fenaroli

• Thompson, Andrew M.; Dal, Nils-Jørgen; Boldrin, Francesca; Rodriguez, Noelia Alonso; Schäfer, Gabriela & Johann, Kerstin [Vis alle 14 forfattere av denne artikkelen] (2026). New antitubercular pretomanid analogues as potent payloads in polymeric micelles: Leveraging zebrafish assays to accelerate lead optimisation. European Journal of Medicinal Chemistry. ISSN 0223-5234. 307. doi: 10.1016/j.ejmech.2026.118622. Fulltekst i vitenarkiv
• Fenaroli, Federico & Griego, Anna (2025). Pre-clinical characterisation : Which animal model is best for infection? I Poma, Alessandro & Rizzello, Loris (Red.), Nanotechnology tools for infection control : Scanning new horizons on next-generation therapies to eradicate pathogens and fight drug resistance. Elsevier. ISSN 9780128239940. s. 281–298. doi: 10.1016/B978-0-12-823994-0.00005-0. Fulltekst i vitenarkiv
• Schäfer, Gabriela; Bi, Dongdong; Fenaroli, Federico; Thompson, Andrew M.; Saris, Anno & Barz, Matthias (2024). Nanoparticles Combining Host-Directed Therapeutics and Antibiotics to Boost Bacterial Killing and Overall Survival of Zebrafish Embryos Infected with Mycobacterium Marinum. Advanced therapeutics. doi: 10.1002/adtp.202400174. Fulltekst i vitenarkiv Vis sammendrag

  The bacterial pathogen, Mycobacterium tuberculosis (Mtb), remains a leading cause of global morbidity and mortality. Due to the complexity of the infection, the limited efficacy of antibiotics, and the increasing incidence of multi-drug resistant strains, novel therapeutics are urgently needed. An interesting new approach is to combine antibiotics with treatments that boost the natural ability of host cells to kill the bacteria, so-called host-directed therapeutics (HDT). Until now, this approach has not been explored in the context of nanoparticle drug delivery, which may offer several advantages. Here, the HDT drug everolimus and the antibiotic ((S)-2-nitro-6-((5-((4-(trifluoromethoxy)phenyl)ethynyl)pyridin-2-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine, drug D) are focused on. Both of these agents, drug D and everolimus, are encapsulated into one single micelle (PeptoMicelles), resulting in formulation C, and compared with micelles containing only drug D (formulation A) or everolimus (formulation B). They are tested in Mtb-infected primary macrophages and THP-1 cells, and in the zebrafish model for TB (Mm infection) using embryo survival analysis. The results show that formulation C, containing drug D and everolimus in one micelle, is significantly more efficient in protecting cells and zebrafish embryos against infection than all other formulations, indicating an improved therapeutic efficacy of HDTs and antibiotics in a single polymeric micelle.

• Bhandari, Madhavi; Soria-Carrera, Héctor; Wohlmann, Jens; Dal, Nils-Jørgen; Fuente, Jesús M. de la & Martín-Rapún, Rafael [Vis alle 8 forfattere av denne artikkelen] (2023). Subcellular localization and therapeutic efficacy of polymeric micellar nanoparticles encapsulating bedaquiline for tuberculosis treatment in zebrafish. Biomaterials Science. ISSN 2047-4830. 11(6), s. 2103–2114. doi: 10.1039/d2bm01835g. Fulltekst i vitenarkiv Vis sammendrag

  The combination drug regimens that have long been used to treat tuberculosis (TB), caused by Mycobacterium tuberculosis, are fraught with problems such as frequent administration, long duration of treatment, and harsh adverse effects, leading to the emergence of multidrug resistance. Moreover, there is no effective preventive vaccine against TB infection. In this context, nanoparticles (NPs) have emerged as a potential alternative method for drug delivery. Encapsulating antibiotics in biodegradable NPs has been shown to provide effective therapy and reduced toxicity against M. tuberculosis in different mammalian models, when compared to conventional free drug administration. Here, we evaluate the localization, therapeutic efficacy and toxic effects of polymeric micellar NPs encapsulating a promising but highly hydrophobic and toxic antitubercular drug bedaquiline (BQ) in zebrafish embryos infected with Mycobacterium marinum. Our study shows that the NP formulation of BQ improves survival and reduces bacterial burden in the infected embryos after treatment when compared to its free form. The intravenously injected BQ NPs have short circulation times due to their rapid and efficient uptake into the endothelial cells, as observed by correlative light and electron microscopy (CLEM).

