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  • 1.
    Boge, Lukas
    et al.
    RISE Res Inst Sweden, S-50115 Boras, Sweden;Chalmers Univ Technol, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden.
    Browning, Kathryn L.
    Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Nordström, Randi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Campana, Mario
    Rutherford Appleton Lab, Didcot OX11 0DE, Oxon, England.
    Darngaard, Liv S. E.
    Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Caous, Josefin Seth
    RISE Res Inst Sweden, S-50115 Boras, Sweden.
    Hellsing, Maja
    RISE Res Inst Sweden, S-50115 Boras, Sweden.
    Ringstad, Lovisa
    RISE Res Inst Sweden, S-50115 Boras, Sweden.
    Andersson, Martin
    Chalmers Univ Technol, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden.
    Peptide-Loaded Cubosomes Functioning as an Antimicrobial Unit against Escherichia coil2019In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 11, no 24, p. 21314-21322Article in journal (Refereed)
    Abstract [en]

    Dispersions of cubic liquid crystalline phases, also known as cubosomes, have shown great promise as delivery vehicles for a wide range of medicines. Due to their ordered structure, comprising alternating hydrophilic and hydrophobic domains, cubosomes possess unique delivery properties and compatibility with both water-soluble and-insoluble drugs. However, the drug delivery mechanism and cubosome interaction with human cells and bacteria are still poorly understood. Herein, we reveal how cubosomes loaded with the human cathelicidin antimicrobial peptide LL-37, a system with high bacteria-killing effect, interact with the bacterial membrane and provide new insights into the eradication mechanism. Combining the advanced experimental techniques neutron reflectivity and quartz crystal microbalance with dissipation monitoring, a mechanistic drug delivery model for LL-37-loaded cubosomes on bacterial mimicking bilayers was constructed. Moreover, the cubosome interaction with Escherichia coli was directly visualized using super-resolution laser scanning microscopy and cryogenic electron tomography. We could conclude that cubosomes loaded with LL-37 adsorbed and distorted bacterial membranes, providing evidence that the peptide-loaded cubosomes function as an antimicrobial unit.

  • 2.
    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.

  • 3.
    Nordström, Randi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Polymeric Nanoparticles as Carriers for Antimicrobial Peptides: Factors Affecting Peptide and Membrane Interactions2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    As resistance towards conventional antibiotics is becoming more pronounced, cationic antimicrobial peptides (AMPs) have received considerable attention as possible therapeutic alternatives. Thousands of potent AMPs occur in humans, animals, plants and fungi as a natural part of the immune system. However, there are several challenges with AMP therapeutics related to formulation and delivery. Examples include proteolytic sensitivity and serum protein binding, resulting in quick degradation, loss of activity and clearance. Therefore, it is important to find a suitable drug delivery system to meet these protection and delivery challenges. Micro-/nanogels are loosely crosslinked polymer colloids with high water content that can be made to trigger at a wide range of stimuli. They have shown promise as delivery systems for AMPs, as the aqueous environment they create allows the peptides to maintain their natural conformation, while their gel networks offer protection and triggered release. This thesis aims towards expanding the knowledge about degradable and non-degradable pH-responsive micro-/nanogels as carriers for AMPs.

    The results in this thesis show that factors relating to the drug delivery system (degradability, charge and crosslinker density), the surrounding media (pH and ionic strength) and the peptide properties (length, charge, PEGylation) all affect the peptide loading to, protection, release from and effect of AMP-loaded gels. Studies of the interaction of AMP-loaded microgels with bacteria-modelling liposomes and lipid bilayers have verified peptide effect after gel incorporation, as further demonstrated by in vitro studies on several bacterial strains. Neutron reflectometry provided detailed mechanistic information on the interaction between AMP-loaded gels and bacteria-modelling lipid bilayers, showing that the antimicrobial unit is the released peptide. All gels showed low, promising hemolysis and some gels could offer protection against proteolytic degradation of AMPs.

    In summary, non-degradable and degradable micro-/nanogels are versatile and interesting candidates as AMP carriers. Small changes in the gel composition or the AMP used can dramatically change the peptide loading, release and effect. It is therefore necessary to carefully consider and evaluate the optimal carrier for every AMP and the application at hand.

