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3. Heparin interferes with the uptake of liposomes in glioma

Author

van Solinge, Thomas S., primary, Friis, Kristina Pagh, additional, O'Brien, Killian, additional, Verschoor, Romy L., additional, van Aarle, Jeroen, additional, Koekman, Arnold, additional, Breakefield, Xandra O., additional, Vader, Pieter, additional, Schiffelers, Raymond, additional, and Broekman, Marike, additional

Published
2023
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5. Heparin interferes with the uptake of liposomes in glioma

Author

CDL Staf Research, CDL Cluster Onderzoek en Onderwijs, Circulatory Health, Centraal Diagnostisch Laboratorium, Cancer, van Solinge, Thomas S, Friis, Kristina Pagh, O'Brien, Killian, Verschoor, Romy L, van Aarle, Jeroen, Koekman, Arnold, Breakefield, Xandra O, Vader, Pieter, Schiffelers, Raymond, Broekman, Marike, CDL Staf Research, CDL Cluster Onderzoek en Onderwijs, Circulatory Health, Centraal Diagnostisch Laboratorium, Cancer, van Solinge, Thomas S, Friis, Kristina Pagh, O'Brien, Killian, Verschoor, Romy L, van Aarle, Jeroen, Koekman, Arnold, Breakefield, Xandra O, Vader, Pieter, Schiffelers, Raymond, and Broekman, Marike

Published
2023

6. Anti-PEG antibodies compromise the integrity of PEGylated lipid-based nanoparticles via complement

Author

Estapé Senti, Mariona, de Jongh, Caroline A., Dijkxhoorn, Kim, Verhoef, Johan J.F., Szebeni, Janos, Storm, Gert, Hack, C. Erik, Schiffelers, Raymond M., Fens, Marcel H., Boross, Peter, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, and Pharmaceutics

Subjects
0303 health sciences, Complement, Pharmaceutical Science, Complement System Proteins, Lipids, PEG, Polyethylene Glycols, Anti-PEG antibodies, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Liposomes, Nanoparticles, LNPs, 030304 developmental biology
Abstract

PEGylation of lipid-based nanoparticles and other nanocarriers is widely used to increase their stability and plasma half-life. However, either pre-existing or de novo formed anti-PEG antibodies can induce hypersensitivity reactions and accelerated blood clearance through binding to the nanoparticle surfaces, leading to activation of the complement system. In this study, we investigated the consequences and mechanisms of complement activation by anti-PEG antibodies interacting with different types of PEGylated lipid-based nanoparticles. By using both liposomes loaded with different (model) drugs and LNPs loaded with mRNA, we demonstrate that complement activation triggered by anti-PEG antibodies can compromise the bilayer/surface integrity, leading to premature drug release or exposure of their mRNA contents to serum proteins. Anti-PEG antibodies also can induce deposition of complement fragments onto the surface of PEGylated lipid-based nanoparticles and induce the release of fluid phase complement activation products. The role of the different complement pathways activated by lipid-based nanoparticles was studied using deficient sera and/or inhibitory antibodies. We identified a major role for the classical complement pathway in the early activation events leading to the activation of C3. Our data also confirm the essential role of amplification of C3 activation by alternative pathway components in the lysis of liposomes. Finally, the levels of pre-existing anti-PEG IgM antibodies in plasma of healthy donors correlated with the degree of complement activation (fixation and lysis) induced upon exposure to PEGylated liposomes and mRNA-LNPs. Taken together, anti-PEG antibodies trigger complement activation by PEGylated lipid-based nanoparticles, which can potentially compromise their integrity, leading to premature drug release or cargo exposure to serum proteins.

