Recent Submissions

  • Co-Delivery of mRNA and pDNA Using Thermally Stabilized Coacervate-Based Core-Shell Nanosystems.

    Nasr, Sarah S; Lee, Sangeun; Thiyagarajan, Durairaj; Boese, Annette; Loretz, Brigitta; Lehr, Claus-Michael; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (MDPI, 2021-11-13)
    Co-delivery of different species of protein-encoding polynucleotides, e.g., messenger RNA (mRNA) and plasmid DNA (pDNA), using the same nanocarrier is an interesting topic that remains scarcely researched in the field of nucleic acid delivery. The current study hence aims to explore the possibility of the simultaneous delivery of mRNA (mCherry) and pDNA (pAmCyan) using a single nanocarrier. The latter is based on gelatin type A, a biocompatible, and biodegradable biopolymer of broad pharmaceutical application. A core-shell nanostructure is designed with a thermally stabilized gelatin-pDNA coacervate in its center. Thermal stabilization enhances the core's colloidal stability and pDNA shielding effect against nucleases as confirmed by nanoparticle tracking analysis and gel electrophoresis, respectively. The stabilized, pDNA-loaded core is coated with the cationic peptide protamine sulfate to enable additional surface-loading with mRNA. The dual-loaded core-shell system transfects murine dendritic cell line DC2.4 with both fluorescent reporter mRNA and pDNA simultaneously, showing a transfection efficiency of 61.4 ± 21.6% for mRNA and 37.6 ± 19.45% for pDNA, 48 h post-treatment, whereas established commercial, experimental, and clinical transfection reagents fail. Hence, the unique co-transfectional capacity and the negligible cytotoxicity of the reported system may hold prospects for vaccination among other downstream applications.
  • Interaction of myxobacteria-derived outer membrane vesicles with biofilms: antiadhesive and antibacterial effects.

    Goes, Adriely; Vidakovic, Lucia; Drescher, Knut; Fuhrmann, Gregor; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Royal Society of Chemistry, 2021-08-02)
    Bacterial biofilms are widespread in nature and in medical settings and display a high tolerance to antibiotics and disinfectants. Extracellular vesicles have been increasingly studied to characterise their origins and assess their potential for use as a versatile drug delivery system; however, it remains unclear whether they also have antibiofilm effects. Outer membrane vesicles are lipid vesicles shed by Gram-negative bacteria and, in the case of myxobacteria, carry natural antimicrobial compounds produced by these microorganisms. In this study, we demonstrate that vesicles derived from the myxobacteria Cystobacter velatus Cbv34 and Cystobacter ferrugineus Cbfe23 are highly effective at inhibiting the formation and disrupting biofilms by different bacterial species.
  • Exploring the permeation of fluoroquinolone metalloantibiotics across outer membrane porins by combining molecular dynamics simulations and a porin-mimetic in vitro model.

    Sousa, Carla F; Coimbra, João T S; Richter, Robert; Morais-Cabral, João H; Ramos, Maria J; Lehr, Claus-Michael; Fernandes, Pedro A; Gameiro, Paula; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Elsevier, 2021-12-08)
    The misuse and overuse of fluoroquinolones in recent years have triggered alarming levels of resistance to these antibiotics. Porin channels are crucial for the permeation of fluoroquinolones across the outer membrane of Gram-negative bacteria and modifications in porin expression are an important mechanism of bacterial resistance. One possible strategy to overcome this problem is the development of ternary copper complexes with fluoroquinolones. Compared to fluoroquinolones, these metalloantibiotics present a larger partition to the lipid bilayer and a more favorable permeation, by passive diffusion, across bacteriomimetic phospholipid-based model membranes. To rule out the porin-dependent pathway for the metalloantibiotics, we explored the permeation through OmpF (one of the most abundant porins present in the outer membrane of Gram-negative bacteria) using a multi-component approach. X-ray studies of OmpF porin crystals soaked with a ciprofloxacin ternary copper complex did not show a well-defined binding site for the compound. Molecular dynamics simulations showed that the translocation of the metalloantibiotic through this porin is less favorable than that of free fluoroquinolone, as it presented a much larger free energy barrier to cross the narrow constriction region of the pore. Lastly, permeability studies of different fluoroquinolones and their respective copper complexes using a porin-mimetic in vitro model corroborated the lower rate of permeation for the metalloantibiotics relative to the free antibiotics. Our results support a porin-independent mechanism for the influx of the metalloantibiotics into the bacterial cell. This finding brings additional support to the potential application of these metalloantibiotics in the fight against resistant infections and as an alternative to fluoroquinolones.
  • PerfuPul-A Versatile Perfusable Platform to Assess Permeability and Barrier Function of Air Exposed Pulmonary Epithelia.

