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  • 1.
    Haridass, Isha N.
    et al.
    Curtin Univ, Australia; Univ Queensland, Australia.
    Wei, Jonathan C. J.
    Univ Queensland, Australia; Delft Univ Technol, Netherlands.
    Mohammed, Yousuf H.
    Univ Queensland, Australia.
    Crichton, Michael L.
    Heriot Watt Univ, Scotland.
    Anderson, Chris
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Henricson, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Sanchez, Washington Y.
    Univ Queensland, Australia.
    Meliga, Stefano C.
    Univ Queensland, Australia.
    Grice, Jeffrey E.
    Univ Queensland, Australia.
    Benson, Heather A. E.
    Curtin Univ, Australia.
    Kendall, Mark A. F.
    Australian Natl Univ, Australia; Univ Queensland, Australia.
    Roberts, Michael S.
    Univ Queensland, Australia; Univ South Australia, Australia.
    Cellular metabolism and pore lifetime of human skin following microprojection array mediation2019In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 306, p. 59-68Article in journal (Refereed)
    Abstract [en]

    Skin-targeting microscale medical devices are becoming popular for therapeutic delivery and diagnosis. We used cryo-SEM, fluorescence lifetime imaging microscopy (FLIM), autofluorescence imaging microscopy and inflammatory response to study the puncturing and recovery of human skin ex vivo and in vivo after discretised puncturing by a microneedle array (Nanopatch (R)). Pores induced by the microprojections were found to close by similar to 25% in diameter within the first 30 min, and almost completely close by similar to 6 h. FLIM images of ex vivo viable epidermis showed a stable fluorescence lifetime for unpatched areas of similar to 1000 ps up to 24 h. Only the cells in the immediate puncture zones (in direct contact with projections) showed a reduction in the observed fluorescence lifetimes to between similar to 518-583 ps. The ratio of free-bound NAD(P)H (alpha 1/alpha 2) in unaffected areas of the viable epidermis was similar to 2.5-3.0, whereas the ratio at puncture holes was almost double at similar to 4.2-4.6. An exploratory pilot in vivo study also suggested similar closure rate with histamine administration to the forearms of human volunteers after Nanopatch (R) treatment, although a prolonged inflammation was observed with Tissue Viability Imaging. Overall, this work shows that the pores created by the microneedle-type medical device, Nanopatch (R), are transient, with the skin recovering rapidly within 1-2 days in the epidermis after application.

  • 2.
    Hernandez, Aura Rocio
    et al.
    Malmo Univ, Sweden; Univ Nacl Colombia, Colombia.
    Boutonnet, Marine
    Malmo Univ, Sweden.
    Svensson, Birgitta
    Bioglan AB, Sweden.
    Butler, Eile
    Biogaia AB, Sweden.
    Lood, Rolf
    Lund Univ, Sweden.
    Blom, Kristina
    Medibiome AB, Sweden.
    Vallejo, Bibiana
    Univ Nacl Colombia, Colombia.
    Anderson, Chris
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Engblom, Johan
    Malmo Univ, Sweden.
    Ruzgas, Tautgirdas
    Malmo Univ, Sweden.
    Bjorklund, Sebastian
    Malmo Univ, Sweden.
    New concepts for transdermal delivery of oxygen based on catalase biochemical reactions studied by oxygen electrode amperometry2019In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 306, p. 121-129Article in journal (Refereed)
    Abstract [en]

