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  • 1.
    Boge, Lucas
    et al.
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Umerska, Anita
    INSERM U 1066, France ; Université Angers, France.
    Matougui, Nada
    INSERM U 1066, France ; Université Angers,France.
    Bysell, Helena
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Ringstad, Lovisa
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Davoudi, Mina
    Lund University, Sweden.
    Eriksson, Jonny
    Uppsala University, Sweden.
    Edwards, Katarina
    Uppsala University, Sweden.
    Andersson, Martin
    Chalmers University of Technology, Sweden.
    Cubosomes post-loaded with antimicrobial peptides: Characterization, bactericidal effect and proteolytic stability2017Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 526, nr 1-2, s. 400-412Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Novel antibiotics, such as antimicrobial peptides (AMPs), have recently attended more and more attraction. In this work, dispersed cubic liquid crystalline gel (cubosomes) was used as drug delivery vehicles for three AMPs (AP114, DPK-060 and LL-37). Association of peptides onto cubosomes was studied at two cubosome/peptide ratios using high performance liquid chromatography, ζ-potential and circular dichroism measurements. AMPs impact on the cubosome structure was investigated using small angle x-ray scattering and cryogenic transmission electron microscopy. The antimicrobial effect of the AMP loaded cubosomes was studied in vitro by minimum inhibitory concentration and time-kill assays. Proteolytic protection was investigated by incubating the formulations with two elastases and the antimicrobial effect after proteolysis was studied using radial diffusion assay. Different association efficacy onto the cubosomes was observed among the AMPs, with LL-37 showing greatest association (>60%). AP114 loaded cubosomes displayed a preserved antimicrobial effect, whereas for LL-37 the broad spectrum bacterial killing was reduced to only comprise Gram-negative bacteria. Interestingly, DPK-060 loaded cubosomes showed a slight enhanced effect against S. aureus and E. coli strains. Moreover, the cubosomes were found to protect LL-37 from proteolytic degradation, resulting in a significantly better bactericidal effect after being subjected to elastase, compared to unformulated peptide.

  • 2.
    Boge, Lukas
    RISE, Sweden; Chalmers University of Technology, Sweden.
    Lipid-based liquid crystals as drug delivery vehicles for antimicrobial peptides2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Många av oss har någon gång blivit tvungna att ta en penicillinkur mot halsfluss eller kanske i samband med någon annan infektion. Oftast har behandlingen varit till stor nytta, och infektioner som förr i tiden kunde leda till döden har varit lätta att behandla med hjälp av antibiotika. I takt med att vi exponerat bakterier för icke-dödliga doser antibiotika, avsiktligt eller ej, så har de under årens lopp utvecklat en stark motståndskraft (resistens) mot dessa läkemedelsmolekyler.  Antibiotikaresistens är idag en stor utmaning inom hälso- och sjukvården runt om i världen och i och med att problemet växer har det fått mycket uppmärksamhet, både i media och bland forskare. Sjukdomsalstrande bakterier har utvecklat resistens mot i princip samtliga kommersiella antibiotikum som finns att tillgå. Behovet av att framställa nya och effektiva läkemedel är således stort och kommer med största sannolikhet att öka i framtiden. Ett skräckscenario, som i dagsläget inte helt och hållet kan uteslutas, är att vi inom en snar framtid noggrant måste överväga nyttan av mindre, eller icke-akuta kirurgiska ingrepp, mot de komplikationer som en bakterieinfektion skulle kunna medföra. Men det finns gott hopp om nya effektiva behandlingsmetoder och det forskas intensivt på just detta runt om i världen. En sorts ny antibiotika som har fått mer och mer uppmärksamhet på senare tid är så kallade antimikrobiella peptider. Dessa molekyler finns i både människor och djur som en del av det naturliga försvaret mot inkräktande bakterier, virus och svampar sedan miljontals år. Forskare har lyckats isolera, modifiera och framställa helt syntetiska antimikrobiella peptider som skulle kunna utnyttjas för behandling av infektioner orsakade av bakterier. Antimikrobiella peptider attackerar bakteriens skyddande hölje (bakteriemembranet), på liknande sätt som diskmedel löser upp fett och smuts, vilket gör det mycket svårt för dem att utveckla hög resistens. Tyvärr har dessa molekylär även vissa bekymmersamma egenskaper. Till exempel så bryts de ofta snabbt ner av olika enzymer som finns i kroppen eller i direkt anslutning till infekterande områden. I vissa fall kan de brytas ner i enbart närvaro av vatten.Denna avhandling handlar om att försöka kapsla in och skydda olika antimikrobiella peptider i mycket små partiklar (<0.5 µm) tillverkade av lipider (”fetter”). Lipiderna som använts består av två kemiskt mycket olika segment; ett hydrofilt (”vattenlösligt”) och ett hydrofobt (”fettlösligt”). Detta medför att lipidmolekylerna spontant ordnar sig (själv-associerar) i mycket komplexa en-, två- och tredimensionella nanostrukturer när de blandas med vatten. De nanostrukturer som då bildas har visat sig mycket användbara för inkapsling och levererans av olika läkemedel, däribland antimikrobiella peptider. I detta arbeta har de peptidladdade partiklarnas bakteriedödande förmåga undersökts grundligt i olika modeller, och hur de tar död på bakterierna har också utretts. Det visade sig att beroende på vilken antimikrobiell peptid och vilken nanostruktur på partiklarna som användes, påverkades deras bakteriedödande förmåga drastiskt. Partiklar av kubisk nanostruktur var mest förddelaktiga att använda sig av. De kunde både skydda en antimikrobiell peptid som är känslig mot enzymatisk nedbrytning och samtidigt uppvisa bra bakteriedödande förmåga.