    Carius, Patrick; Dubois, Aurélie; Ajdarirad, Morvarid; Artzy-Schnirman, Arbel; Sznitman, Josué; Schneider-Daum, Nicole; Lehr, Claus-Michael; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany. (Frontiers, 2021-10-06)
    Complex in vitro models, especially those based on human cells and tissues, may successfully reduce or even replace animal models within pre-clinical development of orally inhaled drug products. Microfluidic lung-on-chips are regarded as especially promising models since they allow the culture of lung specific cell types under physiological stimuli including perfusion and air-liquid interface (ALI) conditions within a precisely controlled in vitro environment. Currently, though, such models are not available to a broad user community given their need for sophisticated microfabrication techniques. They further require systematic comparison to well-based filter supports, in analogy to traditional Transwells®. We here present a versatile perfusable platform that combines the advantages of well-based filter supports with the benefits of perfusion, to assess barrier permeability of and aerosol deposition on ALI cultured pulmonary epithelial cells. The platform as well as the required technical accessories can be reproduced via a detailed step-by-step protocol and implemented in typical bio-/pharmaceutical laboratories without specific expertise in microfabrication methods nor the need to buy costly specialized equipment. Calu-3 cells cultured under liquid covered conditions (LCC) inside the platform showed similar development of transepithelial electrical resistance (TEER) over a period of 14 days as cells cultured on a traditional Transwell®. By using a customized deposition chamber, fluorescein sodium was nebulized via a clinically relevant Aerogen® Solo nebulizer onto Calu-3 cells cultured under ALI conditions within the platform. This not only allowed to analyze the transport of fluorescein sodium after ALI deposition under perfusion, but also to compare it to transport under traditional static conditions.
  • Extracellular vesicles as novel assay tools to study cellular interactions of anti-infective compounds - A perspective.

    Richter, Robert; Lehr, Claus-Michael; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Elsevier, 2021-04-20)
    Sudden outbreaks of novel infectious diseases and the persistent evolution of antimicrobial resistant pathogens make it necessary to develop specific tools to quickly understand pathogen-cell interactions and to study appropriate drug delivery strategies. Extracellular vesicles (EVs) are cell-specific biogenic transport systems, which are gaining more and more popularity as either diagnostic markers or drug delivery systems. Apart from that, there are emerging possibilities for EVs as tools to study drug penetration, drug-membrane interactions as well as pathogen-membrane interactions. However, it appears that the potential of EVs for such applications has not been fully exploited yet. Considering the vast variety of cells that can be involved in an infection, vesicle-based analytical methods are just emerging and the number of reported applications is still relatively small. Aim of this review is to discuss the current state of the art of EV-based assays, especially in the context of antimicrobial research and therapy, and to present some new perspectives for a more exhaustive and creative exploration in the future.
  • Towards the sustainable discovery and development of new antibiotics.

    Miethke, Marcus; Pieroni, Marco; Weber, Tilmann; Brönstrup, Mark; Hammann, Peter; Halby, Ludovic; Arimondo, Paola B; Glaser, Philippe; Aigle, Bertrand; Bode, Helge B; et al. (Springer Nature, 2021-08-19)
    An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
  • A Custom-Made Device for Reproducibly Depositing Pre-metered Doses of Nebulized Drugs on Pulmonary Cells .