• Bauer, Tobias A.; Schramm, Jonas; Fenaroli, Federico; Siemer, Svenja; Seidl, Christine I. & Rosenauer, Christine [Vis alle 11 forfattere av denne artikkelen] (2023). Complex Structures Made Simple – Continuous Flow Production of Core Cross-Linked Polymeric Micelles for Paclitaxel Pro-Drug-Delivery. Advanced Materials. ISSN 0935-9648. 35(21), s. 1–9. doi: 10.1002/adma.202210704. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Translating innovative nanomaterials to medical products requires efficient manufacturing techniques that enable large‐scale high‐throughput synthesis with high reproducibility. Drug carriers in medicine embrace a complex subset of tasks calling for multifunctionality. Here, the synthesisof pro‐drug‐loaded core cross‐linked polymeric micelles (CCPMs) in a continuous flow processis reported, which combines the commonly separated steps of micelle formation, core cross‐linking, functionalization, and purification into a single process. Redox‐responsive CCPMs are formed from thiol‐reactive polypept(o)ides of polysarcosine‐ block ‐poly( S ‐ethylsulfonyl‐ l ‐cysteine) and functional cross‐linkers based on dihydrolipoic acid hydrazide for pH‐dependent release of paclitaxel. The precisely controlled microfluidic process allows the production of spherical micelles ( D h  = 35 nm) with low polydispersity values (PDI < 0.1) while avoiding toxic organic solvents and additives with unfavorable safety profiles. Self‐assembly and cross‐linking via slit interdigital micromixers produces 350–700 mg of CCPMs/h per single system, while purification by online tangential flow filtration successfully removes impurities (unimer ≤ 0.5%). The formed paclitaxel‐loaded CCPMs possess the desired pH‐responsive release profile, display stable drug encapsulation, an improved toxicity profile compared to Abraxane (a trademark of Bristol‐Myers Squibb), and therapeutic efficiency in the B16F1‐xenotransplanted zebrafish model. The combination of reactive polymers, functional cross‐linkers, and microfluidics enables the continuous‐flow synthesis of therapeutically active CCPMs in a single process.

• Dal, Nils-Jørgen; Schäfer, Gabriela; Thompson, Andrew; Schmitt, Sascha; Redinger, Natalja & Rodriguez, Noelia Alonso [Vis alle 16 forfattere av denne artikkelen] (2023). Π-Π interactions stabilize PeptoMicelle-based formulations of Pretomanid derivatives leading to promising therapy against tuberculosis in zebrafish and mouse models. Journal of Controlled Release. ISSN 0168-3659. 354, s. 851–868. doi: 10.1016/j.jconrel.2023.01.037. Fulltekst i vitenarkiv Vis sammendrag

  Tuberculosis is the deadliest bacterial disease globally, threatening the lives of millions every year. New antibiotic therapies that can shorten the duration of treatment, improve cure rates, and impede the development of drug resistance are desperately needed. Here, we used polymeric micelles to encapsulate four second-generation derivatives of the antitubercular drug pretomanid that had previously displayed much better in vivo activity against Mycobacterium tuberculosis than pretomanid itself. Because these compounds were relatively hydrophobic and had limited bioavailability, we expected that their micellar formulations would overcome these limitations, reduce toxicities, and improve therapeutic outcomes. The polymeric micelles were based on polypept(o)ides (PeptoMicelles) and were stabilized in their hydrophobic core by π-π interactions, allowing the efficient encapsulation of aromatic pretomanid derivatives. The stability of these π-π-stabilized PeptoMicelles was demonstrated in water, blood plasma, and lung surfactant by fluorescence cross-correlation spectroscopy and was further supported by prolonged circulation times of several days in the vasculature of zebrafish larvae. The most efficacious PeptoMicelle formulation tested in the zebrafish larvae infection model almost completely eradicated the bacteria at non-toxic doses. This lead formulation was further assessed against Mycobacterium tuberculosis in the susceptible C3HeB/FeJ mouse model, which develops human-like necrotic granulomas. Following intravenous administration, the drug-loaded PeptoMicelles significantly reduced bacterial burden and inflammatory responses in the lungs and spleens of infected mice.

