25 results on '"Kooijmans, Sander"'
Search Results
2. Extracellular vesicles derived from Plasmodium-infected and non-infected red blood cells as targeted drug delivery vehicles
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Borgheti-Cardoso, Livia Neves, Kooijmans, Sander A.A., Chamorro, Lucía Gutiérrez, Biosca, Arnau, Lantero, Elena, Ramírez, Miriam, Avalos-Padilla, Yunuen, Crespo, Isabel, Fernández, Irene, Fernandez-Becerra, Carmen, del Portillo, Hernando A., and Fernàndez-Busquets, Xavier
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- 2020
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3. Interfering with endolysosomal trafficking enhances release of bioactive exosomes
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Ortega, Francisco G., Roefs, Marieke T., de Miguel Perez, Diego, Kooijmans, Sander A., de Jong, Olivier G., Sluijter, Joost P., Schiffelers, Raymond M., and Vader, Pieter
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- 2019
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4. Liposomal prednisolone inhibits tumor growth in a spontaneous mouse mammary carcinoma model
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Deshantri, Anil K., Kooijmans, Sander A.A., Kuijpers, Sylvia A., Coimbra, Maria, Hoeppener, Astrid, Storm, Gert, Fens, Marcel H.A.M., and Schiffelers, Raymond M.
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- 2016
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5. The fluid membrane determines mechanics of erythrocyte extracellular vesicles and is softened in hereditary spherocytosis
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Vorselen, Daan, van Dommelen, Susan M., Sorkin, Raya, Piontek, Melissa C., Schiller, Jürgen, Döpp, Sander T., Kooijmans, Sander A. A., van Oirschot, Brigitte A., Versluijs, Birgitta A., Bierings, Marc B., van Wijk, Richard, Schiffelers, Raymond M., Wuite, Gijs J. L., and Roos, Wouter H.
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- 2018
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6. An in situ gelling liquid crystalline system based on monoglycerides and polyethylenimine for local delivery of siRNAs
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Borgheti-Cardoso, Lívia Neves, Depieri, Lívia Vieira, Kooijmans, Sander A.A., Diniz, Henrique, Calzzani, Ricardo Alexandre Junqueira, Vicentini, Fabiana Testa Moura de Carvalho, van der Meel, Roy, Fantini, Márcia Carvalho de Abreu, Iyomasa, Mamie Mizusaki, Schiffelers, Raymond M., and Bentley, Maria Vitória Lopes Badra
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- 2015
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7. mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells
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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
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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.
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- 2022
8. In-vitro and in-silico evidence for oxidative stress as drivers for RDW.
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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
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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
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9. Increased Bone Marrow Uptake and Accumulation of Very-Late Antigen-4 Targeted Lipid Nanoparticles.
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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
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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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10. Tumour-bound RNA-laden exosomes
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Kooijmans, Sander A. A., Vader, Pieter, and Schiffelers, Raymond M.
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- 2017
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11. Rationally designed mRNA-loaded lipid nanoparticles provoke strong antitumor T cell immunity which critically depends on specific immune cell subsets
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Kooijmans, Sander, Bevers, Sanne, Van De Velde, Elien, Evers, Martijn, Seghers, Sofie, Gitz-François, Jerney, Hassler, Lucie, Breckpot, Karine, Bastogne, Thierry, Schiffelers, Raymond, De Koker, Stefaan, CDL Research, University Medical Center Utrecht, Utrecht, Netherlands, eTheRNA Immunotherapies, Niel, Belgium, Laboratory for Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory for Molecular and Cellular Therapy, CYBERnano [Villers-lès-Nancy], Laboratory for Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium, Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Biology, genetics and statistics (BIGS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), University Medical Center [Utrecht], eTheRNA Immunotherapies NV, Vrije Universiteit Brussel [Bruxelles] (VUB), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), and Bastogne, Thierry
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Vaccine (or Immunomodulatory) ,[STAT.AP]Statistics [stat]/Applications [stat.AP] ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,[STAT.AP] Statistics [stat]/Applications [stat.AP] ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Nanoparticle/nanomaterial ,[SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics ,Formulation development ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,DNA/RNA ,[SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics ,ComputingMilieux_MISCELLANEOUS ,[SDV.BIO] Life Sciences [q-bio]/Biotechnology - Abstract