    Horstmann, Justus C; Thorn, Chelsea R; Carius, Patrick; Graef, Florian; Murgia, Xabier; de Souza Carvalho-Wodarz, Cristiane; Lehr, Claus-Michael; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Frontiers, 2021-04-21)
    The deposition of pre-metered doses (i.e., defined before and not after exposition) at the air-liquid interface of viable pulmonary epithelial cells remains an important but challenging task for developing aerosol medicines. While some devices allow quantification of the deposited dose after or during the experiment, e.g., gravimetrically, there is still no generally accepted way to deposit small pre-metered doses of aerosolized drugs or pharmaceutical formulations, e.g., nanomedicines. Here, we describe a straightforward custom-made device, allowing connection to commercially available nebulizers with standard cell culture plates. Designed to tightly fit into the approximately 12-mm opening of either a 12-well Transwell® insert or a single 24-well plate, a defined dose of an aerosolized liquid can be directly deposited precisely and reproducibly (4.8% deviation) at the air-liquid interface (ALI) of pulmonary cell cultures. The deposited dose can be controlled by the volume of the nebulized solution, which may vary in a range from 20 to 200 μl. The entire nebulization-deposition maneuver is completed after 30 s and is spatially homogenous. After phosphate-buffered saline (PBS) deposition, the viability and barrier properties transepithelial electrical resistance (TEER) of human bronchial epithelial Calu-3 cells were not negatively affected. Straightforward in manufacture and use, the device enables reproducible deposition of metered doses of aerosolized drugs to study the interactions with pulmonary cell cultures grown at ALI conditions.
  • Drug delivery for fighting infectious diseases: a global perspective.

    Loretz, Brigitta; Oh, Yu-Kyoung; Hudson, Sarah; Gu, Zhen; Lehr, Claus-Michael; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (SPringer, 2021-06-09)
    [No abstract available]
  • Towards More Predictive, Physiological and Animal-free in vitro Models: Advances in Cell and Tissue Culture 2020 Conference Proceedings.

    Singh, Bhumika; Abdelgawad, Mohamed Essameldin; Ali, Zulfiqur; Bailey, Jarrod; Budyn, Elisa; Civita, Prospero; Clift, Martin J D; Connelly, John T; Constant, Samuel; Hittinger, Marius; et al. (Fund for the Replacement of Animals in Medical Experiments (FRAME), 2021-07-06)
    Experimental systems that faithfully replicate human physiology at cellular, tissue and organ level are crucial to the development of efficacious and safe therapies with high success rates and low cost. The development of such systems is challenging and requires skills, expertise and inputs from a diverse range of experts, such as biologists, physicists, engineers, clinicians and regulatory bodies. Kirkstall Limited, a biotechnology company based in York, UK, organised the annual conference, Advances in Cell and Tissue Culture (ACTC), which brought together people having a variety of expertise and interests, to present and discuss the latest developments in the field of cell and tissue culture and in vitro modelling. The conference has also been influential in engaging animal welfare organisations in the promotion of research, collaborative projects and funding opportunities. This report describes the proceedings of the latest ACTC conference, which was held virtually on 30th September and 1st October 2020, and included sessions on in vitro models in the following areas: advanced skin and respiratory models, neurological disease, cancer research, advanced models including 3-D, fluid flow and co-cultures, diabetes and other age-related disorders, and animal-free research. The roundtable session on the second day was very interactive and drew huge interest, with intriguing discussion taking place among all participants on the theme of replacement of animal models of disease.
  • Extracellular vesicles as a next-generation drug delivery platform.

    Herrmann, Inge Katrin; Wood, Matthew John Andrew; Fuhrmann, Gregor; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Springer Nature, 2021-07-01)
    Extracellular-vesicle-based cell-to-cell communication is conserved across all kingdoms of life. There is compelling evidence that extracellular vesicles are involved in major (patho)physiological processes, including cellular homoeostasis, infection propagation, cancer development and cardiovascular diseases. Various studies suggest that extracellular vesicles have several advantages over conventional synthetic carriers, opening new frontiers for modern drug delivery. Despite extensive research, clinical translation of extracellular-vesicle-based therapies remains challenging. Here, we discuss the uniqueness of extracellular vesicles along with critical design and development steps required to utilize their full potential as drug carriers, including loading methods, in-depth characterization and large-scale manufacturing. We compare the prospects of extracellular vesicles with those of the well established liposomes and provide guidelines to direct the process of developing vesicle-based drug delivery systems.
  • Mastering the Gram-negative bacterial barrier - Chemical approaches to increase bacterial bioavailability of antibiotics.