• Creamer, Adam; Fiego, Alessandra Lo; Agliano, Alice; Prados-Martin, Lino; Høgset, Håkon & Najer, Adrian [Vis alle 26 forfattere av denne artikkelen] (2023). Modular Synthesis of Semiconducting Graft Copolymers to Achieve “Clickable” Fluorescent Nanoparticles with Long Circulation and Specific Cancer Targeting. Advanced Materials. ISSN 0935-9648. doi: 10.1002/adma.202300413. Fulltekst i vitenarkiv Vis sammendrag

  Semiconducting polymer nanoparticles (SPNs) are explored for applications in cancer theranostics because of their high absorption coefficients, photostability, and biocompatibility. However, SPNs are susceptible to aggregation and protein fouling in physiological conditions, which can be detrimental for in vivo applications. Here, a method for achieving colloidally stable and low‐fouling SPNs is described by grafting poly(ethylene glycol) (PEG) onto the backbone of the fluorescent semiconducting polymer, poly(9,9′‐dioctylfluorene‐5‐fluoro‐2,1,3‐benzothiadiazole), in a simple one‐step substitution reaction, postpolymerization. Further, by utilizing azide‐functionalized PEG, anti‐human epidermal growth factor receptor 2 (HER2) antibodies, antibody fragments, or affibodies are site‐specifically “clicked” onto the SPN surface, which allows the functionalized SPNs to specifically target HER2‐positive cancer cells. In vivo, the PEGylated SPNs are found to have excellent circulation efficiencies in zebrafish embryos for up to seven days postinjection. SPNs functionalized with affibodies are then shown to be able to target HER2 expressing cancer cells in a zebrafish xenograft model. The covalent PEGylated SPN system described herein shows great potential for cancer theranostics.

• Czysch, Christian; Medina-Montano, Carolina; Dal, Nils-Jørgen Knudsen; Dinh, Thi; Fröder, Yannick & Winterwerber, Pia [Vis alle 15 forfattere av denne artikkelen] (2022). End group dye-labeled polycarbonate block copolymers for micellar (immuno-)drug delivery. Macromolecular rapid communications. ISSN 1022-1336. 43(12), s. 1–10. doi: 10.1002/marc.202200095. Fulltekst i vitenarkiv Vis sammendrag

  Defined conjugation of functional molecules to block copolymer end groups is a powerful strategy to enhance the scope of micellar carriers for drug delivery. In this study, an approach to access well-defined polycarbonate-based block copolymers by labeling their end groups with single fluorescent dye molecules is established. Following controlled polymerization conditions, the block copolymers’ primary hydroxy end group can be converted into activated pentafluorophenyl ester carbonates and subsequently aminolyzed with fluorescent dyes that are equipped with primary amines. During a solvent-evaporation process, the resulting end group dye-labeled block copolymers self-assemble into narrowly dispersed ∼25 nm-sized micelles and simultaneously encapsulate hydrophobic (immuno-)drugs. The covalently attached fluorescent tracer can be used to monitor both uptake into cells and stability under biologically relevant conditions, including incubation with blood plasma or during blood circulation in zebrafish embryos. By encapsulation of the toll-like receptor 7/8 (TLR7/8) agonist CL075, immune stimulatory polymeric micelles are generated that get internalized by various antigen-presenting dendritic cells and promote their maturation. Generally, such end group dye-labeled polycarbonate block copolymers display ideal features to permit targeted delivery of hydrophobic drugs to key immune cells for vaccination and cancer immunotherapy.

• Trousil, Jiří; Dal, Nils-Jørgen; Fenaroli, Federico; Schlachet, Inbar; Kubíčková, Pavla & Janoušková, Olga [Vis alle 11 forfattere av denne artikkelen] (2022). Antibiotic-Loaded Amphiphilic Chitosan Nanoparticles Target Macrophages and Kill an Intracellular Pathogen. Small. ISSN 1613-6810. 18(28). doi: 10.1002/smll.202201853. Fulltekst i vitenarkiv
• Najer, Adrian; Belessiotis-Richards, Alexis; Kim, Hyemin; Saunders, Catherine; Fenaroli, Federico & Adrianus, Christopher [Vis alle 15 forfattere av denne artikkelen] (2022). Block Length-Dependent Protein Fouling on Poly(2-oxazoline)-Based Polymersomes: Influence on Macrophage Association and Circulation Behavior. Small. ISSN 1613-6810. 18(27). doi: 10.1002/smll.202201993. Fulltekst i vitenarkiv Vis sammendrag

