13 results on '"Kooijmans, Sander"'
Search Results
2. mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells
- Author
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Bevers, Sanne, Kooijmans, Sander A.A., Van de Velde, Elien, Evers, Martijn J.W., Seghers, Sofie, Gitz-Francois, Jerney J.J.M., van Kronenburg, Nicky C.H., Fens, Marcel H.A.M., Mastrobattista, Enrico, Hassler, Lucie, Sork, Helena, Lehto, Taavi, Ahmed, Kariem E., El Andaloussi, Samir, Fiedler, Katja, Breckpot, Karine, Maes, Michael, Van Hoorick, Diane, Bastogne, Thierry, Schiffelers, Raymond M., De Koker, Stefaan, Afd Pharmaceutics, Pharmaceutics, Laboratory of Molecullar and Cellular Therapy, Basic (bio-) Medical Sciences, Faculty of Medicine and Pharmacy, Afd Pharmaceutics, and Pharmaceutics
- Subjects
LNP ,mRNA ,mRNA-LNP vaccines ,design-of-experiments methodology ,infectious diseases ,Cancer Vaccines ,Drug Discovery ,Genetics ,Animals ,cancer ,Tissue Distribution ,RNA, Messenger ,Molecular Biology ,antitumor ,Pharmacology ,extrahepatic delivery ,SARS-CoV-2 ,Vaccination ,COVID-19 ,vaccination ,lipid-based nanoparticlelipid-based nanoparticle ,immunity ,oncology ,Nanoparticles ,Molecular Medicine ,Immunization ,immunotherapy ,Vaccine ,Spleen - Abstract
mRNA vaccines have recently proved to be highly effective against SARS-CoV-2. Key to their success is the lipid-based nanoparticle (LNP), which enables efficient mRNA expression and endows the vaccine with adjuvant properties that drive potent antibody responses. Effective cancer vaccines require long-lived, qualitative CD8 T cell responses instead of antibody responses. Systemic vaccination appears to be the most effective route, but necessitates adaptation of LNP composition to deliver mRNA to antigen-presenting cells. Using a design-of-experiments methodology, we tailored mRNA-LNP compositions to achieve high-magnitude tumor-specific CD8 T cell responses within a single round of optimization. Optimized LNP compositions resulted in enhanced mRNA uptake by multiple splenic immune cell populations. Type I interferon and phagocytes were found to be essential for the T cell response. Surprisingly, we also discovered a yet unidentified role of B cells in stimulating the vaccine-elicited CD8 T cell response. Optimized LNPs displayed a similar, spleen-centered biodistribution profile in non-human primates and did not trigger histopathological changes in liver and spleen, warranting their further assessment in clinical studies. Taken together, our study clarifies the relationship between nanoparticle composition and their T cell stimulatory capacity and provides novel insights into the underlying mechanisms of effective mRNA-LNP-based antitumor immunotherapy.
- Published
- 2022
3. In-vitro and in-silico evidence for oxidative stress as drivers for RDW.
- Author
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Joosse, Huibert-Jan, van Oirschot, Brigitte A., Kooijmans, Sander A. A., Hoefer, Imo E., van Wijk, Richard A. H., Huisman, Albert, van Solinge, Wouter W., and Haitjema, Saskia
- Subjects
OXIDATIVE stress ,BLOOD cell count ,ERYTHROCYTES ,ERYTHROCYTE deformability ,DATABASES - Abstract
Red blood cell distribution width (RDW) is a biomarker associated with a variety of clinical outcomes. While anemia and subclinical inflammation have been posed as underlying pathophysiology, it is unclear what mechanisms underlie these assocations. Hence, we aimed to unravel the mechanisms in silico using a large clinical dataset and validate our findings in vitro. We retrieved complete blood counts (CBC) from 1,403,663 measurements from the Utrecht Patient Oriented Database, to model RDW using gradient boosting regression. We performed (sex-stratified) analyses in patients with anemia, patients younger/older than 50 and validation across platforms and care settings. We then validated our hypothesis regarding oxidative stress using an in vitro approach. Only percentage microcytic (pMIC) and macrocytic (pMAC) erythrocytes and mean corpuscular volume were most important in modelling RDW (RMSE = 0.40, R
2 = 0.96). Subgroup analyses and validation confirmed our findings. In vitro induction of oxidative stress underscored our results, namely increased RDW and decreased erythrocyte volume, yet no vesiculation was observed. We found that erythrocyte size, especially pMIC, is most informative in predicting RDW, but no role for anemia or inflammation. Oxidative stress affecting the size of the erythrocytes may play a role in the association between RDW and clinical outcomes. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF
4. Increased Bone Marrow Uptake and Accumulation of Very-Late Antigen-4 Targeted Lipid Nanoparticles.
- Author
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Swart, Laura E., Fens, Marcel H. A. M., van Oort, Anita, Waranecki, Piotr, Mata Casimiro, L. Daniel, Tuk, David, Hendriksen, Martijn, van den Brink, Luca, Schweighart, Elizabeth, Seinen, Cor, Nelson, Ryan, Krippner-Heidenreich, Anja, O'Toole, Tom, Schiffelers, Raymond M., Kooijmans, Sander, and Heidenreich, Olaf
- Subjects
BONE marrow cells ,BLOOD diseases ,PROGENITOR cells ,LIPIDS ,STEM cells - Abstract
Lipid nanoparticles (LNPs) have evolved rapidly as promising delivery systems for oligonucleotides, including siRNAs. However, current clinical LNP formulations show high liver accumulation after systemic administration, which is unfavorable for the treatment of extrahepatic diseases, such as hematological disorders. Here we describe the specific targeting of LNPs to hematopoietic progenitor cells in the bone marrow. Functionalization of the LNPs with a modified Leu-Asp-Val tripeptide, a specific ligand for the very-late antigen 4 resulted in an improved uptake and functional siRNA delivery in patient-derived leukemia cells when compared to their non-targeted counterparts. Moreover, surface-modified LNPs displayed significantly improved bone-marrow accumulation and retention. These were associated with increased LNP uptake by immature hematopoietic progenitor cells, also suggesting similarly improved uptake by leukemic stem cells. In summary, we describe an LNP formulation that successfully targets the bone marrow including leukemic stem cells. Our results thereby support the further development of LNPs for targeted therapeutic interventions for leukemia and other hematological disorders. [ABSTRACT FROM AUTHOR]
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- 2023
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- View/download PDF
5. Biodistribution of polymer hydrogel capsules for the delivery of therapeutics
- Author
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Hinton, Tracey M., Monaghan, Paul, Green, Diane, Kooijmans, Sander A.A., Shi, Shuning, Breheney, Kerry, Tizard, Mark, Nicolazzo, Joseph A., Zelikin, Alexander N., and Wark, Kim
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- 2012
- Full Text
- View/download PDF
6. A post-insertion strategy for surface functionalization of bacterial and mammalian cell-derived extracellular vesicles
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Jiang, Linglei, Luirink, Joen, Kooijmans, Sander A A, van Kessel, Kok P M, Jong, Wouter, van Essen, Max, Seinen, Cor W, de Maat, Steven, de Jong, Olivier G, Gitz-François, Jerney F F, Hennink, Wim E, Vader, Pieter, Schiffelers, Raymond M, Pharmaceutics, Afd Pharmaceutics, Molecular Microbiology, AIMMS, LaserLaB - Molecular Biophysics, Pharmaceutics, and Afd Pharmaceutics
- Subjects
Surface Properties ,Blotting, Western ,Biophysics ,Cell Culture Techniques ,Outer membrane vesicles ,02 engineering and technology ,Extracellular vesicles ,Biochemistry ,Post insertion ,03 medical and health sciences ,Mice ,Microscopy, Electron, Transmission ,Labelling ,Cell Line, Tumor ,Animals ,Humans ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Liposome ,Bacteria ,Chemistry ,Translation (biology) ,021001 nanoscience & nanotechnology ,Flow Cytometry ,Poly(ethylene glycol)lipids ,Immunohistochemistry ,Cell biology ,Bacterial Outer Membrane ,HEK293 Cells ,Post-insertion ,Nucleic acid ,Surface modification ,Electrophoresis, Polyacrylamide Gel ,0210 nano-technology ,Drug carrier - Abstract
Extracellular vesicles (EVs) are nanoparticles which are released by cells from all three domains of life: Archaea, Bacteria and Eukarya. They can mediate cell-cell communication by transferring cargoes such as proteins and nucleic acids between cells. EVs receive great interest in both academia and industry as they have the potential to be natural drug carriers or vaccine candidates. However, limitations to their clinical translation exist as efficient isolation, loading, labelling and surface-engineering methods are lacking. In this article, we investigate a ‘post-insertion’ approach, which is commonly used in the functionalization of liposomes in the pharmaceutical field, on two different EV types: mammalian cell-derived EVs and bacteria-derived EVs. We aimed to find an easy and flexible approach to functionalize EVs, thereby improving the labelling, isolation, and surface-engineering.