  • 3.
    Boge, Lukas
    et al.
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering. Chalmers University of Technology, Sweden.
    Browning, Kathryn
    University of Copenhagen, Denmark.
    Nordström, Randi
    Uppsala University, Sweden.
    Campana, Mario
    Rutherford Appleton Laboratory, UK.
    Damgaard, Liv
    University of Copenhagen, Denmark.
    Seth Caous, Josefin
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Hellsing, Maja
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Ringstad, Lovisa
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Andersson, Martin
    Chalmers University of Technology, Sweden.
    Peptide-Loaded Cubosomes Functioning as an Antimicrobial Unit against Escherichia coli2019Ingår i: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 11, nr 24, s. 21314-21322Artikel i tidskrift (Refereegranskat)
    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.

  • 4.
    Boge, Lukas
    et al.
    RISE., SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science. Chalmers University of Technology, Sweden.
    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, Anita
    University of Angers, France.
    Cassisa, Viviane
    CHU Angers, France.
    Eriksson, Jonny
    Uppsala University, Sweden.
    Joly-Guillou, Marie-Laure
    CHU Angers, France.
    Edwards, Katarina
    Uppsala University, Sweden.
    Andersson, Martin
    Chalmers University of Technology, Sweden.
    Lipid-based liquid crystals as carriers for antimicrobial peptides: Phase behavior and antimicrobial effect2016Ingår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 32, nr 17, s. 4217-4228Artikel i tidskrift (Refereegranskat)
    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.