  Polymersomes are vesicular structures self-assembled from amphiphilic block copolymers and are considered an alternative to liposomes for applications in drug delivery, immunotherapy, biosensing, and as nanoreactors and artificial organelles. However, the limited availability of systematic stability, protein fouling (protein corona formation), and blood circulation studies hampers their clinical translation. Poly(2-oxazoline)s (POx) are valuable antifouling hydrophilic polymers that can replace the current gold-standard, poly(ethylene glycol) (PEG), yet investigations of POx functionality on nanoparticles are relatively sparse. Herein, a systematic study is reported of the structural, dynamic and antifouling properties of polymersomes made of poly(2-methyl-2-oxazoline)-block-poly(dimethylsiloxane)-block-poly(2-methyl-2-oxazoline) (PMOXA-b-PDMS-b-PMOXA). The study relates in vitro antifouling performance of the polymersomes to atomistic molecular dynamics simulations of polymersome membrane hydration behavior. These observations support the experimentally demonstrated benefit of maximizing the length of PMOXA (degree of polymerization (DP) > 6) while keeping PDMS at a minimal length that still provides sufficient membrane stability (DP > 19). In vitro macrophage association and in vivo blood circulation evaluation of polymersomes in zebrafish embryos corroborate these findings. They further suggest that single copolymer presentation on polymersomes is outperformed by blends of varied copolymer lengths. This study helps to rationalize design rules for stable and low-fouling polymersomes for future medical applications.

• Bouz, Ghada; Šlechta, Petr; Jand'ourek, Ondřej; Konečná, Klára; Paterová, Pavla & Bárta, Pavel [Vis alle 17 forfattere av denne artikkelen] (2022). Hybridization Approach Toward Novel Antituberculars: Design, Synthesis, and Biological Evaluation of Compounds Combining Pyrazinamide and 4-Aminosalicylic Acid. ACS Infectious Diseases. 9(1), s. 79–96. doi: 10.1021/acsinfecdis.2c00433. Fulltekst i vitenarkiv
• Dal, Nils-Jørgen Knudsen; Speth, Martin Tobias; Johann, Kerstin; Barz, Matthias; Beauvineau, Claire & Wohlmann, Jens [Vis alle 10 forfattere av denne artikkelen] (2022). The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds. Disease Models and Mechanisms. ISSN 1754-8403. 15(1). doi: 10.1242/dmm.049147. Fulltekst i vitenarkiv Vis sammendrag

  ABSTRACT With the increasing emergence of drug-resistant Mycobacterium tuberculosis strains, new and effective antibiotics against tuberculosis (TB) are urgently needed. However, the high frequency of poorly water-soluble compounds among hits in high-throughput drug screening campaigns is a major obstacle in drug discovery. Moreover, in vivo testing using conventional animal TB models, such as mice, is time consuming and costly, and represents a major bottleneck in lead compound discovery and development. Here, we report the use of the zebrafish embryo TB model for evaluating the in vivo toxicity and efficacy of five poorly water-soluble nitronaphthofuran derivatives, which were recently identified as possessing anti-TB activity in vitro. To aid solubilization, compounds were formulated in biocompatible polymeric micelles (PMs). Three of the five PM-formulated nitronaphthofuran derivatives showed low toxicity in vivo, significantly reduced bacterial burden and improved survival in infected zebrafish embryos. We propose the zebrafish embryo TB-model as a quick and sensitive tool for evaluating the in vivo toxicity and efficacy of new anti-TB compounds during early stages of drug development. Thus, this model is well suited for pinpointing promising compounds for further development.

• Siemer, Svenja; Bauer, Tobias A.; Scholz, Paul; Breder, Christina; Fenaroli, Federico & Harms, Gregory [Vis alle 16 forfattere av denne artikkelen] (2021). Targeting Cancer Chemotherapy Resistance by Precision Medicine-Driven Nanoparticle-Formulated Cisplatin. ACS Nano. ISSN 1936-0851. 15(11), s. 18541–18556. doi: 10.1021/acsnano.1c08632. Fulltekst i vitenarkiv Vis sammendrag

  Therapy resistance is the major cause of cancer death. As patients respond heterogeneously, precision/personalized medicine needs to be considered, including the application of nanoparticles (NPs). The success of therapeutic NPs requires to first identify clinically relevant resistance mechanisms and to define key players, followed by a rational design of biocompatible NPs capable to target resistance. Consequently, we employed a tiered experimental pipeline from in silico to analytical and in vitro to overcome cisplatin resistance. First, we generated cisplatin-resistant cancer cells and used next-generation sequencing together with CRISPR/Cas9 knockout technology to identify the ion channel LRRC8A as a critical component for cisplatin resistance. LRRC8A’s cisplatin-specificity was verified by testing free as well as nanoformulated paclitaxel or doxorubicin. The clinical relevance of LRRC8A was demonstrated by its differential expression in a cohort of 500 head and neck cancer patients, correlating with patient survival under cisplatin therapy. To overcome LRRC8A-mediated cisplatin resistance, we constructed cisplatin-loaded, polysarcosine-based core cross-linked polymeric NPs (NPCis, Ø ∼ 28 nm) with good colloidal stability, biocompatibility (low immunogenicity, low toxicity, prolonged in vivo circulation, no complement activation, no plasma protein aggregation), and low corona formation properties. 2D/3D-spheroid cell models were employed to demonstrate that, in contrast to standard of care cisplatin, NPCis significantly (p < 0.001) eradicated all cisplatin-resistant cells by circumventing the LRRC8A-transport pathway via the endocytic delivery route. We here identified LRRC8A as critical for cisplatin resistance and suggest LRRC8A-guided patient stratification for ongoing or prospective clinical studies assessing therapy resistance to nanoscale platinum drug nanoformulations versus current standard of care formulations.