- Published
- 2021
7. Recombinant phosphatidylserine-binding nanobodies for targeting of extracellular vesicles to tumor cells: a plug-and-play approach† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7nr06966a
- Author
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Kooijmans, Sander A. A., Gitz-Francois, Jerney J. J. M., Schiffelers, Raymond M., and Vader, Pieter
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ErbB Receptors ,Chemistry ,Extracellular Vesicles ,Drug Delivery Systems ,HEK293 Cells ,Recombinant Fusion Proteins ,Antigens, Surface ,Humans ,Phosphatidylserines ,Single-Domain Antibodies ,Milk Proteins - Abstract
Decoration of isolated extracellular vesicles with recombinant phosphatidylserine-binding nanobodies increases their uptake by tumor cells., Extracellular vesicles (EVs) are increasingly being recognized as candidate drug delivery systems due to their ability to functionally transfer biological cargo between cells. However, manipulation of targeting properties of EVs through engineering of the producer cells can be challenging and time-consuming. As a novel approach to confer tumor targeting properties to isolated EVs, we generated recombinant fusion proteins of nanobodies against the epidermal growth factor receptor (EGFR) fused to phosphatidylserine (PS)-binding domains of lactadherin (C1C2). C1C2-nanobody fusion proteins were expressed in HEK293 cells and isolated from culture medium with near-complete purity as determined by SDS-PAGE. Fusion proteins specifically bound PS and showed no affinity for other common EV membrane lipids. Furthermore, C1C2 fused to anti-EGFR nanobodies (EGa1-C1C2) bound EGFR with high affinity and competed with binding of its natural ligand EGF, as opposed to C1C2 fused to non-targeting control nanobodies (R2-C1C2). Both proteins readily self-associated onto membranes of EVs derived from erythrocytes and Neuro2A cells without affecting EV size and integrity. EV-bound R2-C1C2 did not influence EV–cell interactions, whereas EV-bound EGa1-C1C2 dose-dependently enhanced specific binding and uptake of EVs by EGFR-overexpressing tumor cells. In conclusion, we developed a novel strategy to efficiently and universally confer tumor targeting properties to PS-exposing EVs after their isolation, without affecting EV characteristics, circumventing the need to modify EV-secreting cells. This strategy may also be employed to decorate EVs with other moieties, including imaging probes or therapeutic proteins.
- Published
- 2018
8. P1500: WHAT’S DRIVING RDW? IN‐VITRO AND IN‐SILICO EVIDENCE FOR OXIDATIVE STRESS.
- Author
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Joosse, Huibert‐Jan, van Oirschot, Brigitte, Kooijmans, Sander A.A., Hoefer, Imo E, Van Wijk, Richard A.H., Huisman, Albert, Van Solinge, Wouter W, and Haitjema, Saskia
- Published
- 2023
- Full Text
- View/download PDF
9. Raman spectroscopy as a quick tool to assess purity of extracellular vesicle preparations and predict their functionality.