    List of papers
    1. Factors Affecting Peptide Interactions with Surface-Bound Microgels
    Open this publication in new window or tab >>Factors Affecting Peptide Interactions with Surface-Bound Microgels
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    2016 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 17, no 2, p. 669-678Article in journal (Refereed) Published
    Abstract [en]

    Effects of electrostatics and peptide size on peptide interactions with surface-bound microgels were investigated with ellipsometry, confocal microscopy, and atomic force microscopy (AFM). Results show that binding of cationic poly-l-lysine (pLys) to anionic, covalently immobilized, poly(ethyl acrylate-co-methacrylic acid) microgels increased with increasing peptide net charge and microgel charge density. Furthermore, peptide release was facilitated by decreasing either microgel or peptide charge density. Analogously, increasing ionic strength facilitated peptide release for short peptides. As a result of peptide binding, the surface-bound microgels displayed pronounced deswelling and increased mechanical rigidity, the latter quantified by quantitative nanomechanical mapping. While short pLys was found to penetrate the entire microgel network and to result in almost complete charge neutralization, larger peptides were partially excluded from the microgel network, forming an outer peptide layer on the microgels. As a result of this difference, microgel flattening was more influenced by the lower Mw peptide than the higher. Peptide-induced deswelling was found to be lower for higher Mw pLys, the latter effect not observed for the corresponding microgels in the dispersed state. While the effects of electrostatics on peptide loading and release were similar to those observed for dispersed microgels, there were thus considerable effects of the underlying surface on peptide-induced microgel deswelling, which need to be considered in the design of surface-bound microgels as carriers of peptide loads, for example, in drug delivery or in functionalized biomaterials.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2016
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-278894 (URN)10.1021/acs.biomac.5b01616 (DOI)000369875900029 ()26750986 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2016-02-26 Created: 2016-02-26 Last updated: 2019-10-12Bibliographically approved
    2. Membrane interactions of microgels as carriers of antimicrobial peptides
    Open this publication in new window or tab >>Membrane interactions of microgels as carriers of antimicrobial peptides
    Show others...
    2018 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 513, p. 141-150Article in journal (Refereed) Published
    Abstract [en]

    Microgels are interesting as potential delivery systems for antimicrobial peptides. In order to elucidate membrane interactions of such systems, we here investigate effects of microgel charge density on antimicrobial peptide loading and release, as well as consequences of this for membrane interactions and antimicrobial effects, using ellipsometry, circular dichroism spectroscopy, nanoparticle tracking analysis, dynamic light scattering and z-potential measurements. Anionic poly(ethyl acrylate-co-methacrylic acid) microgels were found to incorporate considerable amounts of the cationic antimicrobial peptides LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) and DPK-060 (GKHKNKGKKNGKHNGWKWWW) and to protect incorporated peptides from degradation by infection-related proteases at high microgel charge density. As a result of their net negative z-potential also at high peptide loading, neither empty nor peptide-loaded microgels adsorb at supported bacteria-mimicking membranes. Instead, membrane disruption is mediated almost exclusively by peptide release. Mirroring this, antimicrobial effects against several clinically relevant bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa) were found to be promoted by factors facilitating peptide release, such as decreasing peptide length and decreasing microgel charge density. Microgels were further demonstrated to display low toxicity towards erythrocytes. Taken together, the results demonstrate some interesting opportunities for the use of microgels as delivery systems for antimicrobial peptides, but also highlight several key factors which need to be controlled for their successful use.

    Place, publisher, year, edition, pages
    ACADEMIC PRESS INC ELSEVIER SCIENCE, 2018
    Keywords
    Antimicrobial peptide, Drug delivery, Lipid membrane, Microgel
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-351759 (URN)10.1016/j.jcis.2017.11.014 (DOI)000428834900015 ()29145017 (PubMedID)
    Funder
    EU, FP7, Seventh Framework Programme, 604182
    Available from: 2018-05-31 Created: 2018-05-31 Last updated: 2019-10-12Bibliographically approved
    3. Membrane Interactions of Antimicrobial Peptide-Loaded Microgels
    Open this publication in new window or tab >>Membrane Interactions of Antimicrobial Peptide-Loaded Microgels
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    antimicrobial peptide, bilayer, membrane, microgel, neutron reflectometry
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-395109 (URN)
    Available from: 2019-10-12 Created: 2019-10-12 Last updated: 2019-10-12
    4. Microgels as carriers of antimicrobial peptides – effects of peptide PEGylation
    Open this publication in new window or tab >>Microgels as carriers of antimicrobial peptides – effects of peptide PEGylation
    Show others...
    2019 (English)In: Colloids and Surfaces A: Physicochemical and Engineering Aspects, ISSN 0927-7757, E-ISSN 1873-4359, Vol. 565, p. 8-15Article in journal (Refereed) Published
    Abstract [en]

