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Andrén, O. C. J., Ingverud, T., Hult, D., Håkansson, J., Bogestål, Y., Caous, J. S., . . . Malkoch, M. (2019). Antibiotic-Free Cationic Dendritic Hydrogels as Surgical-Site-Infection-Inhibiting Coatings. Advanced Healthcare Materials, 8(5)
Open this publication in new window or tab >>Antibiotic-Free Cationic Dendritic Hydrogels as Surgical-Site-Infection-Inhibiting Coatings
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2019 (English)In: Advanced Healthcare Materials, ISSN 2192-2640, E-ISSN 2192-2659, Vol. 8, no 5Article in journal (Refereed) Published
Abstract [en]

Abstract A non-toxic hydrolytically fast-degradable antibacterial hydrogel is herein presented to preemptively treat surgical site infections during the first crucial 24 h period without relying on conventional antibiotics. The approach capitalizes on a two-component system that form antibacterial hydrogels within 1 min and consist of i) an amine functional linear-dendritic hybrid based on linear poly(ethylene glycol) and dendritic 2,2-bis(hydroxymethyl)propionic acid, and ii) a di-N-hydroxysuccinimide functional poly(ethylene glycol) cross-linker. Broad spectrum antibacterial effect is achieved by multivalent representation of catatonically charged ?-alanine on the dendritic periphery of the linear dendritic component. The hydrogels can be applied readily in an in vivo setting using a two-component syringe delivery system and the mechanical properties can accurately be tuned in the range equivalent to fat tissue and cartilage (G? = 0.5?8 kPa). The antibacterial effect is demonstrated both in vitro toward a range of relevant bacterial strains and in an in vivo mouse model of surgical site infection.

Place, publisher, year, edition, pages
John Wiley & Sons, Ltd, 2019
Keywords
antibacterial, dendrimer, hydrogels, surgical-site infection
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-249169 (URN)10.1002/adhm.201801619 (DOI)000461575200014 ()2-s2.0-85061270456 (Scopus ID)
Note

QC 20190412

Available from: 2019-04-11 Created: 2019-04-11 Last updated: 2019-04-12Bibliographically approved
Zhang, Y., Andrén, O. C. J., Nordström, R., Fan, Y., Malmsten, M., Mongkhontreerat, S. & Malkoch, M. (2019). Off-Stoichiometric Thiol-Ene Chemistry to Dendritic Nanogel Therapeutics. Advanced Functional Materials, 29(18), Article ID 1806693.
Open this publication in new window or tab >>Off-Stoichiometric Thiol-Ene Chemistry to Dendritic Nanogel Therapeutics
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2019 (English)In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 29, no 18, article id 1806693Article in journal (Refereed) Published
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. © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Place, publisher, year, edition, pages
Wiley-VCH Verlag, 2019
Keywords
cancer treatment, dendritic nanogel, drug delivery, nanomedicine, 3D modeling, Biocompatibility, Controlled drug delivery, Medical nanotechnology, Oncology, Self assembly, Targeted drug delivery, Core functionality, Diffusion controlled, Linear dendritic, Master batch, Nanogels, Therapeutic efficacy, Thiol-ene chemistries, Toxic side effects, Nanostructured materials
National Category
Materials Chemistry
Identifiers
urn:nbn:se:kth:diva-252526 (URN)10.1002/adfm.201806693 (DOI)2-s2.0-85062732882 (Scopus ID)
Note

QC 20190605

Available from: 2019-06-05 Created: 2019-06-05 Last updated: 2019-06-05Bibliographically approved
Rozenbaum, R. T., Andrén, O. C. J., van der Mei, H. C., Woudstra, W., Busscher, H. J., Malkoch, M. & Sharma, P. K. (2019). Penetration and Accumulation of Dendrons with Different Peripheral Composition in Pseudomonas aeruginosa Biofilms. Nano letters (Print), 19(7), 4327-4333
Open this publication in new window or tab >>Penetration and Accumulation of Dendrons with Different Peripheral Composition in Pseudomonas aeruginosa Biofilms
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2019 (English)In: Nano letters (Print), ISSN 1530-6984, E-ISSN 1530-6992, Vol. 19, no 7, p. 4327-4333Article in journal (Refereed) Published
Abstract [en]