• Bauer, Tobias A.; Horvat, Natalie K.; Marques, Oriana; Chocarro, Sara; Mertens, Christina & Colucci, Silvia [Vis alle 17 forfattere av denne artikkelen] (2021). Core Cross-Linked Polymeric Micelles for Specific Iron Delivery: Inducing Sterile Inflammation in Macrophages. Advanced Healthcare Materials. ISSN 2192-2640. 10(19), s. 1–13. doi: 10.1002/adhm.202100385. Fulltekst i vitenarkiv Vis sammendrag

  Iron is an essential co-factor for cellular processes. In the immune system, it can activate macrophages and represents a potential therapeutic for various diseases. To specifically deliver iron to macrophages, iron oxide nanoparticles are embedded in polymeric micelles of reactive polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine). Upon surface functionalization via dihydrolipoic acid, iron oxide cores act as crosslinker themselves and undergo chemoselective disulfide bond formation with the surrounding poly(S-ethylsulfonyl-l-cysteine) block, yielding glutathione-responsive core cross-linked polymeric micelles (CCPMs). When applied to primary murine and human macrophages, these nanoparticles display preferential uptake, sustained intracellular iron release, and induce a strong inflammatory response. This response is also demonstrated in vivo when nanoparticles are intratracheally administered to wild-type C57Bl/6N mice. Most importantly, the controlled release concept to deliver iron oxide in redox-responsive CCPMs induces significantly stronger macrophage activation than any other iron source at identical iron levels (e.g., Feraheme), directing to a new class of immune therapeutics.

• Resseguier, Julien; Levraud, Jean-Pierre; Dal, Nils-Jørgen Knudsen; Fenaroli, Federico; Primard, Charlotte & Wohlmann, Jens [Vis alle 10 forfattere av denne artikkelen] (2021). Biodistribution of surfactant-free poly(lactic-acid) nanoparticles and uptake by endothelial cells and phagocytes in zebrafish: Evidence for endothelium to macrophage transfer. Journal of Controlled Release. ISSN 0168-3659. 331, s. 228–245. doi: 10.1016/j.jconrel.2021.01.006. Fulltekst i vitenarkiv Vis sammendrag

  In the development of therapeutic nanoparticles (NP), there is a large gap between in vitro testing and in vivo experimentation. Despite its prominence as a model, the mouse shows severe limitations for imaging NP and the cells with which they interact. Recently, the transparent zebrafish larva, which is well suited for high-resolution live-imaging, has emerged as a powerful alternative model to investigate the in vivo behavior of NP. Poly(D,L lactic acid) (PLA) is widely accepted as a safe polymer to prepare therapeutic NP. However, to prevent aggregation, many NP require surfactants, which may have undesirable biological effects. Here, we evaluate ‘safe-by-design’, surfactant-free PLA-NP that were injected intravenously into zebrafish larvae. Interaction of fluorescent NPs with different cell types labelled in reporter animals could be followed in real-time at high resolution; furthermore, by encapsulating colloidal gold into the matrix of PLA-NP we could follow their fate in more detail by electron microscopy, from uptake to degradation. The rapid clearance of fluorescent PLA-NP from the circulation coincided with internalization by endothelial cells lining the whole vasculature and macrophages. After 30 min, when no NP remained in circulation, we observed that macrophages continued to internalize significant amounts of NP. More detailed video-imaging revealed a new mechanism of NP transfer where NP are transmitted along with parts of the cytoplasm from endothelial cells to macrophages.

