of guanidinium groups and alpha-chiral beta-peptoid residues was also found to have a significant positive effect on uptake in living cells. Together, the findings provide an improved understanding on the behavior of cell-penetrating peptidomimetics in the presence of lipid bilayers and live cells.

  • 32.
    Johansson, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Interaction between lysozyme and poly(acrylic acid) microgels2007In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 316, no 2, p. 350-359Article in journal (Refereed)
    Abstract [en]

    The interaction between lysozyme and oppositely charged poly(acrylic acid) microgels was investigated by micromanipulator-assisted light microscopy, confocal microscopy and circular dichroism. Lysozyme uptake and distribution within the microgel particles, and its effect on microgel deswelling, was studied regarding effects of pH, ionic strength and lysozyme concentration. For a range of conditions, lysozyme distributes nonuniformly within the microgels, forming a lysozyme/microgel shell in the outer parts of the microgel. This shell formation is associated both with increased lysozyme loading to the microgels and with increased lysozyme-induced microgel deswelling. At high microgel charge density, the shell formation displays nonmonotonic ionic strength dependence. The shells formed are characterized by a net positive charge, and by relatively fast exchange of lysozyme between shell and solution, although the exchange kinetics decreases strongly with decreasing ionic strength. At conditions of slower exchange kinetics, the shells are characterized by an effective pore size of less than about 4 nm.

  • 33. Kacprzyk, Lukasz
    et al.
    Rydengård, Victoria
    Mörgelin, Matthias
    Davoudi, Mina
    Pasupuleti, Mukesh
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Schmidtchen, Artur
    Antimicrobial activity of histidine-rich peptides is dependent on acidic conditions2007In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1768, no 11, p. 2667-2680Article in journal (Refereed)
    Abstract [en]

    Synthetic peptides composed of multiples of the consensus heparin-binding Cardin and Weintraub sequences AKKARA and ARKKAAKA are antimicrobial. Replacement of lysine and arginine by histidine in these peptides completely abrogates their antimicrobial and heparin-binding activities at neutral pH. However, the antibacterial activity against Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) as well as the fungus Candida albicans, was restored at acidic conditions (pH 5.5). Fluorescence microscopy and FACS analysis showed that the binding of the histidine-rich peptides to E. coli and Candida was significantly enhanced at pH 5.5. Likewise, fluorescence studies for assessment of membrane permeation as well as electron microscopy analysis of peptide-treated bacteria, paired with studies of peptide effects on liposomes, demonstrated that the peptides induce membrane lysis only at acidic pH. No discernible hemolysis was noted for the histidine-rich peptides. Similar pH-dependent antimicrobial activities were demonstrated for peptides derived from histidine-rich and heparin-binding regions of human kininogen and histidine-rich glycoprotein. The results demonstrate that the presence of art acidic environment is an important regulator of the activity of histidine-rich antimicrobial peptides.

  • 34. Kalle, M.
    et al.
    Papareddy, P.
    Kasetty, G.
    Morgelin, M.
    van der Plas, M. J. A.
    Rydengard, V.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Albiger, B.
    Schmidtchen, A.
    Treatment of endotoxin-mediated shock and Pseudomonas aeruginosa sepsis with thrombin-derived host defense peptides2013In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 303, no S1, p. 45-46Article in journal (Other academic)
  • 35. Kalle, Martina
    et al.
    Papareddy, Praveen
    Kasetty, Gopinath
    Morgelin, Matthias
    van der Plas, Mariena J. A.
    Rydengard, Victoria
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Albiger, Barbara
    Schmidtchen, Artur
    Host Defense Peptides of Thrombin Modulate Inflammation and Coagulation in Endotoxin-Mediated Shock and Pseudomonas aeruginosa Sepsis2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e51313-Article in journal (Refereed)
    Abstract [en]

    Gram-negative sepsis is accompanied by a disproportionate innate immune response and excessive coagulation mainly induced by endotoxins released from bacteria. Due to rising antibiotic resistance and current lack of other effective treatments there is an urgent need for new therapies. We here present a new treatment concept for sepsis and endotoxin-mediated shock, based on host defense peptides from the C-terminal part of human thrombin, found to have a broad and inhibitory effect on multiple sepsis pathologies. Thus, the peptides abrogate pro-inflammatory cytokine responses to endotoxin in vitro and in vivo. Furthermore, they interfere with coagulation by modulating contact activation and tissue factor-mediated clotting in vitro, leading to normalization of coagulation responses in vivo, a previously unknown function of host defense peptides. In a mouse model of Pseudomonas aeruginosa sepsis, the peptide GKY25, while mediating a modest antimicrobial effect, significantly inhibited the pro-inflammatory response, decreased fibrin deposition and leakage in the lungs, as well as reduced mortality. Taken together, the capacity of such thrombin-derived peptides to simultaneously modulate bacterial levels, pro-inflammatory responses, and coagulation, renders them attractive therapeutic candidates for the treatment of invasive infections and sepsis. Citation: Kalle M, Papareddy P, Kasetty G, Morgelin M, van der Plas MJA, et al. (2012) Host Defense Peptides of Thrombin Modulate Inflammation and Coagulation in Endotoxin-Mediated Shock and Pseudomonas aeruginosa Sepsis.