International audience
- Published
- 2021
12. Tuning LNPs to target antigen presenting cells in spleen induces CD8 T-cell responses and tumor regression in mice
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Bevers, Sanne, Kooijmans, Sander, van de Velde, Elien, Evers, Martijn, Seghers, Sofie, Gitz-François, Jerney, Hassler, Lucie, Breckpot, Karine, Bastogne, Thierry, Schiffelers, Raymond, De Koker, Stefaan, eTheRNA Immunotherapies NV, Vrije Universiteit Brussel (VUB), University Medical Center [Utrecht], CYBERnano [Villers-lès-Nancy], Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Biology, genetics and statistics (BIGS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), CIMT Association for Cancer Immunotherapy, Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium, eTheRNA Immunotherapies, Niel, Belgium, CDL Research, University Medical Center Utrecht, Utrecht, Netherlands, Bastogne, Thierry, and Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)
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[STAT.AP]Statistics [stat]/Applications [stat.AP] ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,[STAT.AP] Statistics [stat]/Applications [stat.AP] ,[SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics ,[SDV.BIO] Life Sciences [q-bio]/Biotechnology - Abstract
International audience; Intravenous (i‧v.) delivery of vaccines is emerging as an appealing approach to evoke high-quality T-cell responses needed to combat tumors. Messenger RNA (mRNA) holds huge potential to use in vaccination because of its ease of production, intrinsic adjuvant activity and the high versatility in antigen design, but also requires a potent delivery vehicle to enable antigen expression and immune activation. Lipid based nanoparticles (LNP) are currently the clinically most advanced tool to protect mRNA from degradation and efficiently deliver it inside cells. Yet, i‧v administered LNPs generally tend to distribute to the liver. We hypothesized LNPs can be altered to target antigen presenting cells in the spleen and hereby orchestrate specific and durable immune responses against cancer antigens. By using a design of experiment methodology we were able to screen LNPs in a cost and time effective manner. LNP compositions that were evaluated solely differed in the molar ratios of ionizable lipid, phospholipid, cholesterol and PEG-lipid and the choice of the PEG-lipid. Bayesian Regression modeling enabled us to identify LNP compositions conferring maximum immunogenicity upon i‧v. administration. To link LNP compositions to T cell responses and biodistribution, we prepared the same LNPs packaging either the viral oncoprotein E7 as an antigen or Cy-5 labelled luciferase mRNA. The optimized LNP compositions showed increased localization in the spleen (of mice and non-human primates) and uptake by antigen presenting cells. Furthermore, they induced high magnitude CD8 T cell responses that conferred strong antitumor immunity and prolonged survival of TC-1 tumor bearing mice. Mechanistically, type I interferons and phagocytes were found to be essential for eliciting strong T-cell responses. Unexpectedly, we identified B cells as major mediators of the vaccine- elicited T-cell response, revealing a previously undocumented role of these cells in the immune response to mRNA LNPs. Our data highlight the potential of optimizing LNP compositions by tailoring of the molar ratio of the lipids compromising the LNPs and provide insight in the cell types involved in the mRNA LNP-induced immune response. Collectively, our results illustrate the great promise of intravenous mRNA LNP vaccination for the treatment of cancer.
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- 2021
13. 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
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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.
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- 2021
14. easyQBD: A quality by design SaaS platform. Application to the development of lipid nanoparticles for mRNA delivery
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Bastogne, Thierry, Bevers, Sanne, Kooijmans, Sander, Hassler, Lucie, Andaloussi, Samir El, Schiffelers, Raymond, de Koker, Stefaan, Bastogne, Thierry, Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Biology, genetics and statistics (BIGS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), CYBERnano [Villers-lès-Nancy], eTheRNA Immunotherapies, Niel, Belgium, UMC Utrecht, University Medical Center [Utrecht], Karolinska Institutet [Stockholm], Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), eTheRNA Immunotherapies NV, and Utrecht Brain Center [UMC]
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[STAT.AP]Statistics [stat]/Applications [stat.AP] ,[STAT.AP] Statistics [stat]/Applications [stat.AP] ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,[SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2021
15. 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
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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
16. Exploring interactions between extracellular vesicles and cells for innovative drug delivery system design.
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Kooijmans, Sander A.A., de Jong, Olivier G., and Schiffelers, Raymond M.