• Kocere, Agnese; Resseguier, Julien; Wohlmann, Jens; Skjeldal, Frode Miltzow; Khan, Shanawaz & Speth, Martin [Vis alle 14 forfattere av denne artikkelen] (2020). Real-time imaging of polymersome nanoparticles in zebrafish embryos engrafted with melanoma cancer cells: Localization, toxicity and treatment analysis. EBioMedicine. 58, s. 1–12. doi: 10.1016/j.ebiom.2020.102902. Fulltekst i vitenarkiv Vis sammendrag

  Background The developing zebrafish is an emerging tool in nanomedicine, allowing non-invasive live imaging of the whole animal at higher resolution than is possible in the more commonly used mouse models. In addition, several transgenic fish lines are available endowed with selected cell types expressing fluorescent proteins; this allows nanoparticles to be visualized together with host cells. Methods Here, we introduce the zebrafish neural tube as a robust injection site for cancer cells, excellently suited for high resolution imaging. We use light and electron microscopy to evaluate cancer growth and to follow the fate of intravenously injected nanoparticles. Findings Fluorescently labelled mouse melanoma B16 cells, when injected into this structure proliferated rapidly and stimulated angiogenesis of new vessels. In addition, macrophages, but not neutrophils, selectively accumulated in the tumour region. When injected intravenously, nanoparticles made of Cy5-labelled poly(ethylene glycol)-block-poly(2-(diisopropyl amino) ethyl methacrylate) (PEG-PDPA) selectively accumulated in the neural tube cancer region and were seen in individual cancer cells and tumour associated macrophages. Moreover, when doxorubicin was released from PEG-PDPA, in a pH dependant manner, these nanoparticles could strongly reduce toxicity and improve the treatment outcome compared to the free drug in zebrafish xenotransplanted with mouse melanoma B16 or human derived melanoma cells. Interpretation The zebrafish has the potential of becoming an important intermediate step, before the mouse model, for testing nanomedicines against patient-derived cancer cells.

• Fenaroli, Federico; Robertson, James; Scarpa, Edoardo; Gouveia, Virginia; Guglielmo, Claudia Di & Pace, Cesare De [Vis alle 19 forfattere av denne artikkelen] (2020). Polymersomes Eradicating Intracellular Bacteria. ACS Nano. ISSN 1936-0851. 14(7), s. 8287–8298. doi: 10.1021/acsnano.0c01870. Fulltekst i vitenarkiv
• Dal, Nils-Jørgen Knudsen; Kocere, Agnese; Wohlmann, Jens; Herck, Simon Van; Bauer, Tobias A & Resseguier, Julien [Vis alle 11 forfattere av denne artikkelen] (2020). Zebrafish Embryos Allow Prediction of Nanoparticle Circulation Times in Mice and Facilitate Quantification of Nanoparticle–Cell Interactions. Small. ISSN 1613-6810. 16(5), s. 1–12. doi: 10.1002/smll.201906719. Fulltekst i vitenarkiv Vis sammendrag

  The zebrafish embryo is a vertebrate well suited for visualizing nanoparticles at high resolution in live animals. Its optical transparency and genetic versatility allow noninvasive, real‐time observations of vascular flow of nanoparticles and their interactions with cells throughout the body. As a consequence, this system enables the acquisition of quantitative data that are difficult to obtain in rodents. Until now, a few studies using the zebrafish model have only described semiquantitative results on key nanoparticle parameters. Here, a MACRO dedicated to automated quantitative methods is described for analyzing important parameters of nanoparticle behavior, such as circulation time and interactions with key target cells, macrophages, and endothelial cells. Direct comparison of four nanoparticle (NP) formulations in zebrafish embryos and mice reveals that data obtained in zebrafish can be used to predict NPs' behavior in the mouse model. NPs having long or short blood circulation in rodents behave similarly in the zebrafish embryo, with low circulation times being a consequence of NP uptake into macrophages or endothelial cells. It is proposed that the zebrafish embryo has the potential to become an important intermediate screening system for nanoparticle research to bridge the gap between cell culture studies and preclinical rodent models such as the mouse.

• Trousil, Jiří; Syrová, Zdeňka; Dal, Nils-Jørgen Knudsen; Rak, Dmytro; Konefal, Rafal & Pavlova, Ewa [Vis alle 16 forfattere av denne artikkelen] (2019). Rifampicin Nanoformulation Enhances Treatment of Tuberculosis in Zebrafish. Biomacromolecules. ISSN 1525-7797. 20(4), s. 1798–1815. doi: 10.1021/acs.biomac.9b00214. Fulltekst i vitenarkiv
• Vestre, Katharina; Kjos, Ingrid; Guadagno, Noemi Antonella; Distefano, Marita Borg; Kohler, Felix & Fenaroli, Federico [Vis alle 8 forfattere av denne artikkelen] (2019). Rab6 regulates cell migration and invasion by recruiting Cdc42 and modulating its activity. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 76(13), s. 2593–2614. doi: 10.1007/s00018-019-03057-w. Fulltekst i vitenarkiv Vis sammendrag