- Author
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Gualerzi, Alice, Kooijmans, Sander Alexander Antonius, Niada, Stefania, Picciolini, Silvia, Brini, Anna Teresa, Camussi, Giovanni, and Bedoni, Marzia
- Subjects
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RAMAN spectroscopy , *GEL permeation chromatography , *CELL separation , *HUMAN stem cells , *BONE marrow cells , *STEM cells - Abstract
Extracellular vesicles (EVs) from a variety of stem cell sources are believed to harbour regenerative capacity, which may be exploited for therapeutic purposes. Because of EV interaction with other soluble secreted factors, EV activity may depend on the employed purification method, which limits cross-study comparisons and therapeutic development. Raman spectroscopy (RS) is a quick and easy method to assess EV purity and composition, giving in-depth biochemical overview on EV preparation. Hereby, we show how this method can be used to characterise EVs isolated from human liver stem cells and bone marrow mesenchymal stem/stromal cells by means of conventional ultracentrifugation (UC) and size exclusion chromatography (SEC) protocols. The obtained EV preparations were demonstrated to be characterised by different degrees of purity and a specific Raman fingerprint that represents both the cell source and the isolation procedure used. Moreover, RS provided useful hints to explore the factors underlying the functional diversity of EV preparations from the same cell source, thus representing a valuable tool to assess EV quality prior to functional assays or therapeutic application. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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- View/download PDF
10. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting.
- Author
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Kooijmans, Sander A. A., Aleza, Clara Gómez, Roffler, Steve R., van Solinge, Wouter W., Vader, Pieter, and Schiffelers, Raymond M.
- Subjects
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EPIDERMAL growth factor receptors , *CANCER cells , *DRUG delivery systems - Abstract
Background: Extracellular vesicles (EVs) are attractive candidate drug delivery systems due to their ability to functionally transport biological cargo to recipient cells. However, the apparent lack of target cell specificity of exogenously administered EVs limits their therapeutic applicability. In this study, we propose a novel method to equip EVs with targeting properties, in order to improve their interaction with tumour cells. Methods: EV producing cells were transfected with vectors encoding for anti-epidermal growth factor receptor (EGFR) nanobodies, which served as targeting ligands for tumour cells, fused to glycosylphosphatidylinositol (GPI) anchor signal peptides derived from decay-accelerating factor (DAF). EVs were isolated using ultrafiltration/size-exclusion liquid chromatography and characterized using western blotting, Nanoparticle Tracking Analysis, and electron microscopy. EV-tumour cell interactions were analyzed under static conditions using flow cytometry and under flow conditions using a live-cell fluorescence microscopycoupled perfusion system. Results: EV analysis showed that GPI-linked nanobodies were successfully displayed on EV surfaces and were highly enriched in EVs compared with parent cells. Display of GPI-linked nanobodies on EVs did not alter general EV characteristics (i.e. morphology, size distribution and protein marker expression), but greatly improved EV binding to tumour cells dependent on EGFR density under static conditions. Moreover, nanobody-displaying EVs showed a significantly improved cell association to EGFR-expressing tumour cells under flow conditions. Conclusions: We show that nanobodies can be anchored on the surface of EVs via GPI, which alters their cell targeting behaviour. Furthermore, this study highlights GPI-anchoring as a new tool in the EV toolbox, which may be applied for EV display of a variety of proteins, such as antibodies, reporter proteins and signaling molecules. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
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11. Exosome mimetics: a novel class of drug delivery systems.
- Author
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Kooijmans, Sander A. A., Vader, Pieter, van Dommelen, Susan M., van Solinge, Wouter W., and Schiffelers, Raymond M.