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EXTRACELLULAR vesicles , *DRUG delivery systems , *SYSTEMS design , *SMALL molecules , *DRUG carriers - Abstract
[Display omitted] Extracellular vesicles (EVs) are submicron cell-secreted structures containing proteins, nucleic acids and lipids. EVs can functionally transfer these cargoes from one cell to another to modulate physiological and pathological processes. Due to their presumed biocompatibility and capacity to circumvent canonical delivery barriers encountered by synthetic drug delivery systems, EVs have attracted considerable interest as drug delivery vehicles. However, it is unclear which mechanisms and molecules orchestrate EV-mediated cargo delivery to recipient cells. Here, we review how EV properties have been exploited to improve the efficacy of small molecule drugs. Furthermore, we explore which EV surface molecules could be directly or indirectly involved in EV-mediated cargo transfer to recipient cells and discuss the cellular reporter systems with which such transfer can be studied. Finally, we elaborate on currently identified cellular processes involved in EV cargo delivery. Through these topics, we provide insights in critical effectors in the EV-cell interface which may be exploited in nature-inspired drug delivery strategies. [ABSTRACT FROM AUTHOR]
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- 2021
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17. P1500: WHAT’S DRIVING RDW? IN‐VITRO AND IN‐SILICO EVIDENCE FOR OXIDATIVE STRESS.
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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
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18. Raman spectroscopy as a quick tool to assess purity of extracellular vesicle preparations and predict their functionality.
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Gualerzi, Alice, Kooijmans, Sander Alexander Antonius, Niada, Stefania, Picciolini, Silvia, Brini, Anna Teresa, Camussi, Giovanni, and Bedoni, Marzia
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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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19. Drug Delivery with Extracellular Vesicles: From Imagination to Innovation.
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de Jong, Olivier G., Kooijmans, Sander A. A., Murphy, Daniel E., Jiang, Linglei, Evers, Martijn J. W., Sluijter, Joost P. G., Vader, Pieter, and Schiffelers, Raymond M.
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- 2019
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20. Modulation of tissue tropism and biological activity of exosomes and other extracellular vesicles: New nanotools for cancer treatment.
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Kooijmans, Sander A.A., Schiffelers, Raymond M., Zarovni, Natasa, and Vago, Riccardo
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DRUG delivery systems , *CANCER treatment , *EXOSOMES , *CELL communication , *IMMUNE recognition , *COMPANION diagnostics , *TROPISMS - Abstract
Exosomes are naturally secreted nanovesicles that have recently aroused a great interest in the scientific and clinical community for their roles in intercellular communication in almost all physiological and pathological processes. These 30–100 nm sized vesicles are released from the cells into the extracellular space and ultimately into biofluids in a tightly regulated way. Their molecular composition reflects their cells of origin, may confer specific cell or tissue tropism and underlines their biological activity. Exosomes and other extracellular vesicles (EVs) carry specific sets of proteins, nucleic acids (DNA, mRNA and regulatory RNAs), lipids and metabolites that represent an appealing source of novel noninvasive markers through biofluid biopsies. Exosome-shuttled molecules maintain their biological activity and are capable of modulating and reprogramming recipient cells. This multi-faceted nature of exosomes hold great promise for improving cancer treatment featuring them as novel diagnostic sensors as well as therapeutic effectors and drug delivery vectors. Natural biological activity including the therapeutic payload and targeting behavior of EVs can be tuned via genetic and chemical engineering. In this review we describe the properties that EVs share with conventional synthetic nanoparticles, including size, liposome-like membrane bilayer with customizable surface, and multifunctional capacity. We also highlight unique characteristics of EVs, which possibly allow them to circumvent some limitations of synthetic nanoparticle systems and facilitate clinical translation. The latter are in particular correlated with their innate stability, ability to cross biological barriers, efficiently deliver bioactive cargos or evade immune recognition. Furthermore, we discuss the potential roles for EVs in diagnostics and theranostics, and highlight the challenges that still need to be overcome before EVs can be applied to routine clinical practice. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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21. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting.
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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
- *
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
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22. 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
23. A post-insertion strategy for surface functionalization of bacterial and mammalian cell-derived extracellular vesicles.
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Jiang L, Luirink J, Kooijmans SAA, van Kessel KPM, Jong W, van Essen M, Seinen CW, de Maat S, de Jong OG, Gitz-François JFF, Hennink WE, Vader P, and Schiffelers RM
- Subjects
- Animals, Bacterial Outer Membrane ultrastructure, Blotting, Western methods, Cell Culture Techniques methods, Cell Line, Tumor, Electrophoresis, Polyacrylamide Gel methods, Extracellular Vesicles ultrastructure, Flow Cytometry methods, HEK293 Cells, Humans, Mice, Microscopy, Electron, Transmission methods, Surface Properties, Bacteria chemistry, Bacterial Outer Membrane chemistry, Extracellular Vesicles chemistry, Immunohistochemistry methods
- 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., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
24. Dendritic Cell Targeting mRNA Lipopolyplexes Combine Strong Antitumor T-Cell Immunity with Improved Inflammatory Safety.