  Rab proteins are master regulators of intracellular membrane trafficking, but they also contribute to cell division, signaling, polarization, and migration. The majority of the works describing the mechanisms used by Rab proteins to regulate cell motility involve intracellular transport of key molecules important for migration. Interestingly, a few studies indicate that Rabs can modulate the activity of Rho GTPases, important regulators for the cytoskeleton rearrangements, but the mechanisms behind this crosstalk are still poorly understood. In this work, we identify Rab6 as a negative regulator of cell migration in vitro and in vivo. We show that the loss of Rab6 promotes formation of actin protrusions and influences actomyosin dynamics by upregulating Cdc42 activity and downregulating myosin II phosphorylation. We further provide the molecular mechanism behind this regulation demonstrating that Rab6 interacts with both Cdc42 and Trio, a GEF for Cdc42. In sum, our results uncover a mechanism used by Rab proteins to ensure spatial regulation of Rho GTPase activity for coordination of cytoskeleton rearrangements required in migrating cells.

• Kumar, Sheemal S.; Tandberg, Julia Isabel; Penesyan, Anahit; Elbourne, Liam D. H.; Suarez-Bosche, Nadia & Don, Emily [Vis alle 11 forfattere av denne artikkelen] (2018). Dual Transcriptomics of Host-Pathogen Interaction of Cystic Fibrosis Isolate Pseudomonas aeruginosa PASS1 With Zebrafish. Frontiers in Cellular and Infection Microbiology. doi: 10.3389/fcimb.2018.00406. Fulltekst i vitenarkiv Vis sammendrag

  Pseudomonas aeruginosa is a significant cause of mortality in patients with cystic fibrosis (CF). To explore the interaction of the CF isolate P. aeruginosa PASS1 with the innate immune response, we have used Danio rerio (zebrafish) as an infection model. Confocal laser scanning microscopy (CLSM) enabled visualization of direct interactions between zebrafish macrophages and P. aeruginosa PASS1. Dual RNA-sequencing of host-pathogen was undertaken to profile RNA expression simultaneously in the pathogen and the host during P. aeruginosa infection. Following establishment of infection in zebrafish embryos with PASS1, 3 days post infection (dpi), there were 6739 genes found to be significantly differentially expressed in zebrafish and 176 genes in PASS1. A range of virulence genes were upregulated in PASS1, including genes encoding pyoverdine biosynthesis, flagellin, non-hemolytic phospholipase C, proteases, superoxide dismutase and fimbrial subunits. Additionally, iron and phosphate acquisition genes were upregulated in PASS1 cells in the zebrafish. Transcriptional changes in the host immune response genes highlighted phagocytosis as a key response mechanism to PASS1 infection. Transcriptional regulators of neutrophil and macrophage phagocytosis were upregulated alongside transcriptional regulators governing response to tissue injury, infection, and inflammation. The zebrafish host showed significant downregulation of the ribosomal RNAs and other genes involved in translation, suggesting that protein translation in the host is affected by PASS1 infection.