  • 36. Kalle, Martina
    et al.
    Papareddy, Praveen
    Kasetty, Gopinath
    Tollefsen, Douglas M.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Morgelin, Matthias
    Schmidtchen, Artur
    Proteolytic Activation Transforms Heparin Cofactor II into a Host Defense Molecule2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, no 12, p. 6303-6310Article in journal (Refereed)
    Abstract [en]

    The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity.

  • 37. Kalle, Martina
    et al.
    Papareddy, Praveen
    Kasetty, Gopinath
    van der Plas, Mariena J. A.
    Morgelin, Matthias
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Schmidtchen, Artur
    A Peptide of Heparin Cofactor II Inhibits Endotoxin-Mediated Shock and Invasive Pseudomonas aeruginosa Infection2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e102577-Article in journal (Refereed)
    Abstract [en]

    Sepsis and septic shock remain important medical problems with high mortality rates. Today's treatment is based mainly on using antibiotics to target the bacteria, without addressing the systemic inflammatory response, which is a major contributor to mortality in sepsis. Therefore, novel treatment options are urgently needed to counteract these complex sepsis pathologies. Heparin cofactor II (HCII) has recently been shown to be protective against Gram-negative infections. The antimicrobial effects were mapped to helices A and D of the molecule. Here we show that KYE28, a 28 amino acid long peptide representing helix D of HCII, is antimicrobial against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungus Candida albicans. Moreover, KYE28 binds to LPS and thereby reduces LPS-induced pro-inflammatory responses by decreasing NF-kappa B/AP-1 activation in vitro. In mouse models of LPS-induced shock, KYE28 significantly enhanced survival by dampening the pro-inflammatory cytokine response. Finally, in an invasive Pseudomonas infection model, the peptide inhibited bacterial growth and reduced the pro-inflammatory response, which lead to a significant reduction of mortality. In summary, the peptide KYE28, by simultaneously targeting bacteria and LPS-induced pro-inflammatory responses represents a novel therapeutic candidate for invasive infections.

  • 38. Kapilashrami, A
    et al.
    Eskilsson, K
    Bergström, L
    Malmsten, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Effects of oil viscosity and substrate energy on drying of diluted O/W2004In: Emulsions Colloids Surf A, Vol. 233, p. 155-Article in journal (Refereed)
  • 39. Kilsgard, Ola
    et al.
    Andersson, Pia
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nordin, Sara L.
    Linge, Helena M.
    Eliasson, Mette
    Sorenson, Eva
    Erjefalt, Jonas S.
    Bylund, Johan
    Olin, Anders I.
    Sorensen, Ole E.
    Egesten, Arne
    Peptidylarginine Deiminases Present in the Airways during Tobacco Smoking and Inflammation Can Citrullinate the Host Defense Peptide LL-37, Resulting in Altered Activities2012In: American Journal of Respiratory Cell and Molecular Biology, ISSN 1044-1549, E-ISSN 1535-4989, Vol. 46, no 2, p. 240-248Article in journal (Refereed)
    Abstract [en]

    Bacterial colonization of the lower respiratory tract is frequently seen in chronic obstructive pulmonary disease (COPD), and may cause exacerbations leading to disease progression. Antimicrobial peptides comprise an important part of innate lung immunity, and not least the cathelicidin human cationic antimicrobial protein-18/LL-37. Peptidylarginine deiminases (PADIs) post-translationally modify proteins by converting cationic peptidylarginine residues to neutral peptidylcitrulline. An increased presence of PADI2 and citrullinated proteins was demonstrated in the lungs of smokers. In this study, preformed PADI4, stored in granulocytes and extracellularly in the lumina of bronchi, was found in lung tissue of individuals suffering from COPD. In vitro, recombinant human PADI2 and PADI4 both caused a time-and dose-dependent citrullination of LL-37. The citrullination resulted in impaired antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, and nontypable Haemophilus influenzae, but less so against Pseudomonas aeruginosa. Using artificial lipid bilayers, we observed discrete differences when comparing the disrupting activity of native and citrullinated LL-37, suggesting that differences in cell wall composition are important during interactions with whole bacteria. Furthermore, citrullinated LL-37 showed higher chemotactic activity against mononuclear leukocytes than did native LL-37, but was less efficient at neutralizing lipolysaccharide, and also in converting apoptotic neutrophils into a state of secondary necrosis. In addition, citrullinated LL-37 was more prone to degradation by proteases, whereas the V8 endopetidase of S. aureus cleaved the modified peptide at additional sites, compared with native LL-37. Together, these findings demonstrate novel mechanisms whereby the inflammation-dependent deiminases PADI2 and PADI4 can alter the activites of antibacterial polypeptides, affecting the course of inflammatory disorders such as COPD.