Multidrug resistant bacterial infections threaten to become the number one cause of death by the year 2050. Development of antimicrobial dendritic polymers is considered promising as an alternative infection control strategy. For antimicrobial dendritic polymers to effectively kill bacteria residing in infectious biofilms, they have to penetrate and accumulate deep into biofilms. Biofilms are often recalcitrant to antimicrobial penetration and accumulation. Therefore, this work aims to determine the role of compact dendrons with different peripheral composition in their penetration into Pseudomonas aeruginosa biofilms. Red fluorescently labeled dendrons with pH-responsive NH3+ peripheral groups initially penetrated faster from a buffer suspension at pH 7.0 into the acidic environment of P. aeruginosa biofilms than dendrons with OH or COO- groups at their periphery. In addition, dendrons with NH3+ peripheral groups accumulated near the top of the biofilm due to electrostatic double-layer attraction with negatively charged biofilm components. However, accumulation of dendrons with OH and COO- peripheral groups was more evenly distributed across the depth of the biofilms than NH3+ composed dendrons and exceeded accumulation of NH3+ composed dendrons after 10 min of exposure. Unlike dendrons with NH3+ groups at their periphery, dendrons with OH or COO- peripheral groups, lacking strong electrostatic double-layer attraction with biofilm components, were largely washed-out during exposure to PBS without dendrons. Thus, penetration and accumulation of dendrons into biofilms is controlled by their peripheral composition through electrostatic double-layer interactions, which is an important finding for the further development of new antimicrobial or antimicrobial-carrying dendritic polymers.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
Keywords
Nanomedicine, nanocarriers, nanotechnology, dendrimers, dendritic polymers
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-255568 (URN)10.1021/acs.nanolett.9b00838 (DOI)000475533900015 ()31142116 (PubMedID)
Note

QC 20190802

Available from: 2019-08-02 Created: 2019-08-02 Last updated: 2019-08-02Bibliographically approved
Latorre-Sanchez, A., Johansson, M., Zhang, Y., Malkoch, M. & Pomposo, J. A. (2018). Active quinine-based films able to release antimicrobial compounds via melt quaternization at low temperature. Journal of materials chemistry. B, 6(1), 98-104
Open this publication in new window or tab >>Active quinine-based films able to release antimicrobial compounds via melt quaternization at low temperature
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2018 (English)In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 6, no 1, p. 98-104Article in journal (Refereed) Published
Abstract [en]

The fabrication of antibacterial films based on renewable materials (e.g., chitosan) has attracted significant interest in fields such as food packaging, health care and medicine. However, exploiting the antibacterial properties of cinchona alkaloids to design active nanostructured films able to release quinine-based antimicrobial compounds has not been considered previously. Herein, we develop two different routes to produce active quinine-based nanostructured cross-linked films by exploiting the multiple reactive sites of quinine and, specifically, both the nitrogen atom and the vinyl group of the quinuclidine portion of the molecule, as well as their corresponding orthogonal quaternization and thiol-ene coupling reactions. The first synthetic strategy produces stiff and brittle nanostructured quinine-based films of limited utility for practical applications. Conversely, the second approach produces active, flexible and nanostructured quinine-based films (T-g = - 14 degrees C, Young's modulus = 1.3 GPa), which are able to release antimicrobial compounds against E. coli that, remarkably, are noncytotoxic against mouse macrophage and human dermal fibroblast cells. These kinds of active cinchona alkaloid-based coatings are easy to prepare by means of simple, solvent-free, melt quaternization/spreading procedures at a relatively low temperature (120 degrees C), making this second approach one of the most facile reported procedures to date to produce active nanostructured bio-based films.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2018
National Category
Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-220813 (URN)10.1039/c7tb02739g (DOI)000418379700009 ()2-s2.0-85038944460 (Scopus ID)
Note

QC 20180116

Available from: 2018-01-16 Created: 2018-01-16 Last updated: 2018-03-13Bibliographically approved
Hult, D., Garcia-Gallego, S., Ingverud, T., Andrén, O. & Malkoch, M. (2018). Degradable High Tg Sugar Derived Polycarbonates from Isosorbide and Dihydroxyacetone. Polymer Chemistry
Open this publication in new window or tab >>Degradable High Tg Sugar Derived Polycarbonates from Isosorbide and Dihydroxyacetone
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2018 (English)In: Polymer Chemistry, ISSN 1759-9954, E-ISSN 1759-9962Article in journal (Refereed) Published
Abstract [en]

Polycarbonates from isosorbide and dihydroxyacetone (DHA) have been synthesised using organocatalytic step-growth polymerization of their corresponding diols and bis-carbonylimidazolides monomers. By choice of feed ratio and monomer activation, either isosorbide or ketal protected DHA, random and alternating poly(Iso-co-DHA) carbonates have been formed. Thermal properties by DSC and TGA were herein strongly correlated to monomer composition. Dilution studies using 1H-NMR of a model compound DHA-diethyl carbonate in acetonitrile and deuterated water highlighted the influence of α-substituents on the keto/hydrate equilibrium of DHA. Further kinetics studies of in the pH* range of 4.7 to 9.6 serve to show the hydrolytic pH-profile of DHA-carbonates. The Hydrolytic degradation of deprotected polymer pellets show an increased degradation with increasing DHA content. Pellets with a random or alternating configuration show different characteristics in terms of mass loss and molecular weight loss profile over time.

