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Department of Pharmacy > Employees

Martin Malmsten

Martin Malmsten

Professor

Member of:

    Primary research areas

    Surface and colloid chemistry, nanomaterials, drug delivery, peptide therapeutics

     

    Summary of research achievements 

    Over the years at the University of Lund and at Astra Arcus, Malmsten’s research focused on polymers in solution and at interfaces. Particular emphasis was placed on the interfacial behavior of nonionic polymers, as well as its consequences for forces between polymer-coated surfaces and for steric stabilization of dispersions by such polymers (1,2). Together with colleagues at the Royal Institute of Technology and at the University of Lund, he was among the first in Sweden to employ surface analytical techniques such as ellipsometry, surface force measurements, and neutron scattering on such systems, and was able to demonstrate both interfacial orientation effects and effects of interfacial crowding for surface interactions. Based on thus clarified mechanisms of the temperature dependence displayed by such systems, he was also able to design a method in which this temperature dependence of adsorbed polymers was employed to immobilize proteins to inherently protein-rejecting surfaces, of significant interest, e.g., in solid phase diagnostics and biosensors.  This technology was subsequently out-licenced to a diagnostics company.

    Parallel to the work on polymers at interfaces, Malmsten worked on clarifying the self-assembly of PEO-PPO-PEO block copolymers, primarily in solution, but also at interfaces (3,4). The majority of this work was experimental, but the research contained also theoretical studies through collaborations at Lund University, notably using mean-field models for polymers in solution and at interfaces. Together, this resulted in a series of papers analyzing effects of solutes, homopolymers, and water diffusion, which have all generated considerable citation numbers, and still do so today, some 20 years later. In 1993, Malmsten was awarded the Nordic Surface Chemistry Price for his research in this area.

    After his move to YKI, emphasis was shifted to proteins at interfaces, employing the same experimental techniques used previously for polymers. Within this area, Malmsten demonstrated how ellipsometry in particular could be used to follow the structural progression during adsorbed layer formation, which led to an understanding of effects such as interfacial crowding, re-orientations, and competitive spreading (5). In a second line of research, the role of protein adsorption in biomedical applications was investigated, e.g., clarifying the interplay between serum protein adsorption and bloodstream circulation of lipid-based drug delivery systems (6), and dissecting factors determining the protein rejection displayed by surfaces containing poly(ethylene glycol) chains (7). Also based on methodologies and the concepts derived from the more fundamental research on adsorbed protein layer formation, Malmsten, together with colleagues at the Free University of Berlin (now Charité), designed an atheroschlerosis biosensor, with which model studies of the deposition of various lipoproteins (atherosclerotic risk factors) as well as clinical patient samples was performed, correlating the results obtained with a range of other biomarkers, as well as with clinical results on atherosclerotic risk and effects of drugs in patient groups (8). In a series of investigations, this approach was found to have potential for evaluating candidate drugs, assessing therapies, and monitoring atherosclerotic risk, e.g., for atherosclerosis in diabetes type II patients, as well as secondary atherosclerosis in bypass operation patients. In 2002, Malmsten was awarded the prestidgeous Langmuir Lecture Award from ACS for his research on protein adsorption. 

    After moving to Uppsala University, Malmsten’s research shifted to amphiphilic peptides, an area of intense current interest, e.g., as a result of multi-resistance development against antibiotics. Based on a biological perspective, in which constant microbial colonialization results in proteolytic degradation of endogenous proteins and the release of a host of peptides, a number of endogenous peptides were identified, which display high antimicrobial and anti-inflammatory activity, but little or no toxicity on eukaryotic cells. These peptides, which have been identified from sequences originating from complement proteins, contact activation proteins, matrix proteins, coagulation factors, growth factors, and other serum proteins, have been investigated regarding both their mode-of-action and biological properties in collaboration with colleagues at Lund University. In addition, end-tagging such peptides with short aromatic amino acid stretches was demonstrated as a way to significantly increase potency and selectivity of such peptides (9). Troughout, a broad approach was used, spanning from detailed biophysical studies, to biological tests on the cellular level, and experiments in animal models (9,10). For one of the peptides identified, two successful Phase I/II clinical trials have been performed through a start-up company formed together with a colleague at Lund University and Karolinska Development AB. During the last few years, attention has moved to clarifying the interaction of anti-inflammatory peptides with non-lipid membrane components, notably microbial liposaccharides (LPS and LTA), playing a key role for inflammation triggered by bacteria and fungi. Building on methodologies established for investigating peptide interaction with lipid membranes, this work expanded to such polysaccharides and their different structural moieties. Through this, mechanistic insight could be obtained, notably in relation to direct scavenging of inflammation-triggering lipid A by direct peptide binding, peptide-induced membrane scavenging of LPS, and phagocytosis-facilitating LPS aggregate disruption, the latter two providing alternative pathways to the inflammation-triggering one (11). Furthermore, mechanistic studies led to identification of conditions, under which PEGylation of anti-inflammatory peptides allows adverse effects relating to toxicity, serum protein binding and bloodstream clearence to be suppressed, while maintaining the anti-inflammatory effects of such peptides (12). Again, this fundamental work was accompanied by more applied efforts, in which peptides were evaluated regarding their anti-inflammatory potency through a start-up company formed together with a colleague at Lund University and LUBio. Through this, a collaboration was established with a larger pharmaceutical company for bringing the lead peptide into clinical trials.