  • 5.
    Boge, Lukas
    et al.
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering. Chalmers University of Technology, Sweden.
    Hallstensson, Karin
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Ringstad, Lovisa
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Johansson, Jenny
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Andersson, Therese
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Davoudi, Mina
    Lund University, Sweden.
    Larsson, Tomas
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Mahlapuu, Margit
    Promore Pharma AB, Sweden; University of Gothenburg, Sweden.
    Håkansson, Joakim
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Andersson, Martin
    Chalmers University of Technology, Sweden.
    Cubosomes for topical delivery of the antimicrobial peptide LL-372019Ingår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 134, s. 60-67Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study, the use of cubosomes for topical delivery of the antimicrobial peptide (AMP) LL-37 was investigated. Topical delivery of AMPs is of great interest for treatment of skin infections caused by bacteria, such as Staphylococcus aureus. AMP containing cubosomes were produced by three different preparation protocols and compared: (i) pre-loading, where LL-37 was incorporated into a liquid crystalline gel, which thereafter was dispersed into nanoparticles, (ii) post-loading, where LL-37 was let to adsorb onto pre-formed cubosomes, and (iii) hydrotrope-loading, where LL-37 was incorporated during the spontaneously formed cubosomes in an ethanol/glycerol monooleate mixture. Particle size and size distribution were analyzed using dynamic light scattering (DLS), liquid crystalline structure by small angle x-ray scattering (SAXS) and release of LL-37 by a fluorescamine assay. Proteolytic protection of LL-37 as well as bactericidal effect after enzyme exposure was investigated. The skin irritation potential of cubosomes was examined by an in vitro epidermis model. Finally, the bacterial killing property of the cubosomes was examined by an ex vivo pig skin wound infection model with Staphylococcus aureus. Data showed that a high loading of LL-37 induced formation of vesicles in case of cubosomes prepared by sonication (pre-loading). No release of LL-37 was observed from the cubosomes, indicating strong association of the peptide to the particles. Proteolysis studies showed that LL-37 was fully protected against enzymatic attacks while associated with the cubosomes, also denoting strong association of the peptide to the particles. As a consequence, bactericidal effect after enzyme exposure remained, compared to pure LL-37 which was subjected to proteolysis. No skin irritation potential of the cubosomes was found, thus enabling for topical administration. The ex vivo wound infection model showed that LL-37 in pre-loaded cubosomes killed bacteria most efficient.

  • 6.
    Boge, Lukas
    et al.
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering. Chalmers University of Technology, Sweden.
    Västberg, Amanda
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Umerska, Anita
    Université Bretagne Loire, France.
    Bysell, Helena
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Eriksson, Jonny
    Uppsala University, Sweden.
    Edwards, Katarina
    Uppsala University, Sweden.
    Millqvist-Fureby, Anna
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Andersson, Martin
    Chalmers University of Technology, Sweden.
    Freeze-dried and re-hydrated liquid crystalline nanoparticles stabilized with disaccharides for drug-delivery of the plectasin derivative AP114 antimicrobial peptide2018Ingår i: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 522, s. 126-135Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Liquid crystalline nanoparticles (LCNPs), e.g. cubosomes and hexosomes, are receiving more and more attraction as drug delivery vehicles. Dry powder formulation that forms LCNPs upon hydration can be advantageous to make new routes of administration accessible. In this work, we investigate use of three disaccharides (lactose, trehalose and sucrose) as protective matrices for glycerol monooleate based LCNP forming powders produced by freeze-drying. Phase behavior, particle size and size distributions at the different preparation steps were monitored by small angle x-ray scattering (SAXS) and dynamic light scattering (DLS). Particle appearance was imaged by cryogenic transmission electron microscopy (cryo-TEM). Moreover, the therapeutic relevant antimicrobial peptide AP114 (plectasin derivative) was incorporated in the formulations. Peptide encapsulation and release as well as in vitro antibacterial effect were investigated. Results showed that all freeze-dried powders did form particles with liquid crystalline structure upon hydration. However, a phase transition from the bicontinuous cubic Pn3m to the reversed hexagonal was observed, as a consequence of sugar addition and the freeze-drying procedure. Data indicates that trehalose is the preferred choice of lyo-protectant in order to maintain a mono-modal particle size distribution. In addition, antimicrobial activity of AP114-containing formulations was found to be highest for the formulation containing trehalose. The release kinetics of AP114 from the nanoparticles was strongly affected by the dimensions of the hexagonal phase. Larger dimension of the hexagonal phase, significantly improved the release of AP114 and antimicrobial activity of the formulation.