• Driessche, Alexandra Van; Kocere, Agnese; Everaert, Hannelien; Nuhn, Lutz; Herck, Simon Van & Griffiths, Gareth Wyn [Vis alle 8 forfattere av denne artikkelen] (2018). pH-sensitive hydrazone-linked doxorubicin nanogels via polymeric-activated ester scaffolds: Synthesis, assembly, and in vitro and in vivo evaluation in tumor-bearing zebrafish. Chemistry of Materials. ISSN 0897-4756. 30(23), s. 8587–8596. doi: 10.1021/acs.chemmater.8b03702. Fulltekst i vitenarkiv
• Fenaroli, Federico; Repnik, Urska; Xu, Yitian; Johann, Kerstin; Herck, Simon Van & Dey, Pradip [Vis alle 15 forfattere av denne artikkelen] (2018). Enhanced permeability and retention-like extravasation of nanoparticles from the vasculature into tuberculosis granulomas in zebrafish and mouse models. ACS Nano. ISSN 1936-0851. 12(8), s. 8646–8661. doi: 10.1021/acsnano.8b04433. Fulltekst i vitenarkiv
• Ulanova, Lilia; Pinheiro, Marina; Vibe, Carina Beatrice; Nunes, Clàudia; Misaghian, Dorna & Wilson, Steven Ray Haakon [Vis alle 11 forfattere av denne artikkelen] (2017). Treatment of Francisella infections via PLGA-and lipid-based nanoparticle delivery of antibiotics in a zebrafish model. Diseases of Aquatic Organisms. ISSN 0177-5103. 125(1), s. 19–29. doi: 10.3354/dao03129. Fulltekst i vitenarkiv
• Johansen, Patrick Lie; Fenaroli, Federico; Evensen, Lasse; Griffiths, Gareth & Koster, Gerbrand (2016). Optical micromanipulation of nanoparticles and cells inside living zebrafish. Nature Communications. 7. doi: 10.1038/ncomms10974. Fulltekst i vitenarkiv
• Vibe, Carina Beatrice; Fenaroli, Federico; Pires, David; Wilson, Steven Ray Haakon; Bogoeva, Vanya & Kalluru, Raja Sab [Vis alle 10 forfattere av denne artikkelen] (2016). Thioridazine in PLGA nanoparticles reduces toxicity and improves rifampicin therapy against mycobacterial infection in zebrafish. Nanotoxicology. ISSN 1743-5390. 10(6), s. 680–688. doi: 10.3109/17435390.2015.1107146. Fulltekst i vitenarkiv
• Evensen, Lasse; Johansen, Patrick Lie; Koster, Gerbrand; Zhu, Kaizheng; Herfindal, Lars & Speth, Martin [Vis alle 14 forfattere av denne artikkelen] (2016). Zebrafish as a model system for characterization of nanoparticles against cancer. Nanoscale. ISSN 2040-3364. 8(2), s. 862–877. doi: 10.1039/c5nr07289a. Fulltekst i vitenarkiv
• Ertunc, Meric Erikci; Sikkeland, Jørgen; Fenaroli, Federico; Griffiths, Gareth Wyn; Daniels, Melissa C. & Cao, Haiming [Vis alle 8 forfattere av denne artikkelen] (2015). Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity. Journal of Lipid Research. ISSN 0022-2275. 56(2), s. 423–434. doi: 10.1194/jlr.M055798. Fulltekst i vitenarkiv
• Fenaroli, Federico; Westmoreland, David; Benjaminsen, Jørgen; Kolstad, Terje R Selnes; Skjeldal, Frode Miltzow & Meijer, Annemarie H. [Vis alle 12 forfattere av denne artikkelen] (2014). Nanoparticles as Drug Delivery System against Tuberculosis in Zebrafish Embryos: Direct Visualization and Treatment. ACS Nano. ISSN 1936-0851. 8(7), s. 7014–7026. doi: 10.1021/nn5019126. Fulltekst i vitenarkiv
• Kalluru, Raja Sab; Fenaroli, Federico; Westmoreland, David; Ulanova, Lilia; Maleki, Atoosa & Roos, Norbert [Vis alle 15 forfattere av denne artikkelen] (2013). Polylactide-co-glycolide-rifampicin-nanoparticles efficiently clear Mycobacterium bovis BCG infection in macrophages and remain membrane-bound in phago-lysosomes. Journal of Cell Science. ISSN 0021-9533. 126(14), s. 3043–3054. doi: 10.1242/jcs.121814. Fulltekst i vitenarkiv
• Anna, Lesniak; Fenaroli, Federico; Monopoli, Marco; Åberg, Christoffer; Dawson, Kenneth A. & Salvati, Anna (2012). Effects of the Presence or Absence of a Protein Corona on Silica Nanoparticle Uptake and Impact on Cells. ACS Nano. ISSN 1936-0851. 6(7), s. 5845–5857. doi: 10.1021/nn300223w. Fulltekst i vitenarkiv
• Bexiga, Mariana; Varela, Juan; Wang, Fengjuan; Fenaroli, Federico; Salvati, Anna & Lynch, Iseult [Vis alle 8 forfattere av denne artikkelen] (2011). Cationic nanoparticles induce caspase 3-, 7- and 9-mediated cytotoxicity in a human astrocytoma cell line. Nanotoxicology. ISSN 1743-5390. 5(4), s. 557–567. doi: 10.3109/17435390.2010.539713. Fulltekst i vitenarkiv
• Shapero, Kayle; Fenaroli, Federico; Lynch, Iseult; Cottell, David; Salvati, Anna & Dawson, Kenneth A. (2011). Time and space resolved uptake study of silica nanoparticles by human cells. Molecular Biosystems. ISSN 1742-206X. 7(2), s. 371–378. doi: 10.1039/c0mb00109k. Fulltekst i vitenarkiv

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