Published
2022
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7. TOP-EVs: Technology of Protein delivery through Extracellular Vesicles is a versatile platform for intracellular protein delivery

Author

Ilahibaks, Nazma F., primary, Ardisasmita, Arif I., additional, Xie, Songpu, additional, Gunnarsson, Anders, additional, Brealey, Joseph, additional, Vader, Pieter, additional, de Jong, Olivier G., additional, de Jager, Saskia, additional, Dekker, Niek, additional, Peacock, Ben, additional, Schiffelers, Raymond M., additional, Sluijter, Joost P.G., additional, and Lei, Zhiyong, additional

Published
2023
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8. Exploring interactions between extracellular vesicles and cells for innovative drug delivery system design

Author

Kooijmans, Sander, de Jong, Olivier G., Schiffelers, Raymond, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, and Pharmaceutics

Subjects
Biocompatibility, RNA delivery, Pharmaceutical Science, 02 engineering and technology, Exosomes, Extracellular vesicles, Small Molecule Libraries, Synthetic drugs, Extracellular Vesicles, 03 medical and health sciences, Drug Delivery Systems, Extracellular vesicle surface, Humans, Uptake mechanisms, 030304 developmental biology, Drug Carriers, 0303 health sciences, Chemistry, Effector, Protein delivery, Small molecules, 021001 nanoscience & nanotechnology, Small molecule, Microvesicles, Cell biology, Reporter systems, Drug Design, Drug delivery, 0210 nano-technology
Abstract

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.

Published
2021
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9. Polymeric delivery systems for nucleic acid therapeutics: Approaching the clinic

Author

van den Berg, Annette I.S., Yun, Chae Ok, Schiffelers, Raymond M., Hennink, Wim E., Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, and Pharmaceutics

Subjects
Drug, Cationic polymers, Polymers, media_common.quotation_subject, Genetic enhancement, Genetic Vectors, Pharmaceutical Science, 02 engineering and technology, Gene delivery, Non-viral gene therapy, Viral vector, 03 medical and health sciences, Cations, Nucleic Acids, Internalization, 030304 developmental biology, media_common, 0303 health sciences, Chemistry, Gene Transfer Techniques, 021001 nanoscience & nanotechnology, Lipids, Nanomedicine, Biochemistry, Nucleic acid, Circulation time, 0210 nano-technology, Polyplexes
Abstract

Gene therapy using nucleic acids has many clinical applications for the treatment of diseases with a genetic origin as well as for the development of innovative vaccine formulations. Since nucleic acids in their free form are rapidly degraded by nucleases present in extracellular matrices, have poor pharmacokinetics and hardly pass cellular membranes, carrier systems are required. Suitable carriers that protect the nucleic acid payload against enzymatic attack, prolong circulation time after systemic administration and assist in cellular binding and internalization are needed to develop nucleic acid based drug products. Viral vectors have been investigated and are also clinically used as delivery vehicles. However, some major drawbacks are associated with their use. Therefore there has been substantial attention on the use of non-viral carrier systems based on cationic lipids and polymers. This review focuses on the properties of polymer-based nucleic acid formulations, also referred as polyplexes. Different polymeric systems are summarized, and the cellular barriers polyplexes encounter and ways to tackle these are discussed. Finally attention is given to the clinical status of non-viral nucleic acid formulations.

Published
2021
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10. mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells

Author

Bevers, Sanne, primary, Kooijmans, Sander A.A., additional, Van de Velde, Elien, additional, Evers, Martijn J.W., additional, Seghers, Sofie, additional, Gitz-Francois, Jerney J.J.M., additional, van Kronenburg, Nicky C.H., additional, Fens, Marcel H.A.M., additional, Mastrobattista, Enrico, additional, Hassler, Lucie, additional, Sork, Helena, additional, Lehto, Taavi, additional, Ahmed, Kariem E., additional, El Andaloussi, Samir, additional, Fiedler, Katja, additional, Breckpot, Karine, additional, Maes, Michael, additional, Van Hoorick, Diane, additional, Bastogne, Thierry, additional, Schiffelers, Raymond M., additional, and De Koker, Stefaan, additional

Published
2022
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11. VhH anti‐thrombomodulin clone 1 inhibits TAFI activation and enhances fibrinolysis in human whole blood under flow

Author

van Moorsel, Marc V.A., primary, Poolen, Geke C., additional, Koekman, Cornelis A., additional, Verhoef, Sandra, additional, de Maat, Steven, additional, Barendrecht, Arjan, additional, van Kleef, Nadine D., additional, Meijers, Joost C.M., additional, Schiffelers, Raymond M., additional, Maas, Coen, additional, and Urbanus, Rolf T., additional