    Delivery systems are likely to be central for the translation of antimicrobial peptides (AMPs) towards therapeutics. Addressing AMP interactions with microgel carriers, we here investigate how poly(ethylene glycol) conjugation ('PEGylation') of AMPs affect their loading and release to/from microgels, combining structural studies using nuclear magnetic resonance (NMR) with ellipsometry, circular dichroism spectroscopy (CD), and light scattering. Such studies demonstrate that poly(ethyl acrylate-co-methacrylic acid) microgels bind considerable amounts of the positively charged AMP KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR) and its PEGylated variants KYE28-PEG48, PEG48-KYE28, and PEG24-KYE28-PEG24. Z-potential measurements indicate that KYE28 resides primarily inside the microgel core, and that localization of the PEGylated peptides is shifted towards the microgel corona. Furthermore, while all peptides are disordered in solution, CD measurements report on helix induction on microgel binding, particularly so for the PEGylated peptides. Addressing such conformational changes in more detail, NMR structural studies showed that peptide-microgel interactions are facilitated by a hydrophobic domain formed by the peptide after microgel binding, and with modulating electrostatic/salt bridge interaction between the positively charged peptide residues and negative microgel charges. As the microgels remain negatively charged also at high peptide load, membrane disruption and antimicrobial effects necessitates peptide release, demonstrated to be promoted by PEGylation and high ionic strength. Importantly, microgel loading, as well as peptide localization, conformation, and release, did not depend significantly on PEG conjugation site, but instead seems to be dictated by the PEG content of the peptide conjugates.

    Keywords
    Antimicrobial peptide, Drug delivery, Microgel, NMR, PEGylation
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-361401 (URN)10.1016/j.colsurfa.2018.12.049 (DOI)000457062300002 ()
    Funder
    Swedish Research Council, 2012-1842Swedish Research Council, 2015-06720
    Available from: 2018-09-24 Created: 2018-09-24 Last updated: 2019-10-12Bibliographically approved
    5. Degradable dendritic nanogels as carriers for antimicrobial peptides
    Open this publication in new window or tab >>Degradable dendritic nanogels as carriers for antimicrobial peptides
    Show others...
    2019 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 554, p. 592-602Article in journal (Refereed) Published
    Abstract [en]

    In the present study, we investigate degradable anionic dendritic nanogels (DNG) as carriers for antimicrobial peptides (AMPs). In such systems, the dendritic part contains carboxylic acid-based anionic binding sites for cationic AMPs, whereas linear poly(ethylene glycol) (PEG) chains form a shell for promotion of biological stealth. In order to clarify factors influencing membrane interactions of such systems, we here address effects of nanogel charge, cross-linking, and degradation on peptide loading/release, as well as consequences of these factors for lipid membrane interactions and antimicrobial effects. The DNGs were found to bind the AMPs LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) and DPK-060 (GKHKNKGKKNGKHNGWKWWW). For the smaller DPK-060 peptide, loading was found to increase with increasing nanogel charge density. For the larger LL-37, on the other hand, peptide loading was largely insensitive to nanogel charge density. In line with this, results on the secondary structure, as well as on the absence of stabilization from proteolytic degradation by the nanogels, show that the larger LL-37 is unable to enter into the interior of the nanogels. While 40–60% nanogel degradation occurred over 10 days, promoted at high ionic strength and lower cross-linking density/higher anionic charge content, peptide release at physiological ionic strength was substantially faster, and membrane destabilization not relying on nanogel degradation. Ellipsometry and liposome leakage experiments showed both free peptide and peptide/DNG complexes to cause membrane destabilization, indicated also by antimicrobial activities being comparable for nanogel-bound and free peptide. Finally, the DNGs were demonstrated to display low toxicity towards erythrocytes even at peptide concentrations of 100 µM.