    Ropponen, Henni-Karoliina; Richter, Robert; Hirsch, Anna K H; Lehr, Claus Michael; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Elsevier, 2021-03-08)
    To win the battle against resistant, pathogenic bacteria, novel classes of anti-infectives and targets are urgently needed. Bacterial uptake, distribution, metabolic and efflux pathways of antibiotics in Gram-negative bacteria determine what we here refer to as bacterial bioavailability. Understanding these mechanisms from a chemical perspective is essential for anti-infective activity and hence, drug discovery as well as drug delivery. A systematic and critical discussion of in bacterio, in vitro and in silico assays reveals that a sufficiently accurate holistic approach is still missing. We expect new findings based on Gram-negative bacterial bioavailability to guide future anti-infective research.
  • Tobramycin Liquid Crystal Nanoparticles Eradicate Cystic Fibrosis-Related Pseudomonas aeruginosa Biofilms.

    Thorn, Chelsea R; Carvalho-Wodarz, Cristiane de Souza; Horstmann, Justus C; Lehr, Claus-Michael; Prestidge, Clive A; Thomas, Nicky; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Wiley-VCH, 2021-05-12)
    Pseudomonas aeruginosa biofilms cause persistent and chronic infections, most known clinically in cystic fibrosis (CF). Tobramycin (TOB) is a standard anti-pseudomonal antibiotic; however, in biofilm infections, its efficacy severely decreases due to limited permeability across the biofilm matrix. Herewith, a biomimetic, nanostructured, lipid liquid crystal nanoparticle-(LCNP)-formulation is discovered to significantly enhance the efficacy of TOB and eradicate P. aeruginosa biofilm infections. Using an advanced, biologically-relevant co-culture model of human CF bronchial epithelial cells infected with P. aeruginosa biofilms at an air-liquid interface, nebulized TOB-LCNPs completely eradicated 1 × 109 CFU mL-1 of P. aeruginosa after two doses, a 100-fold improvement over the unformulated antibiotic. The enhanced activity of TOB is not observed with a liposomal formulation of TOB or with ciprofloxacin, an antibiotic that readily penetrates biofilms. It is demonstrated that the unique nanostructure of the LCNPs drives the enhanced penetration of TOB across the biofilm barrier, but not through the healthy lung epithelium barrier, significantly increasing the available antibiotic concentration at the site of infection. The LCNPs are an innovative strategy to improve the performance of TOB as a directed pulmonary therapy, enabling the administration of lower doses, reducing the toxicity, and amplifying the anti-biofilm activity of the anti-pseudomonal antibiotic.
  • Spray-dried lactose-leucine microparticles for pulmonary delivery of antimycobacterial nanopharmaceuticals.

    Thiyagarajan, Durairaj; Huck, Benedikt; Nothdurft, Birgit; Koch, Marcus; Rudolph, David; Rutschmann, Mark; Feldmann, Claus; Hozsa, Constantin; Furch, Marcus; Besecke, Karen F W; et al. (2021-06-08)
  • Fucosylated lipid nanocarriers loaded with antibiotics efficiently inhibit mycobacterial propagation in human myeloid cells.