  • 7.
    Håkansson, Joakim
    et al.
    RISE - Research Institutes of Sweden (2017-2019), Biovetenskap och material, Kemi och material.
    Ringstad, Lovisa
    RISE - Research Institutes of Sweden (2017-2019), Biovetenskap och material, Kemi och material.
    Umerska, Anita
    Université de Lorraine, France; Université Bretagne Loire, France.
    Johansson, Jenny
    RISE - Research Institutes of Sweden (2017-2019), Biovetenskap och material, Kemi och material.
    Andersson, Therese
    RISE - Research Institutes of Sweden (2017-2019), Biovetenskap och material, Kemi och material.
    Boge, Lukas
    RISE - Research Institutes of Sweden (2017-2019), Biovetenskap och material, Kemi och material.
    Rozenbaum, René T
    University of Groningen, The Netherlands.
    Sharma, Prashant K
    University of Groningen, The Netherlands.
    Tollbäck, Petter
    RISE - Research Institutes of Sweden (2017-2019), Biovetenskap och material, Kemi och material.
    Björn, Camilla
    RISE - Research Institutes of Sweden (2017-2019), Biovetenskap och material, Kemi och material.
    Saulnier, Patrick
    Université Bretagne Loire, France.
    Mahlapuu, Margit
    Promore Pharma AB, Sweden.
    Characterization of the in vitro, ex vivo, and in vivo Efficacy of the Antimicrobial Peptide DPK-060 Used for Topical Treatment.2019Ingår i: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 9, artikel-id 174Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antimicrobial peptides, also known as host defense peptides, have recently emerged as a promising new category of therapeutic agents for the treatment of infectious diseases. This study evaluated the preclinical in vitro, ex vivo, and in vivo antimicrobial activity, as well as the potential to cause skin irritation, of human kininogen-derived antimicrobial peptide DPK-060 in different formulations designed for topical delivery. We found that DPK-060 formulated in acetate buffer or poloxamer gel caused a marked reduction of bacterial counts of Staphylococcus aureus in vitro (minimum microbicidal concentration <5 μg/ml). We also found that DPK-060 in poloxamer gel significantly suppressed microbial survival in an ex vivo wound infection model using pig skin and in an in vivo mouse model of surgical site infection (≥99 or ≥94% reduction in bacterial counts was achieved with 1% DPK-060 at 4 h post-treatment, respectively). Encapsulation of DPK-060 in different types of lipid nanocapsules or cubosomes did not improve the bactericidal potential of the peptide under the applied test conditions. No reduction in cell viability was observed in response to administration of DPK-060 in any of the formulations tested. In conclusion, the present study confirms that DPK-060 has the potential to be an effective and safe drug candidate for the topical treatment of microbial infections; however, adsorption of the peptide to nanocarriers failed to show any additional benefits.

  • 8.
    Matougui, Nada
    et al.
    Inserm, France.
    Boge, Lukas
    RISE., SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Groo, Anne-Claire
    Inserm, France.
    Umerska, Anita
    Inserm, France.
    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, Patrick
    Inserm, France; CHU Angers, France.
    Lipid-based nanoformulations for peptide delivery2016Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 502, nr 1-2, s. 80-97Artikel, forskningsöversikt (Refereegranskat)
    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.

  • 9.
    Mira, Isabel
    et al.
    RISE., SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Andersson, Martin
    RISE., SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Boge, Lukas
    RISE., SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Blute, Irena
    RISE., SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science.
    Carlsson, Gilbert
    RISE., SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor.
    Foam forming revisited Part I. Foaming behaviour of fibre-surfactant systems2014Ingår i: Nordic Pulp & Paper Research Journal, ISSN 0283-2631, E-ISSN 2000-0669, Vol. 29, nr 4, s. 679-688Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The foaming properties of typical chemithermo-mechanical (CTMP) and kraft pulp paper making formulations in the presence of a series of surfactants were investigated using a lab-scale foaming set up. Foamability, foam stability, and bubble size distribution of the generated foam-fibre systems were measured. The foaming behaviour of the fibre/surfactant systems was found to be dependent on the surfactant concentration. Foams fulfilling the target requirements of air content (ca. 65% v/v air) and average bubble size (25 to 75 μm in radius) were obtained with all the seven surfactants tested. Three of the surfactants were found to allow for a rapid foaming in the system, namely sodium dodecyl sulphate (SDS), a commercial mixture of alkyl and ethoxylated alkyl sulphates, (MixSAES) and a commercial mixture of short chain alkyl glucosides (C8/C10Gluc). The rapid foaming is believed to be an intrinsic property of mixtures of surfactants with the right molecular structures and in the right proportion with respect to each other. On the other hand, the minimum surfactant concentrations required to reach the target foam volumes were lowest for surfactants with an anionic character. Further, the type of pulp fibre and the presence of GCC in the surfactant/pulp formulation were found to have very little effect on the foaming performance of the suspensions.