- Published
- 2012
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- View/download PDF
12. Delivery of modified mRNA to damaged myocardium by systemic administration of lipid nanoparticles
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Evers, Martijn J.W., Du, Wenjuan, Yang, Qiangbing, Kooijmans, Sander A.A., Vink, Aryan, van Steenbergen, Mies, Vader, Pieter, de Jager, Saskia C.A., Fuchs, Sabine A., Mastrobattista, Enrico, Sluijter, Joost P.G., Lei, Zhiyong, Schiffelers, Raymond, Afd Pharmaceutics, Virologie, Pharmaceutics, Afd Pharmaceutics, Virologie, and Pharmaceutics
- Subjects
Myocardium ,Pharmaceutical Science ,Reperfusion injury ,Mice ,Myocardial infarction ,Systemic delivery ,Infarction ,Luciferases, Firefly ,Modified mRNA ,Liposomes ,Lipid nanoparticles ,Animals ,Nanoparticles ,RNA, Messenger ,RNA, Small Interfering - Abstract
Lipid Nanoparticles (LNPs) are a promising drug delivery vehicle for clinical siRNA delivery. Modified mRNA (modRNA) has recently gained great attention as a therapeutic molecule in cardiac regeneration. However, for mRNA to be functional, it must first reach the diseased myocardium, enter the target cell, escape from the endosomal compartment into the cytosol and be translated into a functional protein. However, it is unknown if LNPs can effectively deliver mRNA, which is much larger than siRNA, to the ischemic myocardium. Here, we evaluated the ability of LNPs to deliver mRNA to the myocardium upon ischemia-reperfusion injury functionally. By exploring the bio-distribution of fluorescently labeled LNPs, we observed that, upon reperfusion, LNPs accumulated in the infarct area of the heart. Subsequently, the functional delivery of modRNA was evaluated by the administration of firefly luciferase encoding modRNA. Concomitantly, a significant increase in firefly luciferase expression was observed in the heart upon myocardial reperfusion when compared to sham-operated animals. To characterize the targeted cells within the myocardium, we injected LNPs loaded with Cre modRNA into Cre-reporter mice. Upon LNP infusion, Tdtomato+ cells, derived from Cre mediated recombination, were observed in the infarct region as well as the epicardial layer upon LNP infusion. Within the infarct area, most targeted cells were cardiac fibroblasts but also some cardiomyocytes and macrophages were found. Although the expression levels were low compared to LNP-modRNA delivery into the liver, our data show the ability of LNPs to functionally deliver modRNA therapeutics to the damaged myocardium, which holds great promise for modRNA-based cardiac therapies.
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13. mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells.
- Author
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Bevers S, Kooijmans SAA, Van de Velde E, Evers MJW, Seghers S, Gitz-Francois JJJM, van Kronenburg NCH, Fens MHAM, Mastrobattista E, Hassler L, Sork H, Lehto T, Ahmed KE, El Andaloussi S, Fiedler K, Breckpot K, Maes M, Van Hoorick D, Bastogne T, Schiffelers RM, and De Koker S
- Subjects
- Animals, Immunization methods, Immunotherapy, RNA, Messenger metabolism, SARS-CoV-2 genetics, Spleen, Tissue Distribution, Vaccination methods, COVID-19, Cancer Vaccines, Nanoparticles
- Abstract
mRNA vaccines have recently proved to be highly effective against SARS-CoV-2. Key to their success is the lipid-based nanoparticle (LNP), which enables efficient mRNA expression and endows the vaccine with adjuvant properties that drive potent antibody responses. Effective cancer vaccines require long-lived, qualitative CD8 T cell responses instead of antibody responses. Systemic vaccination appears to be the most effective route, but necessitates adaptation of LNP composition to deliver mRNA to antigen-presenting cells. Using a design-of-experiments methodology, we tailored mRNA-LNP compositions to achieve high-magnitude tumor-specific CD8 T cell responses within a single round of optimization. Optimized LNP compositions resulted in enhanced mRNA uptake by multiple splenic immune cell populations. Type I interferon and phagocytes were found to be essential for the T cell response. Surprisingly, we also discovered a yet unidentified role of B cells in stimulating the vaccine-elicited CD8 T cell response. Optimized LNPs displayed a similar, spleen-centered biodistribution profile in non-human primates and did not trigger histopathological changes in liver and spleen, warranting their further assessment in clinical studies. Taken together, our study clarifies the relationship between nanoparticle composition and their T cell stimulatory capacity and provides novel insights into the underlying mechanisms of effective mRNA-LNP-based antitumor immunotherapy., Competing Interests: Declaration of interests S.B., E.V.d.V., S.S., M.M., D.V.H., and S.D.K. are employees of eTheRNA Immunotherapies NV. S.B., S.A.A.K., R.M.S., and S.D.K. have applied for patents related to this study., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
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