    In a second leg of research, delivery systems for amphiphilic peptide drugs have been investigated, with particular focus on microgels. These offer interesting possibilities in this context due to an "abrupt responsiveness" (swelling/deswelling, non-adhesion/adhesion, stability/aggregation, release/encapsulation) related to their macromolecular nature. Together with colleagues at Uppsala University, Malmsten established an experimental platform for investigating such systems in detail, based on micromanipulator-assisted light and fluorescence microscopy for detailed studies of microgel swelling/deswelling kinetics, and confocal microscopy for investigation of peptide distribution and dynamics within microgels (13). Through these and various additional experimental tools, as well as theoretical models, Malmsten employed the peptide-design experience developed in the membrane work to microgels. Through controlled structural variations on the single amino acid level, this enabled elucidation of effects of peptide charge (distribution), hydrophobicity (distribution), length, conformational stability, end-caps, and cyclization on microgel loading, distribution, and release, together with effects of gel properties and ambient conditions (14). Also factors affecting biodegradation of peptides loaded into microgels, and of microgels containing peptides/proteins, have been elucidated (15). In 2012, Malmsten was awarded the Norblad-Ekstrand Medal for his work on amphiphilic peptides.

    In parallel, attention has been increasingly placed on a wider range of delivery systems for antimicrobial and anti-inflammatory peptides, aiming at addressing challenging infections such as those characterized by biofilm formation and/or extensive proteolytic activity (e.g., burn wounds and cystic fibrosis), or for infections in which bacteria are localized within macrophages (e.g., tuberculosis). Here, attention has been placed on inorganic nanoparticles, such as mesoporous silica (nanoparticles) and layered double hydroxide nanoparticles, where effects of particle size and charge asymmetry, or charge/porosity, have been investigated with a battery of biophysical methods in combination with biological effect studies of antimicrobial effect, cell toxicity, and protection from proteolytic degradation (16,17). In addition to membrane disruption, the latter studies have demonstrated the importance also of bacterial flocculation as a mechanism for infection confinement, of potential therapeutic interest (18).

    In addition of work on infection and inflammation, focus has also been placed on anti-cancer therapeutics and anti-cancer delivery systems. For example, W-tagging of arginine-rich peptides was demonstrated to provide a tool for increasing selective peptide internalization in melanoma cells, resulting in toxicity against these, but not against the non-malignant cells. From a combination of biophysical studies on membrane binding/destabilization and biological studies on cell uptake and toxicity, these effects were shown to be due to increased peptide adsorption to the outer membrane in melanoma cells, caused by the presence of anionic lipids such as phosphatidylserine and ganglioside GM1, and to peptide effects on mitochondria membranes and resulting apoptosis. In addition, such W-tagged peptides could be used for achieving targeted uptake of nanoparticles/drug carriers in melanoma, as well as for facilitating uptake of the low Mw anticancer drug doxorubicin (19). Furthermore, Malmsten et al. introduced the concept of hybrid nanoparticles, prepared by precipitation of polymer-based nanoparticles by sub- or super-critical CO2, as carriers for protein kinase inhibitors, enabling delivery of high doses of these very challenging but therapeutically extremely important drugs. Following structure-function analyses of composition and processing, such hybrid nanoparticles were demonstrated to result in 8-fold increase in oral bioavailability in dogs (compared to the existing product on the market) for nilotinib (20). Subsequently, a similar 5-10-fold increase in oral bioavailability in dogs was demonstrated in follow-up studies for a number of key protein kinase inhibitors. In addition, hybrid nanoparticles were demonstrated in a series of clinical trials on humans to result in excellent bioavailability. Considering the dominating role of protein kinase inhibitors in cancer therapeutics, reaching increased performance of such drugs is potentially very important. Again, parallel to the academic research, development aspects of tumor delivery systems were addressed in a start-up company formed together with colleagues at Uppsala University. 

    After his move to the University of Copenhagen late 2016, research focus on drug delivery has been further accentuated, notably in relation to cutaneous drug delivery of both biologicals and low molecular weight drugs, where current efforts focus on the combination of advanced analytical techniques, novel delivery systems, and novel biological models as a tool to reach improved therapeutic outcome.

    Selected publications

    1.         Ellipsometry Studies of the Adsorption of Cellulose Ethers.

                M. Malmsten and B. Lindman,

                Langmuir 1990, 6, 357.

    2.         Temperature-Dependent Forces Between Hydrophobic Surfaces Coated with              Ethyl(hydroxyethyl)cellulose.