    Keywords
    Antimicrobial peptide, Degradable, Dendritic, Hyperbranched, drug delivery, Membrane, Nanogel
    National Category
    Pharmaceutical Sciences Physical Chemistry
    Research subject
    Pharmaceutical Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-389746 (URN)10.1016/j.jcis.2019.07.028 (DOI)000487346200061 ()31330426 (PubMedID)
    Funder
    Swedish Research Council, 2016-05157Swedish Research Council, 2017-02341EU, FP7, Seventh Framework Programme, 604182
    Available from: 2019-07-23 Created: 2019-07-23 Last updated: 2019-11-01Bibliographically approved
  • 4.
    Nordström, Randi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Andrén, Oliver C.J.
    Kungliga Tekniska Högskolan.
    Singh, Shalini
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malkoch, Michael
    Kungliga Tekniska Högskolan.
    Davoudi, Mina
    Lunds universitet.
    Schmidtchen, Artur
    Lunds universitet; Köpenhamns universitet.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Department of Pharmacy, University of Copenhagen.
    Degradable dendritic nanogels as carriers for antimicrobial peptides2019In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 554, p. 592-602Article in journal (Refereed)
    Abstract [en]

    In the present study, we investigate degradable anionic dendritic nanogels (DNG) as carriers for antimicrobial peptides (AMPs). In such systems, the dendritic part contains carboxylic acid-based anionic binding sites for cationic AMPs, whereas linear poly(ethylene glycol) (PEG) chains form a shell for promotion of biological stealth. In order to clarify factors influencing membrane interactions of such systems, we here address effects of nanogel charge, cross-linking, and degradation on peptide loading/release, as well as consequences of these factors for lipid membrane interactions and antimicrobial effects. The DNGs were found to bind the AMPs LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) and DPK-060 (GKHKNKGKKNGKHNGWKWWW). For the smaller DPK-060 peptide, loading was found to increase with increasing nanogel charge density. For the larger LL-37, on the other hand, peptide loading was largely insensitive to nanogel charge density. In line with this, results on the secondary structure, as well as on the absence of stabilization from proteolytic degradation by the nanogels, show that the larger LL-37 is unable to enter into the interior of the nanogels. While 40–60% nanogel degradation occurred over 10 days, promoted at high ionic strength and lower cross-linking density/higher anionic charge content, peptide release at physiological ionic strength was substantially faster, and membrane destabilization not relying on nanogel degradation. Ellipsometry and liposome leakage experiments showed both free peptide and peptide/DNG complexes to cause membrane destabilization, indicated also by antimicrobial activities being comparable for nanogel-bound and free peptide. Finally, the DNGs were demonstrated to display low toxicity towards erythrocytes even at peptide concentrations of 100 µM.

  • 5. Nordström, Randi
    et al.
    Browning, Kathryn
    Parra-Ortiz, Elisa
    Dangaard, Liv Sofia Elinor
    Malekkhaiat-Häffner, Sara
    Maestro, Armando
    Campbell, Richard A.
    Cooper, Joshaniel F. K.
    Malmsten, Martin
    Membrane Interactions of Antimicrobial Peptide-Loaded MicrogelsManuscript (preprint) (Other academic)
  • 6.
    Nordström, Randi
    et al.
    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. Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark..
    Delivery systems for antimicrobial peptides2017In: Advances in Colloid and Interface Science, ISSN 0001-8686, E-ISSN 1873-3727, Vol. 242, p. 17-34Article in journal (Refereed)
    Abstract [en]

    Due to rapidly increasing resistance development against conventional antibiotics, finding novel approaches for the treatment of infections has emerged as a key health issue. Antimicrobial peptides (AMPs) have attracted interest in this context, and there is by now a considerable literature on the identification such peptides, as well as on their optimization to reach potent antimicrobial and anti-inflammatory effects at simultaneously low toxicity against human cells. In comparison, delivery systems for antimicrobial peptides have attracted considerably less interest. However, such delivery systems are likely to play a key role in the development of potent and safe AMP based therapeutics, e.g., through reducing chemical or biological degradation of AMPs either in the formulation or after administration, by reducing adverse side-effects, by controlling AMP release rate, by promoting biofilm penetration, or through achieving co-localization with intracellular pathogens. Here, an overview is provided of the current understanding of delivery systems for antimicrobial peptides, with special focus on AMP-carrier interactions, as well as consequences of these interactions for antimicrobial and related biological effects of AMP-containing formulations.