Published
2022
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13. Delivery of modified mRNA to damaged myocardium by systemic administration of lipid nanoparticles

Author

Evers, Martijn J.W., primary, Du, Wenjuan, additional, Yang, Qiangbing, additional, Kooijmans, Sander A.A., additional, Vink, Aryan, additional, van Steenbergen, Mies, additional, Vader, Pieter, additional, de Jager, Saskia C.A., additional, Fuchs, Sabine A., additional, Mastrobattista, Enrico, additional, Sluijter, Joost P.G., additional, Lei, Zhiyong, additional, and Schiffelers, Raymond, additional

Published
2022
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15. Extracellular vesicles as drug delivery systems: Why and how?

Author

Elsharkasy, Omnia M, Nordin, Joel Z, Hagey, Daniel W, de Jong, Olivier G, Schiffelers, Raymond M, Andaloussi, Samir El, Vader, Pieter, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, and Pharmaceutics

Subjects
Drug, Computer science, media_common.quotation_subject, Pharmaceutical Science, Nanotechnology, 02 engineering and technology, Exosomes, Extracellular vesicles, Isolation, Synthetic drugs, 03 medical and health sciences, Drug Delivery Systems, Engineering, Upscaling, Animals, Humans, 030304 developmental biology, media_common, Targeting, 0303 health sciences, 021001 nanoscience & nanotechnology, Microvesicles, Nanomedicine, Drug delivery, Safety, 0210 nano-technology, Drug carrier
Abstract

Over the past decades, a multitude of synthetic drug delivery systems has been developed and introduced to the market. However, applications of such systems are limited due to inefficiency, cytotoxicity and/or immunogenicity. At the same time, the field of natural drug carrier systems has grown rapidly. One of the most prominent examples of such natural carriers are extracellular vesicles (EVs). EVs are cell-derived membranous particles which play important roles in intercellular communication. EVs possess a number of characteristics that qualify them as promising vehicles for drug delivery. In order to take advantage of these attributes, an in-depth understanding of why EVs are such unique carrier systems and how we can exploit their qualities is pivotal. Here, we review unique EV features that are relevant for drug delivery and highlight emerging strategies to make use of those features for drug loading and targeted delivery.

Published
2020
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17. Liposomal dexamethasone inhibits tumor growth in an advanced human-mouse hybrid model of multiple myeloma

Author

Deshantri, Anil K, Fens, Marcel H, Ruiter, Ruud W J, Metselaar, Josbert M, Storm, Gert, van Bloois, Louis, Varela-Moreira, Aida, Mandhane, Sanjay N, Mutis, Tuna, Martens, Anton C M, Groen, Richard W J, Schiffelers, Raymond M, Afd Pharmaceutics, Pharmaceutics, Biomaterials Science and Technology, Afd Pharmaceutics, Pharmaceutics, Hematology laboratory, and CCA - Cancer biology and immunology

Subjects
Antineoplastic Agents, Hormonal, Angiogenesis, UT-Hybrid-D, Pharmaceutical Science, 02 engineering and technology, Bone and Bones, Dexamethasone, 03 medical and health sciences, Pharmacokinetics, Multiple myeloma, In vivo, multiple nyeloma, Cell Line, Tumor, Animals, Humans, Medicine, Bone marrow, Tissue Distribution, Glucocorticoids, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Tumor microenvironment, business.industry, Body Weight, EPR effect, 021001 nanoscience & nanotechnology, medicine.disease, n/a OA procedure, Tumor Burden, Disease Models, Animal, medicine.anatomical_structure, Drug delivery, Liposomes, Cancer research, Female, Multiple Myeloma, 0210 nano-technology, business, medicine.drug
Abstract