    Durán, Verónica; Grabski, Elena; Hozsa, Constantin; Becker, Jennifer; Yasar, Hanzey; Monteiro, João T; Costa, Bibiana; Koller, Nicole; Lueder, Yvonne; Wiegmann, Bettina; et al. (Elsevier, 2021-04-16)
    Antibiotic treatment of tuberculosis (TB) is complex, lengthy, and can be associated with various adverse effects. As a result, patient compliance often is poor, thus further enhancing the risk of selecting multi-drug resistant bacteria. Macrophage mannose receptor (MMR)-positive alveolar macrophages (AM) constitute a niche in which Mycobacterium tuberculosis replicates and survives. Therefore, we encapsulated levofloxacin in lipid nanocarriers functionalized with fucosyl residues that interact with the MMR. Indeed, such nanocarriers preferentially targeted MMR-positive myeloid cells, and in particular, AM. Intracellularly, fucosylated lipid nanocarriers favorably delivered their payload into endosomal compartments, where mycobacteria reside. In an in vitro setting using infected human primary macrophages as well as dendritic cells, the encapsulated antibiotic cleared the pathogen more efficiently than free levofloxacin. In conclusion, our results point towards carbohydrate-functionalized nanocarriers as a promising tool for improving TB treatment by targeted delivery of antibiotics.
  • Development and evaluation of a quality control system based on transdermal electrical resistance for skin barrier function in vitro.

    Knoth, Katharina; Zäh, Ralf-Kilian; Veldung, Barbara; Burgio, Dominic; Wiegand, Birgit; Smola, Hans; Bock, Udo; Lehr, Claus-Michael; Hittinger, Marius; Groß, Henrik; et al. (Wiley & Sons, 2021-01-06)
    Background: In vitro skin permeation experiments are highly relevant for pharmaceutical, cosmetic, agricultural developments, and regulatory evaluation. A key requirement is the skin barrier integrity, that is accompanied by an intact stratum corneum (SC) which implements high skin quality. A variety of integrity tests are currently available, for example, measurement of transepidermal water loss, monitoring the permeation of tritiated water and the measurement of transdermal electrical resistance (TER). Materials and methods: We aimed for a non-destructive examination of barrier integrity as quality control system, based on TER. Therefore, the in-house developed instrument SkinTER measures electrical resistance on excised human skin samples in a non-invasive and easy-to-use pattern. In this proof of concept study, we compared three human in vitro skin models with focus on their TER and permeation properties. The skin integrity was impaired to mimic conditions of skin during age, lifestyle (eg, shaving) or diseases (eg, obesity, psoriasis, and atopic dermatitis). The OECD permeation marker caffeine was correlated to the corresponding TER value. Results: A correlation between both was obtained by having a Pearson coefficient of -0.830. Hereby, a minimum TER value for intact skin samples of ~1.77 kΩ*cm2 was suggested. Intact samples are significantly different (α = ≤0.05) to their impaired counterparts in flux and TER values. Conclusion: The new SkinTER instrument gives a quick and non-invasive feedback on skin quality before a permeation experiment.
  • Approaches to surface engineering of extracellular vesicles.

    Richter, Maximilian; Vader, Pieter; Fuhrmann, Gregor; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Elsevier, 2021-04-06)
    Extracellular vesicles (EVs) are cell-derived nanoparticles that are important mediators in intercellular communication. This function makes them auspicious candidates for therapeutic and drug-delivery applications. Among EVs, mammalian cell derived EVs and outer membrane vesicles (OMVs) produced by gram-negative bacteria are the most investigated candidates for pharmaceutical applications. To further optimize their performance and to utilize their natural abilities, researchers have strived to equip EVs with new moieties on their surface while preserving the integrity of the vesicles. The aim of this review is to give a comprehensive overview of techniques that can be used to introduce these moieties to the vesicle surface. Approaches can be classified in regards to whether they take place before or after the isolation of EVs. The producing cells can be subjected to genetic manipulation or metabolic engineering to produce surface modified vesicles or EVs are engineered after their isolation by physical or chemical means. Here, the advantages and disadvantages of these processes and their applicability for the development of EVs as therapeutic agents are discussed.
  • Formulation and evaluation of transdermal nanogel for delivery of artemether.

