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  • 1. Ekdahl, Kristina N.
    et al.
    Davoodpour, Padideh
    Ekstrand-Hammarström, Barbro
    Fromell, Karin
    Hamad, Osama A.
    Hong, Jaan
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Division of CBRN Defence and Security, Swedish Defence Research Agency, Umeå, Sweden.
    Mohlin, Camilla
    Seisenbaeva, Gulaim A.
    Kessler, Vadim G.
    Nilsson, Bo
    Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of alpha-Fe2O3 nanoparticles2018In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 14, no 3, p. 735-744Article in journal (Refereed)
    Abstract [en]

    Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. α-Fe2O3 NPs were synthesized, characterized and tested in a model for toxicity utilizing human whole blood without added anticoagulant. MALDI-TOF of the corona was performed and activation markers for plasma cascade systems (complement, contact and coagulation systems), platelet consumption and release of growth factors, MPO, and chemokine/cytokines from blood cells were analyzed. The coronas formed on the pristine α-Fe2O3 NPs contained contact system proteins and they induced massive activation of the contact (kinin/kallikrein) system, as well as thrombin generation, platelet activation, and release of two pro-angiogeneic growth factors: platelet-derived growth factor and vascular endothelial growth factor, whereas complement activation was unaffected. The α-Fe2O3 NPs exhibited a noticeable toxicity, with kinin/kallikrein activation, which may be associated with hypotension and long-term angiogenesis in vivo, with implications for cancer, arteriosclerosis and pulmonary disease.

  • 2. Kumar, Abhinav
    et al.
    Bicer, Elif Melis
    Morgan, Anna Babin
    Pfeffer, Paul E.
    Monopoli, Marco
    Dawson, Kenneth A.
    Eriksson, Jonny
    Edwards, Katarina
    Lynham, Steven
    Arno, Matthew
    Behndig, Annelie F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Somers, Graham
    Hassall, Dave
    Dailey, Lea Ann
    Forbes, Ben
    Mudway, Ian S.
    Enrichment of immunoregulatory proteins in the biomolecular corona of nanoparticles within human respiratory tract lining fluid2016In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 12, no 4, p. 1033-1043Article in journal (Refereed)
    Abstract [en]

    When inhaled nanoparticles deposit in the lungs, they transit through respiratory tract lining fluid (RTLF) acquiring a biomolecular corona reflecting the interaction of the RTLF with the nanomaterial surface. Label-free snapshot proteomics was used to generate semiquantitative profiles of corona proteins formed around silica (SiO2) and poly(vinyl) acetate (PVAc) nanoparticles in RTLF, the latter employed as an archetype drug delivery vehicle. The evolved PVAc corona was significantly enriched compared to that observed on SiO2 nanoparticles (698 vs. 429 proteins identified); however both coronas contained a substantial contribution from innate immunity proteins, including surfactant protein A, napsin A and complement (C1q and C3) proteins. Functional protein classification supports the hypothesis that corona formation in RTLF constitutes opsonisation, preparing particles for phagocytosis and clearance from the lungs. These data highlight how an understanding of the evolved corona is necessary for the design of inhaled nanomedicines with acceptable safety and tailored clearance profiles. From the Clinical Editor: Inhaled nanoparticles often acquire a layer of protein corona while they go through the respiratory tract. Here, the authors investigated the identity of these proteins. The proper identification would improve the understanding of the use of inhaled nanoparticles in future therapeutics. (C) 2016 Published by Elsevier Inc.