  • 7.
    Nordström, Randi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nyström, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Andren, Oliver C. J.
    Royal Inst Technol, Dept Fibre & Polymer Technol, SE-10044 Stockholm, Sweden..
    Malkoch, Michael
    Royal Inst Technol, Dept Fibre & Polymer Technol, SE-10044 Stockholm, Sweden..
    Umerska, Anita
    Univ Bretagne Loire, CNRS 6021, INSERM U1066, Univ Angers,MINT, Angers, France..
    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..
    Malmsten, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark..
    Membrane interactions of microgels as carriers of antimicrobial peptides2018In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 513, p. 141-150Article in journal (Refereed)
    Abstract [en]

    Microgels are interesting as potential delivery systems for antimicrobial peptides. In order to elucidate membrane interactions of such systems, we here investigate effects of microgel charge density on antimicrobial peptide loading and release, as well as consequences of this for membrane interactions and antimicrobial effects, using ellipsometry, circular dichroism spectroscopy, nanoparticle tracking analysis, dynamic light scattering and z-potential measurements. Anionic poly(ethyl acrylate-co-methacrylic acid) microgels were found to incorporate considerable amounts of the cationic antimicrobial peptides LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) and DPK-060 (GKHKNKGKKNGKHNGWKWWW) and to protect incorporated peptides from degradation by infection-related proteases at high microgel charge density. As a result of their net negative z-potential also at high peptide loading, neither empty nor peptide-loaded microgels adsorb at supported bacteria-mimicking membranes. Instead, membrane disruption is mediated almost exclusively by peptide release. Mirroring this, antimicrobial effects against several clinically relevant bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa) were found to be promoted by factors facilitating peptide release, such as decreasing peptide length and decreasing microgel charge density. Microgels were further demonstrated to display low toxicity towards erythrocytes. Taken together, the results demonstrate some interesting opportunities for the use of microgels as delivery systems for antimicrobial peptides, but also highlight several key factors which need to be controlled for their successful use.

  • 8.
    Nordström, Randi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Ms, Dept Pharm, Uppsala, Sweden.
    Nyström, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Andren, Oliver
    Royal Inst Technol KTH, Stockholm, Sweden.
    Malkoch, Michael
    Royal Inst Technol KTH, Stockholm, Sweden.
    Umerska, Anita
    MINT Univ Angers, Angers, France.
    Davoudi, Mina
    Lund Univ, Dept Clin Sci, Lund, Sweden.
    Schmidtchen, Artur
    Lund Univ, Dept Clin Sci, Lund, Sweden.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Poly(acrylic acid) microgels as carriers for antimicrobial peptides2018In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 255Article in journal (Other academic)
  • 9.
    Nordström, Randi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nyström, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ilyas, Humaira
    Bose Insitute, Kolkata, India.
    Atreya, Hanudatta S
    Indian Insitute of Science, Bangalore, India.
    Borro, Bruno C
    University of Copenhagen, Copenhagen, Denmark.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Microgels as carriers of antimicrobial peptides – effects of peptide PEGylation2019In: Colloids and Surfaces A: Physicochemical and Engineering Aspects, ISSN 0927-7757, E-ISSN 1873-4359, Vol. 565, p. 8-15Article in journal (Refereed)
    Abstract [en]