    The development of formulation concepts for improved skin tissue oxygenation, including methods for measuring oxygen (O-2) transport across biological barriers, are important research topics with respect to all processes that are affected by the O-2 concentration, such as radiation therapy in oncology treatments, wound healing, and the general health status of skin. In this work we approach this topic by a novel strategy based on the antioxidative enzyme catalase, which is naturally present in the skin organ where it enables conversion of the reactive oxygen species hydrogen peroxide (H2O2) into O-2. We introduce various applications of the skin covered oxygen electrode (SCOE) as an in-vitro tool for studies of catalase activity and function. The SCOE is constructed by placing an excised skin membrane directly on an O-2 electrode and the methodology is based on measurements of the electrical current generated by reduction of O-2 as a function of time (i.e. chronoamperometry). The results confirm that a high amount of native catalase is present in the skin organ, even in the outermost stratum corneum (SC) barrier, and we conclude that excised pig skin (irrespective of freeze-thaw treatment) represents a valid model for ex vivo human skin for studying catalase function by the SCOE setup. The activity of native catalase in skin is sufficient to generate considerable amounts of O-2 by conversion from H2O2 and proof-of-concept is presented for catalase-based transdermal O-2 delivery from topical formulations containing H2O2. In addition, we show that this concept can be further improved by topical application of external catalase on the skin surface, which enables transdermal O-2 delivery from 50 times lower concentrations of H2O2. These important results are promising for development of novel topical or transdermal formulations containing low and safe concentrations of H2O2 for skin tissue oxygenation. Further, our results indicate that the O-2 production by catalase, derived from topically applied S. epidermidis (a simple model for skin microbiota) is relatively low as compared to the O-2 produced by the catalase naturally present in skin. Still, the catalase activity derived from S. epidermidis is measurable. Taken together, this work illustrates the benefits and versatility of the SCOE as an in vitro skin research tool and introduces new and promising strategies for transdermal oxygen delivery, with simultaneous detoxification of H2O2, based on native or topically applied catalase.

  • 3.
    Lin, Qing
    et al.
    Sichuan Univ, Peoples R China; Univ Cambridge, England.
    Qu, Mengke
    Sichuan Univ, Peoples R China.
    Zhou, Bingjie
    Sichuan Univ, Peoples R China.
    Patra, Hirak Kumar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Cambridge, England.
    Sun, Zihan
    Sichuan Univ, Peoples R China.
    Luo, Qiong
    Sichuan Univ, Peoples R China.
    Yang, Wenyu
    Sichuan Univ, Peoples R China.
    Wu, Yongcui
    Sichuan Univ, Peoples R China.
    Zhang, Yu
    Sichuan Univ, Peoples R China.
    Li, Lin
    Sichuan Univ, Peoples R China.
    Deng, Lang
    Sichuan Univ, Peoples R China.
    Wang, Leilei
    Sichuan Univ, Peoples R China.
    Gong, Tao
    Sichuan Univ, Peoples R China.
    He, Qin
    Sichuan Univ, Peoples R China.
    Zhang, Ling
    Sichuan Univ, Peoples R China.
    Sun, Xun
    Sichuan Univ, Peoples R China.
    Zhang, Zhirong
    Sichuan Univ, Peoples R China.
    Exosome-like nanoplatform modified with targeting ligand improves anti-cancer and anti-inflammation effects of imperialine2019In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 311, p. 104-116Article in journal (Refereed)
    Abstract [en]

    Currently, most anti-cancer therapies are still haunted by serious and deleterious adverse effects. Here, we report a highly biocompatible tumor cell-targeting delivery systems utilizing exosome-like vesicles (ELVs) that delivers a low-toxicity anti-cancer agent imperialine against non-small cell lung cancer (NSCLC). First, we introduced a novel micelle-aided method to efficiently load imperialine into intact ELVs. Then, integrin alpha 3 beta 1-binding octapeptide cNGQGEQc was modified onto ELV platform for tumor targeting as integrin alpha 3 beta 1 is overexpressed on NSCLC cells. This system not only significantly improved imperialine tumor accumulation and retention, but also had extremely low systemic toxicity both in vitro and in vivo. Our discoveries offer new ways to utilize ELV more efficiently for both drug loading and targeting. The solid pharmacokinetics improvement and extraordinary safety of this system also highlight possibilities of alternative long course cancer therapies using similar strategies.