- Author
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Van der Jeught K, De Koker S, Bialkowski L, Heirman C, Tjok Joe P, Perche F, Maenhout S, Bevers S, Broos K, Deswarte K, Malard V, Hammad H, Baril P, Benvegnu T, Jaffrès PA, Kooijmans SAA, Schiffelers R, Lienenklaus S, Midoux P, Pichon C, Breckpot K, and Thielemans K
- Subjects
- Animals, Dendritic Cells immunology, Female, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Particle Size, Polymers chemistry, Surface Properties, Tumor Cells, Cultured, Inflammation immunology, Lipids immunology, RNA, Messenger immunology, T-Lymphocytes immunology
- Abstract
In vitro transcribed mRNA constitutes a versatile platform to encode antigens and to evoke CD8 T-cell responses. Systemic delivery of mRNA packaged into cationic liposomes (lipoplexes) has proven particularly powerful in achieving effective antitumor immunity in animal models. Yet, T-cell responses to mRNA lipoplexes critically depend on the induction of type I interferons (IFN), potent pro-inflammatory cytokines, which inflict dose-limiting toxicities. Here, we explored an advanced hybrid lipid polymer shell mRNA nanoparticle (lipopolyplex) endowed with a trimannose sugar tree as an alternative delivery vehicle for systemic mRNA vaccination. Like mRNA lipoplexes, mRNA lipopolyplexes were extremely effective in conferring antitumor T-cell immunity upon systemic administration. Conversely to mRNA lipoplexes, mRNA lipopolyplexes did not rely on type I IFN for effective T-cell immunity. This differential mode of action of mRNA lipopolyplexes enabled the incorporation of N1 methyl pseudouridine nucleoside modified mRNA to reduce inflammatory responses without hampering T-cell immunity. This feature was attributed to mRNA lipopolyplexes, as the incorporation of thus modified mRNA into lipoplexes resulted in strongly weakened T-cell immunity. Taken together, we have identified lipopolyplexes containing N1 methyl pseudouridine nucleoside modified mRNA as potent yet low-inflammatory alternatives to the mRNA lipoplexes currently explored in early phase clinical trials.
- Published
- 2018
- Full Text
- View/download PDF
25. In Situ Gelling Liquid Crystalline System as Local siRNA Delivery System.
- Author
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Borgheti-Cardoso LN, Kooijmans SAA, Fens MHAM, van der Meel R, Vicentini FTMC, Fantini MCA, Bentley MVLB, and Schiffelers RM
- Subjects
- Monoglycerides chemistry, Polyethyleneimine chemistry, Propylene Glycol chemistry, RNA, Small Interfering genetics, Gene Silencing physiology, Liquid Crystals chemistry
- Abstract
An effective short interfering RNA (siRNA) delivery system protects the siRNA from degradation, facilitates its cellular uptake, and promotes its release into the cytoplasm. Local administration of siRNA presents advantages over systemic administration, such as the possibility to use lower doses and allow local and sustained release. In this context, in situ solidifying organogels based on monoglycerides (MO), polyethylenimine (PEI), propylene glycol (PG) and tris buffer are an attractive strategy for intratumoral delivery of siRNA. In this study, precursor fluid formulation (PFF) composed of MO/PEI/PG/tris buffer at 7.85:0.65:76.5:15 (w/w/w/w) was used to deliver siRNA to tumor cells. The internal structure of the gel obtained from PFF was characterized using small angle X-ray scattering (SAXS). In addition, its ability to complex siRNA, protect it from degradation, and functionally deliver it to tumor cells was investigated. Moreover, in vivo gel formation following intratumoral injection was evaluated. The gel formed in excess water from PFF was found to comprise a mixture of hexagonal and cubic phases. The system was able to complex high amounts of siRNA, protect it from degradation, promote siRNA internalization, and induce gene silencing in vitro in a variety of tumor cell lines. Moreover, a gel formed in situ following intratumoral injection in a murine xenograft model. In conclusion, PFF is a potential delivery system for local and sustained delivery of siRNA to tumor tissue after intratumoral administration.
- Published
- 2017
- Full Text
- View/download PDF
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