  • 10.
    Simoni, Edi
    et al.
    University of Padua, Italy.
    Valente, Filippo
    Ear Science Institute Australia, Australia; University of Western Australia, Australia.
    Boge, Lukas
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Eriksson, Mimmi
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Gentilin, Erica
    University of Padua, Italy.
    Candito, Mariarita
    University of Padua, Italy.
    Cazzador, Diego
    University of Padua, Italy.
    Astolfi, Laura
    University of Padua, Italy.
    Biocompatibility of glycerol monooleate nanoparticles as tested on inner ear cells2019Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 572, artikel-id 118788Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sensorineural hearing loss due to aging, noise exposure, trauma or drug ototoxicity is irreversible because cochlear hair cells and neurons cannot regenerate. Recently, therapeutic strategies involving nanoparticles have been developed as innovative drug delivery systems. Thermodynamically stable liquid crystalline nanoparticles based on the polar lipid glycerol monooleate (GMO NP, cubosomes), nontoxic and able to encapsulate both hydrophilic and hydrophobic compounds, were produced and tested for biocompatibility in an immortalized Organ of Corti derived cell line (OC-k3), through cell viability and cytomorphological assays, and Western blot expression profiles of apoptotic markers. Overall, the GMO NP were biocompatible in OC-k3 at the doses and time tested, supporting previous data obtained in a neuronal cell line (PC12). The results encourage further tests on GMO NP-mediated drug release with improved target specificity and could be useful to develop innovative therapies against sensorineural hearing loss.

  • 11.
    Valente, Filippo
    et al.
    University of Padua, Italy.
    Bysell, Helena
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Simoni, Edi
    University of Padua, Italy.
    Boge, Lukas
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Eriksson, Mimmi
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Martini, Alessandro
    University of Padua, Italy.
    Astolfi, Laura
    University of Padua, Italy.
    Evaluation of toxicity of glycerol monooleate nanoparticles on PC12 cell line.2018Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 539, nr 1-2, s. 23-30, artikel-id S0378-5173(18)30054-1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An innovative approach to improve drug delivery is the use of glycerol monooleate nanoparticles. Numerous studies describe their high versatility, low toxicity and ability to carry relatively high loads of conjugated compounds including scarcely soluble ones, providing sustained drug release and increasing drug diffusion and half-life. Despite a growing interest in their potential use for therapeutic applications, there are surprisingly few literature data concerning the toxic effects of these nanoparticles at high concentrations in vitro and in vivo, and their effects on cell metabolism. We produced and characterized from a physical-chemical point of view glycerol monooleate nanoparticles and tested them on the PC12 cell line, a rat model of neuronal differentiation. The toxicity of these nanoparticles was evaluated by molecular methods on cell viability, cell cycle, nanoparticle uptake and induction of apoptosis. The results showed that glycerol monooleate nanoparticles up to 100 μg/mL had no toxic effects on PC12 cells, did not induce significant changes in the cell cycle nor cause apoptosis. The nanoparticles entered PC12 cells 8 h after treatment, successfully delivering the conjugate compound inside cells. Overall, glycerol monooleate nanoparticles did not exhibit significant toxicity on PC12 cell line in concentrations up to 100 µg/mL, supporting their therapeutic use as drug delivery systems.

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