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  • 1.
    Björn, Camilla
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik.
    Mahlapuu, M.
    Mattsby-Baltzer, I.
    Håkansson, Joakim
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik.
    Anti-infective efficacy of the lactoferrin-derived antimicrobial peptide HLR1r2016In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 81, p. 21-28Article in journal (Refereed)
    Abstract [en]

    Antimicrobial peptides (AMPs) have emerged as a new class of drug candidates for the treatment of infectious diseases. Here we describe a novel AMP, HLR1r, which is structurally derived from the human milk protein lactoferrin and demonstrates a broad spectrum microbicidal action in vitro. The minimum concentration of HLR1r needed for killing ≥99% of microorganisms in vitro, was in the range of 3-50 μg/ml for common Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and for the yeast Candida albicans, when assessed in diluted brain-heart infusion medium. We found that HLR1r also possesses anti-inflammatory properties as evidenced by inhibition of tumor necrosis factor alpha (TNF-α) secretion from human monocyte-derived macrophages and by repression of interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) secretion from human mesothelial cells, without any cytotoxic effect observed at the concentration range tested (up to 400 μg/ml). HLR1r demonstrated pronounced anti-infectious effect in in vivo experimental models of cutaneous candidiasis in mice and of excision wounds infected with MRSA in rats as well as in an ex vivo model of pig skin infected with S. aureus. In conclusion, HLR1r may constitute a new therapeutic alternative for local treatment of skin infections.

  • 2.
    Boge, Lukas
    et al.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science. Department of Chemical and Chemical Engineering, Applied Chemistry, Chalmers University of Technology.
    Bysell, Helena
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Ringstad, Lovisa
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Wennman, David
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Process Development, Analys och fastfas.
    Umerska, A.
    Cassisa, V.
    Eriksson, J.
    Joly-Guillou, M. -L
    Edwards, K.
    Andersson, M.
    Lipid-based liquid crystals as carriers for antimicrobial peptides: Phase behavior and antimicrobial effect2016In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 32, no 17, p. 4217-4228Article in journal (Refereed)
    Abstract [en]

    The number of antibiotic-resistant bacteria is increasing worldwide, and the demand for novel antimicrobials is constantly growing. Antimicrobial peptides (AMPs) could be an important part of future treatment strategies of various bacterial infection diseases. However, AMPs have relatively low stability, because of proteolytic and chemical degradation. As a consequence, carrier systems protecting the AMPs are greatly needed, to achieve efficient treatments. In addition, the carrier system also must administrate the peptide in a controlled manner to match the therapeutic dose window. In this work, lyotropic liquid crystalline (LC) structures consisting of cubic glycerol monooleate/water and hexagonal glycerol monooleate/oleic acid/water have been examined as carriers for AMPs. These LC structures have the capability of solubilizing both hydrophilic and hydrophobic substances, as well as being biocompatible and biodegradable. Both bulk gels and discrete dispersed structures (i.e., cubosomes and hexosomes) have been studied. Three AMPs have been investigated with respect to phase stability of the LC structures and antimicrobial effect: AP114, DPK-060, and LL-37. Characterization of the LC structures was performed using small-angle X-ray scattering (SAXS), dynamic light scattering, ζ-potential, and cryogenic transmission electron microscopy (Cryo-TEM) and peptide loading efficacy by ultra performance liquid chromatography. The antimicrobial effect of the LCNPs was investigated in vitro using minimum inhibitory concentration (MIC) and time-kill assay. The most hydrophobic peptide (AP114) was shown to induce an increase in negative curvature of the cubic LC system. The most polar peptide (DPK-060) induced a decrease in negative curvature while LL-37 did not change the LC phase at all. The hexagonal LC phase was not affected by any of the AMPs. Moreover, cubosomes loaded with peptides AP114 and DPK-060 showed preserved antimicrobial activity, whereas particles loaded with peptide LL-37 displayed a loss in its broad-spectrum bactericidal properties. AMP-loaded hexosomes showed a reduction in antimicrobial activity.

  • 3. Colombo, S.
    et al.
    Brisander, M.
    Haglöf, J.
    Sjövall, Peter
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik.
    Andersson, P.
    Østergaard, J.
    Malmsten, M.
    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. 205-217, article id 15114Article 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.