    Delivery systems are likely to be central for the translation of antimicrobial peptides (AMPs) towards therapeutics. Addressing AMP interactions with microgel carriers, we here investigate how poly(ethylene glycol) conjugation ('PEGylation') of AMPs affect their loading and release to/from microgels, combining structural studies using nuclear magnetic resonance (NMR) with ellipsometry, circular dichroism spectroscopy (CD), and light scattering. Such studies demonstrate that poly(ethyl acrylate-co-methacrylic acid) microgels bind considerable amounts of the positively charged AMP KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR) and its PEGylated variants KYE28-PEG48, PEG48-KYE28, and PEG24-KYE28-PEG24. Z-potential measurements indicate that KYE28 resides primarily inside the microgel core, and that localization of the PEGylated peptides is shifted towards the microgel corona. Furthermore, while all peptides are disordered in solution, CD measurements report on helix induction on microgel binding, particularly so for the PEGylated peptides. Addressing such conformational changes in more detail, NMR structural studies showed that peptide-microgel interactions are facilitated by a hydrophobic domain formed by the peptide after microgel binding, and with modulating electrostatic/salt bridge interaction between the positively charged peptide residues and negative microgel charges. As the microgels remain negatively charged also at high peptide load, membrane disruption and antimicrobial effects necessitates peptide release, demonstrated to be promoted by PEGylation and high ionic strength. Importantly, microgel loading, as well as peptide localization, conformation, and release, did not depend significantly on PEG conjugation site, but instead seems to be dictated by the PEG content of the peptide conjugates.

  • 10.
    Nordström, Randi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nyström, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Saunders, Brian
    Univ Manchester, Manchester, Lancs, England.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Responsive nanogels as carriers for antimicrobial peptides2017In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 253Article in journal (Other academic)
  • 11.
    Nyström, Lina
    et al.
    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.
    Bramhill, Jane
    Univ Manchester, Manchester, Lancs, England.
    Saunders, Brian
    Univ Manchester, Manchester, Lancs, England.
    Alvarez-Asencio, Ruben
    KTH Royal Inst Technol, Sch Chem Sci & Engn, Dept Surface & Corros Sci, Stockholm, Sweden;IMDEA Nanosci, Inst Adv Studies, Madrid, Spain.
    Rutland, Mark
    KTH Royal Inst Technol, Sch Chem Sci & Engn, Dept Surface & Corros Sci, Stockholm, Sweden;SP Tech Res Inst Sweden, SP Chem Mat & Surfaces, Stockholm, Sweden.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, Copenhagen, Denmark.
    Peptide-loaded microgels as carriers of antimicrobial peptides2018In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 255Article in journal (Other academic)
  • 12.
    Nyström, Lina
    et al.
    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.
    Bramhill, Jane
    Manchester University.
    Saunders, Brian R
    Manchester University.
    Álvarez-Asencio, Rubén
    KTH.
    Rutland, Mark W
    KTH.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Factors Affecting Peptide Interactions with Surface-Bound Microgels2016In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 17, no 2, p. 669-678Article in journal (Refereed)
    Abstract [en]

    Effects of electrostatics and peptide size on peptide interactions with surface-bound microgels were investigated with ellipsometry, confocal microscopy, and atomic force microscopy (AFM). Results show that binding of cationic poly-l-lysine (pLys) to anionic, covalently immobilized, poly(ethyl acrylate-co-methacrylic acid) microgels increased with increasing peptide net charge and microgel charge density. Furthermore, peptide release was facilitated by decreasing either microgel or peptide charge density. Analogously, increasing ionic strength facilitated peptide release for short peptides. As a result of peptide binding, the surface-bound microgels displayed pronounced deswelling and increased mechanical rigidity, the latter quantified by quantitative nanomechanical mapping. While short pLys was found to penetrate the entire microgel network and to result in almost complete charge neutralization, larger peptides were partially excluded from the microgel network, forming an outer peptide layer on the microgels. As a result of this difference, microgel flattening was more influenced by the lower Mw peptide than the higher. Peptide-induced deswelling was found to be lower for higher Mw pLys, the latter effect not observed for the corresponding microgels in the dispersed state. While the effects of electrostatics on peptide loading and release were similar to those observed for dispersed microgels, there were thus considerable effects of the underlying surface on peptide-induced microgel deswelling, which need to be considered in the design of surface-bound microgels as carriers of peptide loads, for example, in drug delivery or in functionalized biomaterials.