National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-224753 (URN)10.1039/C8PY00256H (DOI)000431183700004 ()2-s2.0-85046299922 (Scopus ID)
Funder
Swedish Research Council, 2011-5358 2010-435 2015-04779Knut and Alice Wallenberg Foundation, 2012-0196
Note

QC 20180322

Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-05-15Bibliographically approved
Martin-Serrano Ortiz, A., Stenström, P., Antunez, P. M., Andrén, O. C. J., Torres, M. J., Montanez, M. I. & Malkoch, M. (2018). Design of multivalent fluorescent dendritic probes for site-specific labeling of biomolecules. Journal of Polymer Science Part A: Polymer Chemistry, 56(15), 1609-1616
Open this publication in new window or tab >>Design of multivalent fluorescent dendritic probes for site-specific labeling of biomolecules
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2018 (English)In: Journal of Polymer Science Part A: Polymer Chemistry, ISSN 0887-624X, E-ISSN 1099-0518, Vol. 56, no 15, p. 1609-1616Article in journal (Refereed) Published
Abstract [en]

Herein, the synthesis and characterization of orthogonal dendrons decorated with multiple units of fluorescent and a chemoselective group at a focal point, followed by specific antibody labeling, is presented. Fluorescence results confirm the applicability of the fluorescent probes for biomolecule labeling and fluorescent signal amplification.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
antibodies, click chemistry, conjugation chemistry, dendrimers, dyes, fluorescence, imaging, multivalent labeling, polyester dendrons, selectivity
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-232228 (URN)10.1002/pola.29055 (DOI)000436543800001 ()2-s2.0-85049074485 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2012-0196
Note

QC 20180720

Available from: 2018-07-20 Created: 2018-07-20 Last updated: 2018-07-20Bibliographically approved
Stenström, P., Manzanares, D., Zhang, Y., Ceña, V. & Malkoch, M. (2018). Evaluation of amino-functional polyester dendrimers based on Bis-MPA as nonviral vectors for siRNA delivery. Molecules, 23(8), Article ID 2028.
Open this publication in new window or tab >>Evaluation of amino-functional polyester dendrimers based on Bis-MPA as nonviral vectors for siRNA delivery
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2018 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 23, no 8, article id 2028Article in journal (Refereed) Published
Abstract [en]

Herein, we present the first evaluation of cationic dendrimers based on 2,2-bis(methylol)propionic acid (bis-MPA) as nonviral vectors for transfection of short interfering RNA (siRNA) in cell cultures. The study encompassed dendrimers of generation one to four (G1-G4), modified to bear 6-48 amino end-groups, where the G2-G4 proved to be capable of siRNA complexation and protection against RNase-mediated degradation. The dendrimers were nontoxic to astrocytes, glioma (C6), and glioblastoma (U87), while G3 and G4 exhibited concentration dependent toxicity towards primary neurons. The G2 showed no toxicity to primary neurons at any of the tested concentrations. Fluorescence microscopy experiments suggested that the dendrimers are highly efficient at endo-lysosomal escape since fluorescently labeled dendrimers were localized specifically in mitochondria, and diffuse cytosolic distribution of fluorescent siRNA complexed by dendrimers was observed. This is a desired feature for intracellular drug delivery, since the endocytic pathway otherwise transfers the drugs into lysosomes where they can be degraded without reaching their intended target. siRNA-transfection was successful in C6 and U87 cell lines using the G3 and G4 dendrimers followed by a decrease of approximately 20% of target protein p42-MAPK expression.

Place, publisher, year, edition, pages
MDPI AG, 2018
Keywords
Bis-MPA, Dendrimer, Monodisperse, Polycation, RNAi, SiRNA
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-238030 (URN)10.3390/molecules23082028 (DOI)000445295500193 ()2-s2.0-85053600476 (Scopus ID)
Note

Export Date: 30 October 2018; Article; CODEN: MOLEF; Correspondence Address: Malkoch, M.; Fiber and Polymer Technology, KTH Royal Institute of TechnologySweden; email: malkoch@kth.se

QC 20190115

Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Granskog, V., Garcia-Gallego, S., von Kieseritzky, J., Pettersson, J., Stenlund, P., Zhang, Y., . . . Malkoch, M. (2018). High-performance and biocompatible thiol-ene based adhesive for bone fracture fixation. Paper presented at 256th National Meeting and Exposition of the American-Chemical-Society (ACS) - Nanoscience, Nanotechnology and Beyond, AUG 19-23, 2018, Boston, MA. Abstract of Papers of the American Chemical Society, 256
Open this publication in new window or tab >>High-performance and biocompatible thiol-ene based adhesive for bone fracture fixation
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2018 (English)In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 256Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-238547 (URN)000447609105053 ()
Conference
256th National Meeting and Exposition of the American-Chemical-Society (ACS) - Nanoscience, Nanotechnology and Beyond, AUG 19-23, 2018, Boston, MA
Note