                M. Malmsten, P.M. Claesson, E. Pezron and I. Pezron,

                Langmuir 1990, 6, 1572.

    3.         Self-Assembly in Aqueous Block Copolymer Solutions.

                M. Malmsten and B. Lindman,

                Macromolecules 1992, 25, 5440.

    4.         Temperature-Dependent Micellization in Aqueous Block Copolymer              Solutions.

                P. Linse and M. Malmsten,

                Macromolecules  1992, 25, 5434.

    5.         Ellipsometry Studies of Protein Layers Adsorbed at Hydrophobic                   Surfaces.

                M. Malmsten

                J. Colloid Interface Sci. 1994, 166, 333. 

    6.         Protein Adsorption at Phospholipid Surfaces.

                M. Malmsten

                J. Colloid Interface Sci. 1995, 172, 106. 

    7.         Effects of Chain Density on Inhibition of Protein Adsorption by Poly(ethylene glycol)       Based Coatings.

                M. Malmsten,  K Emoto and J.M. Van Alstine

                J. Colloid Interface Sci.1998, 202, 507.

    8.         Reduction of Arteriosclerotic Nanoplaque Formation and Size by Ginkgo Biloba (EGb 761) in Cardiovascular High-Risk Patients

    M. Rodríguez, L. Ringstad, P. Schäfer, S. Just, H.W. Hofer, M. Malmsten, and G. Siegel

    Atherosclerosis 2007, 192, 438.

    9.         Boosting Antimicrobial Peptides by Hydrophobic Amino Acids

    A. Schmidtchen, M. Pasupuleti, M. Mörgelin, M. Davoudi, J. Alenfall, A. Chalupka and M. Malmsten

    J. Biol. Chem. 2009, 284, 17584.

    10.       An Electrochemical Study on the Interaction between Complement-Derived Peptides and DOPC Mono- and Bilayers

    L. Ringstad, E. Protopapa, B. Lindholm-Sethson, A. Schmidtchen, A. Nelson and M. Malmsten

    Langmuir 2008, 24, 208.

    11.       Importance of Lipopolysaccharide Aggregate Disruption for Anti-Endotoxic Effects of Heparin Cofactor II Peptides

                S. Singh, M. Kalle, P. Papareddy, A. Schmidtchen, and M. Malmsten

                Biochim. Biophys. Acta. 2013, 1828, 2709. 

    12.       Effect of PEGylation on Membrane and Lipopolysaccharide Interactions of Host Defense Peptides

    S. Singh, P. Papareddy, M. Mörgelin, A. Schmidtchen, and M. Malmsten

    Biomacromolecules 2014, 15, 1337.

    13.       Visualizing the Interaction between Poly-L-Lysine and Poly(Acrylic Acid) Microgels using Microscopy Techniques: Effect of Electrostatics and Peptide Size

                H. Bysell and M. Malmsten

                Langmuir 2006, 22, 5476.

    14.       Effect of Charge Density on the Interaction between Cationic Peptides and Oppositely Charged Microgels

    H. Bysell, P. Hansson, and M. Malmsten

    J. Phys. Chem. B 2010, 114, 7207.

    15.       Factors Affecting Enzymatic Degradation of Microgel-Bound Peptides

    R. Månsson, G. Frenning, and M. Malmsten

    Biomacromolecules 2013, 14, 2317.

    16.       Incorporation of Antimicrobial Compounds in Mesoporous Silica

    I. Izquierdo-Barba, M. Vallet-Regi, N. Kupferschmidt, O. Terasaki, A. Schmidtchen and M. Malmsten

    Biomaterials 2009, 30, 5729. 

    17.       Membrane Interactions of Mesoporous Silica Nanoparticles as Carriers of Antimicrobial         Peptides

    K. Braun, A. Pochert, M. Lindén, M. Davoudi, A. Schmidtchen, R. Nordström, and M. Malmsten

                J. Colloid Interface Sci. 2016, 475, 161.

    18.       Membrane Interactions and Antimicrobial Effects of Layered Double Hydroxide Nanoparticles

                S. Malekkhaiat Häffner, L. Nyström, R. Nordström, Z.P. Xu, M. Davoudi, A.             Schmidtchen, and M. Malmsten

    Phys. Chem. Chem. Phys., 2017, 19, 23832.

    19.       Pronounced Peptide Selectivity for Melanoma through Tryptophan End-Tagging

                D.T. Duong, S. Singh, M. Bagheri, N.K. Verma, A. Schmitchen, and M. Malmsten

                Sci. Reports 2016, 6:24952, 1.

    20.       Carbon Dioxide-Mediated Generation of Hybrid Nanoparticles for Improved Bioavailability of Protein Kinase Inhibitors

    G. Jesson, M. Brisander, P. Andersson, M. Demirbüker, H. Derand, H. Lennernäs, and M. Malmsten

    Pharm. Res. 2014, 31, 694.

    Primary fields of research

    Nanomaterials, drug delivery, amphiphilic peptide therapeutics

    ID: 166302730