  • 40.
    Malekkhaiat Häffner, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark..
    Malmsten, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark.;Uppsala Univ, Dept Pharm, POB 580, SE-75123 Uppsala, Sweden..
    Membrane interactions and antimicrobial effects of inorganic nanoparticles2017In: Advances in Colloid and Interface Science, ISSN 0001-8686, E-ISSN 1873-3727, Vol. 248, p. 105-128Article in journal (Refereed)
    Abstract [en]

    Interactions between nanoparticles and biological membranes are attracting increasing attention in current nanomedicine, and play a key role both for nanotoxicology and for utilizing nanomaterials in diagnostics, drug delivery, functional biomaterials, as well as combinations of these, e.g., in theranostics. In addition, there is considerable current interest in the use of nanomaterials as antimicrobial agents, motivated by increasing resistance development against conventional antibiotics. Here, various nanomaterials offer opportunities for triggered functionalites to combat challenging infections. Although the performance in these diverse applications is governed by a complex interplay between the nanomaterial, the properties of included drugs (if any), and the biological system, nanoparticle-membrane interactions constitute a key initial step and play a key role for the subsequent biological response. In the present overview, the current understanding of inorganic nanomaterials as antimicrobial agents is outlined, with special focus on the interplay between antimicrobial effects and membrane interactions, and how membrane interactions and antimicrobial effects of such materials depend on nano particle properties, membrane composition, and external (e.g., light and magnetic) fields.

  • 41.
    Malekkhaiat Häffner, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark..
    Nyström, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nordström, Randi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Xu, Z. P.
    Univ Queensland, Australian Inst Bioengn & Nanotechnol, St Lucia, Qld 4072, Australia..
    Davoudi, M.
    Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden..
    Schmidtchen, A.
    Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden.;Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore..
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark..
    Membrane interactions and antimicrobial effects of layered double hydroxide nanoparticles2017In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 19, no 35, p. 23832-23842Article in journal (Refereed)
    Abstract [en]

    Membrane interactions are critical for the successful use of inorganic nanoparticles as antimicrobial agents and as carriers of, or co-actives with, antimicrobial peptides (AMPs). In order to contribute to an increased understanding of these, we here investigate effects of particle size (42-208 nm) on layered double hydroxide (LDH) interactions with both bacteria-mimicking and mammalian-mimicking lipid membranes. LDH binding to bacteria-mimicking membranes, extraction of anionic lipids, as well as resulting membrane destabilization, was found to increase with decreasing particle size, also translating into size-dependent synergistic effects with the antimicrobial peptide LL-37. Due to strong interactions with anionic lipopolysaccharide and peptidoglycan layers, direct membrane disruption of both Gram-negative and Gram-positive bacteria is suppressed. However, LDH nanoparticles cause size-dependent charge reversal and resulting flocculation of both liposomes and bacteria, which may provide a mechanism for bacterial confinement or clearance. Taken together, these findings demonstrate a set of previously unknown behaviors, including synergistic membrane destabilization and dual confinement/killing of bacteria through combined LDH/AMP exposure, of potential therapeutic interest.

  • 42.
    Malmsten, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Soft drug delivery systems2006In: Soft Matter, Vol. 2, p. 760-Article in journal (Refereed)
  • 43.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Antimicrobial peptides2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 199-204Article, review/survey (Refereed)
    Abstract [en]

    With increasing antibiotics resistance, there is an urgent need for novel infection therapeutics. Since antimicrobial peptides provide opportunities for this, identification and optimization of such peptides have attracted much interest during recent years. Here, a brief overview of antimicrobial peptides is provided, with focus placed on how selected hydrophobic modifications of antimicrobial peptides can be employed to combat also more demanding pathogens, including multi-resistant strains, without conferring unacceptable toxicity.