QC 20181105

Available from: 2018-11-05 Created: 2018-11-05 Last updated: 2018-11-05Bibliographically approved
Nordström, R., Nyström, L., Andrén, O. C. J., Malkoch, M., Umerska, A., Davoudi, M., . . . Malmsten, M. (2018). Membrane interactions of microgels as carriers of antimicrobial peptides. Journal of Colloid and Interface Science, 513, 141-150
Open this publication in new window or tab >>Membrane interactions of microgels as carriers of antimicrobial peptides
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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., 2018
Keywords
Antimicrobial peptide, Drug delivery, Lipid membrane, Microgel, Bacteria, Charge density, Circular dichroism spectroscopy, Dichroism, Drug interactions, Escherichia coli, Gels, Light scattering, Membranes, Microorganisms, Polypeptides, Anti-microbial effects, Cationic antimicrobial peptides, Lipid membranes, Methicillin-resistant staphylococcus aureus, Nanoparticle tracking analysis, Pseudomonas aeruginosa, Peptides, anion, cathelicidin antimicrobial peptide LL 37, cation, dpk 060, drug carrier, poly(acrylate methacrylate), poly(ethyl methacrylate), polypeptide antibiotic agent, proteinase, triton x 100, unclassified drug, adsorption kinetics, analytic method, aqueous solution, Article, bacterial membrane, bactericidal activity, binding kinetics, cell interaction, circular dichroism, conformational transition, controlled study, cytotoxicity, drug delivery system, drug distribution, drug release, electrical parameters, ellipsometry, erythrocyte, gel, hemolysis assay, hydrophobicity, in vitro study, ionic strength, membrane damage, methicillin resistant Staphylococcus aureus, minimum inhibitory concentration, nanoencapsulation, nonhuman, particle size, photon correlation spectroscopy, priority journal, protein degradation, protein secretion, protein stability, static electricity, zeta potential
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-223121 (URN)10.1016/j.jcis.2017.11.014 (DOI)2-s2.0-85034020350 (Scopus ID)
Note

Export Date: 13 February 2018; Article; CODEN: JCISA; Correspondence Address: Nordström, R.; Department of Pharmacy, Uppsala UniversitySweden; email: randi.nordstrom@farmaci.uu.se; Funding details: 604182. QC 20180327

Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-03-27Bibliographically approved
Kikionis, S., Ioannou, E., Andrén, O. C. J., Chronakis, I. S., Fahmi, A., Malkoch, M., . . . Roussis, V. (2018). Nanofibrous nonwovens based on dendritic-linear-dendritic poly(ethylene glycol) hybrids. Journal of Applied Polymer Science, 135(10), Article ID 45949.
Open this publication in new window or tab >>Nanofibrous nonwovens based on dendritic-linear-dendritic poly(ethylene glycol) hybrids
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2018 (English)In: Journal of Applied Polymer Science, ISSN 0021-8995, E-ISSN 1097-4628, Vol. 135, no 10, article id 45949Article in journal (Refereed) Published
Abstract [en]

Dendritic-linear-dendritic (DLD) hybrids are highly functional materials combining the properties of linear and dendritic polymers. Attempts to electrospin DLD polymers composed of hyperbranched dendritic blocks of 2,2-bis(hydroxymethyl) propionic acid on a linear poly(ethylene glycol) core proved unsuccessful. Nevertheless, when these DLD hybrids were blended with an array of different biodegradable polymers as entanglement enhancers, nanofibrous nonwovens were successfully prepared by electrospinning. The pseudogeneration degree of the DLDs, the nature of the co-electrospun polymer and the solvent systems used for the preparation of the electrospinning solutions exerted a significant effect on the diameter and morphology of the electrospun fibers. It is worth-noting that aqueous solutions of the DLD polymers and only 1% (w/v) poly(ethylene oxide) resulted in the production of smoother and thinner nanofibers. Such dendritic nanofibrous scaffolds can be promising materials for biomedical applications due to their bio-compatibility, biodegradability, multifunctionality, and advanced structural architecture.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-220581 (URN)10.1002/app.45949 (DOI)000417601900014 ()2-s2.0-85032836783 (Scopus ID)
Note

QC 20180124

Available from: 2018-01-24 Created: 2018-01-24 Last updated: 2018-03-13Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-9200-8004

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