  • 4.
    Patzelt, Alexa
    et al.
    Charite, Germany.
    Cheung Mak, Wing
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Jung, Sora
    Charite, Germany.
    Knorr, Fanny
    Charite, Germany.
    Meinke, Martina C.
    Charite, Germany.
    Richter, Heike
    Charite, Germany.
    Ruehl, Eckart
    Free University of Berlin, Germany.
    Cheung, Kitt
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Tran, Ngo Bich Nga Nathalie
    Charite, Germany.
    Lademann, Juergen
    Charite, Germany.
    Do nanoparticles have a future in dermal drug delivery?2017In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 246, p. 174-182Article in journal (Refereed)
    Abstract [en]

    More and more investigations confirm that nanoparticles are incapable of overcoming the intact skin barrier in vivo. Do nanoparticles still have a future in dermal drug delivery? Unlike many other topically applied substances, nanoparticles have not been reported to utilize the intercellular penetration pathway and preferentially make use of the follicular penetration pathway. Deep penetration into the follicular ducts has been described for a variety of particles and appears to be strongly influenced by particle size. For targeted drug delivery, smart nanoparticles are required which are able to release their loaded drugs subsequent to internal or external trigger stimuli, and thereby enable the translocation of the active agents into the viable epidermis. In the recent manuscript, three nanoparticles systems are summarized and compared which release their model drugs upon different trigger mechanisms. The BSA hydrogel nanoparticles release their model drug TRITC-dextran by passive diffusion due to a concentration gradient via a porous surface. The protease-triggered controlled release BSA nanoparticles release their model drug if they are applied simultaneously with protease nanoparticles, resulting in an enzymatic degradation of the particles and a release of the model drug FITC. Finally, the IR-triggered controlled release AuNP-doped BSA nanoparticles release their model drug FITC after photoactivation with wIRA. For all three nanoparticle systems, the release of their model drugs could be observed. For the first nanoparticle system, only low follicular penetration depths were found which might by due do an agglomeration effect. For the last two nanoparticle systems, deep follicular penetration and even an uptake by the sebaceous glands were verified. In conclusion, it could be demonstrated that nanoparticles do have a future in dermal drug delivery if smart nanoparticle systems are utilized which are able to release their drug at specific times and locations within the hair follicle. (C) 2016 Elsevier B.V. All rights reserved.

  • 5.
    Piletska, EV
    et al.
    Cranfield University, Institute BioScience and Technology, Silsoe MK45 4DT, Beds, England; .
    Turner, NW
    Cranfield University, UK.
    Turner, APF
    Cranfield University, UK.
    Piletsky, SA
    Cranfield University, Institute BioScience and Technology, Silsoe MK45 4DT, Beds, England; .
    Controlled release of the herbicide simazine from computationally designed molecularly imprinted polymers2005In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 108, no 1, p. 132-139Article in journal (Refereed)
    Abstract [en]

    The present study describes the development of materials suitable for environmental control of algae. Molecularly imprinted polymers (MIPs) were used as simazine carriers able to provide the controlled release of simazine into water. Three polymers were designed using computational modelling. The selection of methaerylic acid (MA) and hydroxyethyl methacrylate (HEM) as functional monomers was based on results obtained using the Leapfrog algorithm. A cross-linked polymer made without functional monomers was also prepared and tested as a control. The release of simazine from all three polymers was studied. It was shown that the presence of functional monomers is important for polymer affinity and for controlled release of herbicide. The speed of release of herbicide correlated with the calculated binding characteristics. The high-affinity MA-based polymer released similar to 2% and the low-affinity HEM-based polymer released similar to 27% of the template over 25 days. The kinetics of simazine release from HEM-based polymer show that total saturation of an aqueous environment could be achieved over a period of 3 weeks and this corresponds to the maximal simazine solubility in water. The possible use of these types of polymers in the field of controlled release is discussed. (c) 2005 Elsevier B.V. All rights reserved.