  • 44.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Inorganic nanomaterials as delivery systems for proteins, peptides, DNA, and siRNA2013In: Current Opinion in Colloid & Interface Science, ISSN 1359-0294, E-ISSN 1879-0399, Vol. 18, no 5, p. 468-480Article, review/survey (Refereed)
    Abstract [en]

    With large current interest in nanomedicine, there has been rapid progress during the last couple of years in the understanding of opportunities offered by advanced materials in diagnostics, drug delivery, functional biomaterials, and biosensors, as well as combinations of these, e.g., theranostics. In the present overview, focus is placed on drug delivery aspects of inorganic nanomaterials, notably as carriers for proteins, peptides, DNA, and siRNA. Throughout, an attempt is made to illustrate how structure and interactions affect loading and release of such biomacromolecular drugs in various inorganic delivery systems, and how this translates into functional advantages.

  • 45.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Interactions of Antimicrobial Peptides with Bacterial Membranes and Membrane Components2015In: Current Topics in Medicinal Chemistry, ISSN 1568-0266, E-ISSN 1873-4294, Vol. 16, no 1, p. 16-24Article, review/survey (Refereed)
    Abstract [en]

    Antimicrobial peptides (AMPs) have attracted considerable recent interest as potential therapeutics, motivated by increasing resistance development against conventional antibiotics. This brief overview summarizes some key aspects related to the interaction of AMPs with bacterial and cell membranes, as well as with membrane components, which is at the core of the mode-of-action of these compounds. Throughout, studies on peptide interactions with model lipid membranes and membrane components are correlated to biological results on antimicrobial and anti-inflammatory effects of AMPs, and translated into therapeutic considerations.

  • 46.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Phase transformations in self-assembly systems for drug delivery applications2007In: Journal of Dispersion Science and Technology, ISSN 0193-2691, E-ISSN 1532-2351, Vol. 28, no 1, p. 63-72Article in journal (Refereed)
    Abstract [en]

    This brief review aims at providing some illustrative examples on the use of self-assembly structures formed by surfactants, (polar) lipids, and (block) copolymers in drug delivery, with particular focus placed on how phase transformations in such systems may offer functional opportunities in relation to drug administration.

  • 47.
    Malmsten, Martin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Davoudi, Mina
    Schmidtchen, Artur
    Bacterial killing by heparin-binding peptides from PRELP and thrombospondin.2006In: Matrix Biol, ISSN 0945-053X, Vol. 25, no 5, p. 294-300Article in journal (Refereed)
  • 48.
    Malmsten, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Davoudi, Mina
    Walse, Björn
    Rydengård, Victoria
    Pasupuleti, Mukesh
    Mörgelin, Matthias
    Schmidtchen, Artur
    Antimicrobial peptides derived from growth factors2007In: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 25, no 1, p. 60-70Article in journal (Refereed)
    Abstract [en]

    Growth factors, comprising diverse protein and peptide families, are involved in a multitude of developmental processes, including embryogenesis, angiogenesis, and wound healing. Here we show that peptides derived from HB-EGF, amphiregulin, hepatocyte growth factor, PDGF-A and PDGF-B, as well as various FGFs are antimicrobial, demonstrating a previously unknown activity of growth factor-derived peptides. The peptides killed the Gram-negative bacteria Escherichia coli, Pseudomonas aeruginosa, and the Gram-positive Bacillus subtilis, as well as the fungus Candida albicans. Several peptides were also active against the Gram-positive S. aureus. Electron microscopy analysis of peptide-treated bacteria, paired with analysis of peptide effects on liposomes, showed that the peptides exerted membrane-breaking effects similar to those seen after treatment with the “classical” human antimicrobial peptide LL-37. Furthermore, HB-EGF was antibacterial per se, and its epitope GKRKKKGKGLGKKRDPCLRKYK retained its activity in presence of physiological salt and plasma. No discernible hemolysis was noted for the growth factor-derived peptides. Besides providing novel templates for design of peptide-based antimicrobials, our findings demonstrate a previously undisclosed link between the family of growth factors and antimicrobial peptides, both of which are induced during tissue remodelling and repair.

  • 49.
    Malmsten, Martin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Kassner, Ursula
    Winkler, Karl
    Schmidt, Annette
    Buddecke, Eckhart
    Saunders, Ramsey
    Siegel, Günter
    An ellipsometry-based Alzheimer plaque mimic: Effect of beta-amyloid, lipoprotein identity and apolipoprotein E isoform.2004In: J Colloid Interface Sci, ISSN 0021-9797, Vol. 276, no 2, p. 503-6Article in journal (Refereed)
  • 50.
    Malmsten, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Schmidtchen, Artur
    Antimicrobial C3a - Biology, biophysics, and evolution2007In: Current Topics in Innate Immunity: Candida-Albicans. Complement-System, Antibacterial Peptides, Human Neutrophil, Component C3, Anaphylatoxin, Membranes, Proteins, Sequence, Immunity, Springer Berlin/Heidelberg, 2007, Vol. 598, p. 141-158Chapter in book (Other academic)
123 1 - 50 of 116
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