  • 3. Kumar, Abhinav
    et al.
    Bicer, Elif Melis
    Pfeffer, Paul
    Monopoli, Marco P.
    Dawson, Kenneth A.
    Eriksson, Jonny
    Edwards, Katarina
    Lynham, Steven
    Arno, Matthew
    Behndig, Annelie F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Somers, Graham
    Hassall, Dave
    Dailey, Lea Ann
    Forbes, Ben
    Mudway, Ian
    Differences in the coronal proteome acquired by particles depositing in the lungs of asthmatic versus healthy humans2017In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 13, no 8, p. 2517-2521Article in journal (Refereed)
    Abstract [en]

    Most inhaled nanomedicines in development are for the treatment of lung disease, yet little is known about their interaction with the respiratory tract lining fluids (RTLFs). Here we combined the use of nano-silica, as a protein concentrator, with label-free snapshot proteomics (LC-MS/MS; key findings confirmed by ELISA) to generate a quantitative profile of the RTLF proteome and provided insight into the evolved corona; information that may be used in future to improve drug targeting to the lungs by inhaled medicines. The asthmatic coronal proteome displayed a reduced contribution of surfactant proteins (SP-A and B) and a higher contribution of alpha 1-antitrypsin. Pathway analysis suggested that asthmatic RTLFs may also be deficient in proteins related to metal handling (e.g. lactoferrin). This study demonstrates how the composition of the corona acquired by inhaled nanoparticles is modified in asthma and suggests depressed mucosal immunity even in mild airway disease.

  • 4. Louw, Andrew M
    et al.
    Kolar, Mallappa K
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Kjems, Jørgen
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Chitosan polyplex mediated delivery of miRNA-124 reduces activation of microglial cells in vitro and in rat models of spinal cord injury2016In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 12, no 3, p. 643-653Article in journal (Refereed)
    Abstract [en]

    Traumatic injury to the central nervous system (CNS) is further complicated by an increase in secondary neuronal damage imposed by activated microglia/macrophages. MicroRNA-124 (miR-124) is responsible for mouse monocyte quiescence and reduction of their inflammatory cytokine production. We describe the formulation and ex vivo transfection of chitosan/miR-124 polyplex particles into rat microglia and the resulting reduction of reactive oxygen species (ROS) and TNF-α and lower expression of MHC-II. Upon microinjection into uninjured rat spinal cords, particles formed with Cy3-labeled control sequence RNA, were specifically internalized by OX42 positive macrophages and microglia cells. Alternatively particles injected in the peritoneum were transported by macrophages to the site of spinal cord injury 72h post injection. Microinjections of chitosan/miR-124 particles significantly reduced the number of ED-1 positive macrophages in the injured spinal cord. Taken together, these data present a potential treatment technique to reduce inflammation for a multitude of CNS neurodegenerative conditions.

  • 5. Nordin, Joel Z.
    et al.
    Lee, Yi
    Vader, Pieter
    Maeger, Imre
    Johansson, Henrik J.
    Heusermann, Wolf
    Wiklander, Oscar P. B.
    Hallbrink, Mattias
    Seow, Yiqi
    Bultema, Jarred J.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Davies, Tim
    Fairchild, Paul J.
    Gabrielsson, Susanne
    Meisner-Kober, Nicole C.
    Lehtio, Janne
    Smith, C. I. Edvard
    Wood, Matthew J. A.
    Andaloussi, Samir E. L.
    Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties2015In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 11, no 4, p. 879-883Article in journal (Refereed)
    Abstract [en]

    Extracellular vesicles (EVs) are natural nanoparticles that mediate intercellular transfer of RNA and proteins and are of great medical interest; serving as novel biomarkers and potential therapeutic agents. However, there is little consensus on the most appropriate method to isolate high-yield and high-purity EVs from various biological fluids. Here, we describe a systematic comparison between two protocols for EV purification: ultrafiltration with subsequent liquid chromatography (UF-LC) and differential ultracentrifugation (UC). A significantly higher EV yield resulted from UF-LC as compared to UC, without affecting vesicle protein composition. Importantly, we provide novel evidence that, in contrast to UC-purified EVs, the biophysical properties of UF-LC-purified EVs are preserved, leading toadifferent in vivo biodistribution, with less accumulation in lungs. Finally, we show that UF-LC is scalable and adaptable for EV isolation from complex media types such as stem cell media, which is of huge significance for future clinical applications involving EVs. 

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