    Nnamani, Petra O; Ugwu, Agatha A; Nnadi, Ogechukwu H; Kenechukwu, Franklin C; Ofokansi, Kenneth C; Attama, Anthony A; Lehr, Claus-Michael; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Springer, 2021-03-19)
    rtemether (ART) is second to artesunate in being the most widely used derivatives of artemisinin in combination therapy of malaria. Nanostructured lipid carrier (NLC) formulations were prepared following our previous report using optimized ART concentration of 0.25 g dissolved in 5% w/v mixture of solid (Gelucire 43/01 and Phospholipon 85G) and liquid (Transcutol) lipids at 90 °C. An aqueous surfactant phase at 90 °C was added (dropwise) under magnetic stirring (1000 rpm) for 5 min. The pre-emulsion was speedily homogenized at 28,000 rpm for 15 min and further probe sonicated at 60% amplitude (15 min). Resultant sample was cooled at room temperature and frozen at - 80 °C prior to lyophilization. The freeze-dried sample was used for solid-state characterization as well as in the formulation of transdermal nanogels using three polymers (Carbopol 971P, Poloxamer 407, and Prosopis africana peel powder) to embed the ART-NLC, using ethanol as a penetration enhancer. Transdermal ART-nanogels were characterized accordingly (physical examination, pH, drug content, rheology, spreadability, stability, particle size and morphology, skin irritation, in vitro and ex vivo skin permeation, and analysis of permeation data), P < 0.05. Results indicated that ART nanogels showed good encapsulation, drug release, pH-dependent swelling, stability, and tolerability. Overall, ART nanogels prepared from Poloxamer 407 showed the most desirable drug permeation, pH, swellability, spreadability, viscosity, and transdermal antiplasmodial properties superior to PAPP-ANG > C971P-ANG. A two-patch/week concurrent application of the studied nanogels could offer 100% cure of malaria as a lower-dose (50 mg ART) patient-friendly regimen devoid of the drug's many side effects.
  • Bacterial extracellular vesicles: Understanding biology promotes applications as nanopharmaceuticals.

    Jahromi, Leila Pourtalebi; Fuhrmann, Gregor; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Elsevier, 2021-03-25)
    Extracellular vesicle (EV)-mediated communication between proximal and distant cells is a highly conserved characteristic in all of the life domains, including bacteria. These vesicles that contain a variety of biomolecules, such as proteins, lipids, nucleic acids, and small-molecule metabolites play a key role in the biology of bacteria. They are one of the key underlying mechanisms behind harmful or beneficial effects of many pathogenic, symbiont, and probiotic bacteria. These nanoscale EVs mediate extensive crosstalk with mammalian cells and deliver their cargos to the host. They are stable in physiological condition, can encapsulate diverse biomolecules and nanoparticles, and their surface could be engineered with available technologies. Based on favorable characteristics of bacterial vesicles, they can be harnessed for designing a diverse range of therapeutics and diagnostics for treatment of disorders including tumors and resistant infections. However, technical limitations for their production, purification, and characterization must be addressed in future studies.
  • Extracellular vesicles as antigen carriers for novel vaccination avenues.

    Mehanny, Mina; Lehr, Claus-Michael; Fuhrmann, Gregor; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Elsevier, 2021-03-26)
    Antigen delivery has always been a challenge in scientific practice of vaccine formulation. Yet, mammalian extracellular vesicles (EVs) or bacterial membrane vesicles (MVs) provide an innovative avenue for safe and effective delivery of antigenic material. They include intrinsically loaded antigens from EV-secreting cells or extrinsically loaded antigens onto pre-formed vesicles. Interestingly, many studies shed light on potential novel anti-cancer vaccination immunotherapy for therapeutic applications from mammalian cell host-derived EVs, as well as conventional vaccination for prophylactic applications using bacterial cell-derived MVs against infectious diseases. Here, we discuss the rationale, status quo and potential for both vaccine applications using EVs.
  • A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms

    Schütz, Christian; Ho, Duy‐Khiet; Hamed, Mostafa Mohamed; Abdelsamie, Ahmed Saad; Röhrig, Teresa; Herr, Christian; Kany, Andreas Martin; Rox, Katharina; Schmelz, Stefan; Siebenbürger, Lorenz; et al. (Wiley and Sons Inc., 2021-03-18)
    Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence – can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry‐driven hit‐to‐lead optimization and in‐depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter‐gene with IC50 values as low as 200 and 11 × 10−9 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI‐tobramycin (Tob) combination against PA biofilms using a tailor‐made squalene‐derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32‐fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker‐mediated therapy against PA infections opening up avenues for preclinical development.

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