  • 13.
    Nyström, Lina
    et al.
    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.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Saunders, Brian
    Univ Manchester, Manchester, Lancs, England.
    Alvarez-Asencio, Ruben
    KTH Royal Inst Technol, Dept Surface & Corros Sci, Stockholm, Sweden.
    Rutland, Mark
    KTH Royal Inst Technol, Dept Surface & Corros Sci, Stockholm, Sweden.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Peptide loaded microgels as antimicrobial surface coatings2017In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 253Article in journal (Other academic)
  • 14.
    Nyström, Lina
    et al.
    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.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Saunders, Brian
    Univ Manchester, Manchester, Lancs, England.
    Alvarez-Asencio, Ruben
    KTH, Div Surface Corros Chem, Stockholm, Sweden.
    Rutland, Mark
    KTH, Div Surface Corros Chem, Stockholm, Sweden.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Peptide-loaded microgels as antimicrobial surface coatings2018In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 255Article in journal (Other academic)
  • 15.
    Parra-Ortiz, Elisa
    et al.
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Browning, Kathryn L.
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Damgaard, Liv S. E.
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Nordström, Randi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Micciulla, Samantha
    Inst Laue Langevin, F-38000 Grenoble, France.
    Bucciarelli, Saskia
    Univ Copenhagen, Dept Drug Design & Pharmacol, 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.
    Effects of oxidation on the physicochemical properties of polyunsaturated lipid membranes2019In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 538, p. 404-419Article in journal (Refereed)
    Abstract [en]

    The exposure of biological membranes to reactive oxygen species (ROS) plays an important role in many pathological conditions such as inflammation, infection, or sepsis. ROS also modulate signaling processes and produce markers for damaged tissue. Lipid peroxidation, mainly affecting polyunsaturated phospholipids, results in a complex mixture of oxidized products, which may dramatically alter membrane properties. Here, we have employed a set of biophysical and surface-chemical techniques, including neutron and X-ray scattering, to study the structural, compositional, and stability changes due to oxidative stress on phospholipid bilayers composed of lipids with different degrees of polyunsaturation. In doing so, we obtained real-time information about bilayer degradation under in situ UV exposure using neutron reflectometry. We present a set of interrelated physicochemical effects, including gradual increases in area per molecule, head group and acyl chain hydration, as well as bilayer thinning, lateral phase separation, and defect formation leading to content loss upon membrane oxidation. Such effects were observed to depend on the presence of polyunsaturated phospholipids in the lipid membrane, suggesting that these may also play a role in the complex oxidation processes occurring in cells.

  • 16.
    Zhang, Yuning
    et al.
    KTH Royal Inst Technol, Dept Fibre & Polymer Technol, SE-10044 Stockholm, Sweden.
    Andren, Oliver C. J.
    KTH Royal Inst Technol, Dept Fibre & Polymer Technol, SE-10044 Stockholm, Sweden.
    Nordström, Randi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Fan, Yanmiao
    KTH Royal Inst Technol, Dept Fibre & Polymer Technol, SE-10044 Stockholm, Sweden.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mongkhontreerat, Surinthra
    Sweden Polymer Factory Sweden AB, SE-11428 Stockholm, Sweden.
    Malkoch, Michael
    KTH Royal Inst Technol, Dept Fibre & Polymer Technol, SE-10044 Stockholm, Sweden.
    Off-Stoichiometric Thiol-Ene Chemistry to Dendritic Nanogel Therapeutics2019In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 29, no 18, article id 1806693Article in journal (Refereed)
    Abstract [en]

    A novel platform of dendritic nanogels is herein presented, capitalizing on the self-assembly of allyl-functional polyesters based on dendritic-linear-dendritic amphiphiles followed by simple cross-linking with complementary monomeric thiols via UV initiated off-stoichiometric thiol-ene chemistry. The facile approach enabled multigram creation of allyl reactive nanogel precursors, in the size range of 190-295 nm, being readily available for further modifications to display a number of core functionalities while maintaining the size distribution and characteristics of the master batch. The nanogels are evaluated as carriers of a spread of chemotherapeutics by customizing the core to accommodate each individual cargo. The resulting nanogels are biocompatible, displaying diffusion controlled release of cargo, maintained therapeutic efficacy, and decreased cargo toxic side effects. Finally, the nanogels are found to successfully deliver pharmaceuticals into a 3D pancreatic spheroids tumor model.

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