  • 6.
    Ron-Doitch, Sapir
    et al.
    Hebrew University of Jerusalem, Israel.
    Sawodny, Beate
    Fraunhofer IGB, Germany.
    Kuehbacher, Andreas
    Fraunhofer IGB, Germany.
    Nordling David, Mirjam M.
    Hebrew University of Jerusalem, Israel.
    Samanta, Ayan
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology.
    Phopase, Jaywant
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Burger-Kentischer, Anke
    Fraunhofer IGB, Germany.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Golomb, Gershon
    Hebrew University of Jerusalem, Israel.
    Rupp, Steffen
    Fraunhofer IGB, Germany.
    Reduced cytotoxicity and enhanced bioactivity of cationic antimicrobial peptides liposomes in cell cultures and 3D epidermis model against HSV2016In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 229, p. 163-171Article in journal (Refereed)
    Abstract [en]

    Cationic antimicrobial peptides (AMPs) are part of the innate immunity, and act against a wide variety of pathogenic microorganisms by perturbation of the microorganisms plasma membrane. Although attractive for clinical applications, these agents suffer from limited stability and activity in vivo, as well as non-specific interaction with host biological membranes, leading to cytotoxic adverse effects. We hypothesized that encapsulation of AMPs within liposomes could result in reduced cytotoxicity, and with enhanced stability as well as bioactivity against herpes simplex virus 1 (HSV-1). We formulated nano-sized liposomal formulations of LL-37 and indolicidin, and their physicochemical properties, cellular uptake, in vitro cytotoxicity and antiviral efficacy have been determined. Lower cytotoxicity of LL-37 liposomes was found in comparison to indolicidin liposomes attributed to the superior physicochemical properties, and to the different degree of interaction with the liposomal membrane. The disc-like shaped LL-37 liposomes (106.8 +/- 10.1 nm, shelf-life stability of N1 year) were taken up more rapidly and to a significantly higher extent than the free peptide by human keratinocyte cell line (HaCaT), remained intact within the cells, followed by release of the active peptide within the cytoplasm and migration of the vesicles lipids to the plasma membrane. LL-37 liposomes were found significantly less toxic than both the free agent and liposomal indolicidin. In the new 3D epidermis model (immortalized primary keratinocytes) liposomal LL-37 treatment (N20 mu M), but not free LL-37, efficiently protected the epidermis, inhibiting HSV-1 infection. This positive antiviral effect was obtained with no cytotoxicity even at very high concentrations (400 mu M). Thus, the antiviral activity of encapsulated LL-37 was significantly improved, expanding its therapeutic window. Liposomal LL-37 appears to be a promising delivery system for HSV therapy. (C) 2016 Elsevier B.V. All rights reserved.

  • 7.
    Wing Cheung, Mak
    et al.
    Hong Kong University of Science and Technology, China.
    Alexa, Patzelt
    Universitätsmedizin Berlin, Germany.
    Heike, Richter
    Universitätsmedizin Berlin, Germany.
    Reinhard, Renneberg
    Hong Kong University of Science and Technology, China.
    Kwok Kei, Lai
    Hong Kong University of Science and Technology, China.
    Eckhardt, Rühl
    Freie Universität Berlin, Germany.
    Wolfram, Sterry
    Universitätsmedizin Berlin, Germany.
    Jürgen, Lademann
    Universitätsmedizin Berlin, Germany.
    Triggering of drug relase of particles in hair follicles2012In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 160, p. 509-514Article in journal (Refereed)
    Abstract [en]

    Particulate drug delivery via hair follicles represents a promising concept, although requirements are high. This process must be realized at the desired depth and at the appropriate time, due to the fact that the particles themselves are not able to overcome the follicular skin barrier.

    In the present study, a novel triggering concept for the release of a model drug from the delivering particles is presented based on the application of two different particle types of the same size, where one particle type is the drug carrier, and the second one is loaded with a protease. The latter particle type is supposed to interact with the drug-carrying particles to trigger the drug release. A mixture of both particles was applied onto porcine skin samples, followed by follicular analysis. As a control, the particles were applied unaided without protease, whereas one skin area remained untreated. The investigations revealed that the protease was able to release the model drug from the delivering particles in significant depths within the hair follicle (866 ± 62 nm). Additionally, an uptake of the model drug in the sebaceous gland was observed after release providing a promising novel approach for the development of treatment strategies for different skin diseases.

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