  • 4.
    Kuna, V K
    et al.
    University of Gothenburg, Sweden.
    Padma, A M
    University of Gothenburg, Sweden.
    Håkansson, Joakim
    RISE - Research Institutes of Sweden, Bioscience and Materials, Chemistry and Materials.
    Nygren, J
    TATAA Biocenter, Sweden.
    Sjöback, R
    TATAA Biocenter, Sweden.
    Petronis, Sarunas
    RISE - Research Institutes of Sweden, Bioscience and Materials, Chemistry and Materials.
    Sumitran-Holgersson, S
    University of Gothenburg, Sweden.
    Significantly accelerated wound healing of full-thickness skin using a novel composite gel of porcine acellular dermal matrix and human peripheral blood cells2017In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 2, p. 293-307Article in journal (Refereed)
    Abstract [en]

    Herein, we report the fabrication of a novel composite gel from decellularized gal-gal-knockout porcine skin and human peripheral blood mononuclear cells (hPBMC) for full-thickness skin wound healing. Decellularized skin extracellular matrix (ECM) powder was prepared via chemical treatment, freeze-drying and homogenization. The powder was mixed with culture medium containing hyaluronic acid to generate a pig skin gel (PSG). The effect of the gel in regeneration of full-thickness wound was studied in nude mice. We found significantly accelerated wound closure already on day 15 in animals treated with PSG only or PSG+hPBMC as compared to untreated and hyaluronic acid treated controls (p<0.05). Addition of the hPBMC to the gel resulted in marked increase of host blood vessels as well as the presence of human blood vessels. At day 25, histologically, the wounds in animals treated with PSG only or PSG+hPBMC were completely closed as compared to controls. Thus, the gel facilitated generation of new skin with well arranged epidermal cells and restored bilayer structure of the epidermis and dermis. These results suggest that porcine skin ECM gel together with human cells may be a novel and promising biomaterial for medical applications especially for patients with acute and chronic skin wounds.

  • 5. Mahlapuu, Margit
    et al.
    Håkansson, Joakim
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik.
    Ringstad, Lovisa
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Björn, Camilla
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik. The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg.
    Antimicrobial peptides: An emerging category of therapeutic agents2016In: Frontiers in Cellular and Infection Microbiology, Vol. 6, no DEC, article id 194Article in journal (Refereed)
    Abstract [en]

    Antimicrobial peptides (AMPs), also known as host defense peptides, are short and generally positively charged peptides found in a wide variety of life forms from microorganisms to humans. Most AMPs have the ability to kill microbial pathogens directly, whereas others act indirectly by modulating the host defense systems. Against a background of rapidly increasing resistance development to conventional antibiotics all over the world, efforts to bring AMPs into clinical use are accelerating. Several AMPs are currently being evaluated in clinical trials as novel anti-infectives, but also as new pharmacological agents to modulate the immune response, promote wound healing, and prevent post-surgical adhesions. In this review, we provide an overview of the biological role, classification, and mode of action of AMPs, discuss the opportunities and challenges to develop these peptides for clinical applications, and review the innovative formulation strategies for application of AMPs.

  • 6. Matougui, N.
    et al.
    Boge, Lukas
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Groo, A. -C
    Umerska, A.
    Ringstad, Lovisa
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Bysell, Helena
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Saulnier, P.
    Lipid-based nanoformulations for peptide delivery2016In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 502, no 1-2, p. 80-97Article, review/survey (Refereed)
    Abstract [en]

    Nanoformulations have attracted a lot of attention because of their size-dependent properties. Among the array of nanoformulations, lipid nanoformulations (LNFs) have evoked increasing interest because of the advantages of their high degree of biocompatibility and versatility. The performance of lipid nanoformulations is greatly influenced by their composition and structure. Therapeutic peptides represent a growing share of the pharmaceutical market. However, the main challenge for their development into commercial products is their inherent physicochemical and biological instability. Important peptides such as insulin, calcitonin and cyclosporin A have been incorporated into LNFs. The association or encapsulation of peptides within lipid-based carriers has shown to protect the labile molecules against enzymatic degradation. This review describes strategies used for the formulation of peptides and some methods used for the assessment of association efficiency. The advantages and drawbacks of such carriers are also described.

  • 7. Nyström, L.
    et al.
    Nordström, R.
    Bramhill, J.
    Saunders, B. R.
    Álvarez-Asencio, R.
    Rutland, Mark W.
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science. Department of Surface and Corrosion Science, School of Chemical Science and Engineering, KTH Royal Institute of Technology.
    Malmsten, M.
    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.

  • 8. Stensen, Wenche
    et al.
    Turner, Rob
    Brown, Marc
    Kondori, Nahid
    Svendsen, John Sigurd
    Svenson, Johan
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik.
    Short cationic antimicrobial peptides display superior antifungal activities toward Candidiasis and Onychomycosis in comparison with Terbinafine and Amorolfine2016In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392Article in journal (Refereed)
    Abstract [en]

    Novel antifungals are in high demand due to the challenges associated with resistant, persistent, and systemic fungal infections. Synthetic mimics of antimicrobial peptides are emerging as a promising class of compounds for antifungal treatment. In the current study, five synthetic cationic antimicrobial tripeptides were evaluated as antifungal therapeutics against 24 pathogenic strains of fungi. Three of the peptides displayed strong general antifungal properties at low micromolar inhibitory concentrations. The most promising peptide, compound 5, was selected and evaluated as an antifungal remedy for Candida albicans candidiasis in a human skin model and for the treatment of Trichophyton rubrum induced onychomycosis in an infected human nail model. Compound 5 was shown to display antifungal properties and a rapid mode of action superior to those of both the commercial comparators Loceryl and Lamisil. Compound 5 was also active against a clinical isolate of Candida albicans with acquired fluconazole resistance.

  • 9. Svagan, A. J.
    et al.
    Benjamins, Jan-Willem
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Al-Ansari, Z.
    Shalom, D. B.
    Müllertz, A.
    Wågberg, L.
    Löbmann, K.
    Solid cellulose nanofiber based foams – Towards facile design of sustained drug delivery systems2016In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 244, p. 74-82Article in journal (Refereed)
    Abstract [en]

    Control of drug action through formulation is a vital and very challenging topic within pharmaceutical sciences. Cellulose nanofibers (CNF) are an excipient candidate in pharmaceutical formulations that could be used to easily optimize drug delivery rates. CNF has interesting physico-chemical properties that, when combined with surfactants, can be used to create very stable air bubbles and dry foams. Utilizing this inherent property, it is possible to modify the release kinetics of the model drug riboflavin in a facile way. Wet foams were prepared using cationic CNF and a pharmaceutically acceptable surfactant (lauric acid sodium salt). The drug was suspended in the wet-stable foams followed by a drying step to obtain dry foams. Flexible cellular solid materials of different thicknesses, shapes and drug loadings (up to 50 wt%) could successfully be prepared. The drug was released from the solid foams in a diffusion-controlled, sustained manner due to the presence of intact air bubbles which imparted a tortuous diffusion path. The diffusion coefficient was assessed using Franz cells and shown to be more than one order of magnitude smaller for the cellular solids compared to the bubble-free films in the wet state. By changing the dimensions of dry foams while keeping drug load and total weight constant, the drug release kinetics could be modified, e.g. a rectangular box-shaped foam of 8 mm thickness released only 59% of the drug after 24 h whereas a thinner foam sample (0.6 mm) released 78% of its drug content within 8 h. In comparison, the drug release from films (0.009 mm, with the same total mass and an outer surface area comparable to the thinner foam) was much faster, amounting to 72% of the drug within 1 h. The entrapped air bubbles in the foam also induced positive buoyancy, which is interesting from the perspective of gastroretentive drug-delivery.

  • 10.
    Svenson, Johan
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik.
    På jakt efter nya läkemedel i Ishavet2016In: Naturvetare, ISSN 2000-2424, Vol. 6, p. 24-28Article in journal (Other (popular science, discussion, etc.))
    Abstract [sv]

    Ungefär en tredjedel av alla läkemedel har sin källai naturen. Forskaren Johan Svenson skriver självom sin expedition i Arktis, där forskarna samlar inalger och andra organismer i sökandet efter nyamolekyler, som till exempel kan bli ny antibiotika.

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