Glucocorticoids are the cornerstone in the clinic for treatment of hematological malignancies, including multiple myeloma. Nevertheless, poor pharmacokinetic properties of glucocorticoids require high and frequent dosing with the off-target adverse effects defining the maximum dose. Recently, nanomedicine formulations of glucocorticoids have been developed that improve the pharmacokinetic profile, limit adverse effects and improve solid tumor accumulation. Multiple myeloma is a hematological malignancy characterized by uncontrolled growth of plasma cells. These tumors initiate increased angiogenesis and microvessel density in the bone marrow, which might be exploited using nanomedicines, such as liposomes. Nano-sized particles can accumulate as a result of the increased vascular leakiness at the bone marrow tumor lesions. Pre-clinical screening of novel anti-myeloma therapeutics in vivo requires a suitable animal model that represents key features of the disease. In this study, we show that fluorescently labeled long circulating liposomes were found in plasma up to 24 h after injection in an advanced human-mouse hybrid model of multiple myeloma. Besides the organs involved in clearance, liposomes were also found to accumulate in tumor bearing human-bone scaffolds. The therapeutic efficacy of liposomal dexamethasone phosphate was evaluated in this model showing strong tumor growth inhibition while free drug being ineffective at an equivalent dose (4 mg/kg) regimen. The liposomal formulation slightly reduced total body weight of myeloma-bearing mice during the course of treatment, which appeared reversible when treatment was stopped. Liposomal dexamethasone could be further developed as monotherapy or could fit in with existing therapy regimens to improve therapeutic outcomes for multiple myeloma.

Published
2019
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19. A post-insertion strategy for surface functionalization of bacterial and mammalian cell-derived extracellular vesicles

Author

Jiang, Linglei, primary, Luirink, Joen, additional, Kooijmans, Sander A.A., additional, van Kessel, Kok P.M., additional, Jong, Wouter, additional, van Essen, Max, additional, Seinen, Cor W., additional, de Maat, Steven, additional, de Jong, Olivier G., additional, Gitz-François, Jerney F.F., additional, Hennink, Wim E., additional, Vader, Pieter, additional, and Schiffelers, Raymond M., additional

Published
2021
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22. Delivering the power of nanomedicine to patients today

Author

Germain, Matthieu, primary, Caputo, Fanny, additional, Metcalfe, Su, additional, Tosi, Giovanni, additional, Spring, Kathleen, additional, Åslund, Andreas K.O., additional, Pottier, Agnes, additional, Schiffelers, Raymond, additional, Ceccaldi, Alexandre, additional, and Schmid, Ruth, additional

Published
2020
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23. Polymeric micelles loaded with carfilzomib increase tolerability in a humanized bone marrow-like scaffold mouse model

Author

Afd Pharmaceutics, Dep Farmaceutische wetenschappen, Pharmaceutics, Varela-Moreira, Aida, van Straten, Demian, van Leur, Heleen F, Ruiter, Ruud W J, Deshantri, Anil K, Hennink, Wim E, Fens, Marcel H A M, Groen, Richard W J, Schiffelers, Raymond M, Afd Pharmaceutics, Dep Farmaceutische wetenschappen, Pharmaceutics, Varela-Moreira, Aida, van Straten, Demian, van Leur, Heleen F, Ruiter, Ruud W J, Deshantri, Anil K, Hennink, Wim E, Fens, Marcel H A M, Groen, Richard W J, and Schiffelers, Raymond M

Published
2020

28. Tumor Seeding During Colonoscopy as a Possible Cause for Metachronous Colorectal Cancer

Author

Backes, Yara, primary, Seerden, Tom C.J., additional, van Gestel, Rosanne S.F. E., additional, Kranenburg, Onno, additional, Ubink, Inge, additional, Schiffelers, Raymond M., additional, van Straten, Demian, additional, van der Capellen, Malu S., additional, van de Weerd, Simone, additional, de Leng, Wendy W.J., additional, Siersema, Peter D., additional, Offerhaus, G. Johan A., additional, Morsink, Folkert H., additional, Ramphal, Winesh, additional, Terhaar Sive Droste, Jochiim, additional, van Lent, Anja U.G., additional, Geesing, Joost M.J., additional, Vleggaar, Frank P., additional, Elias, Sjoerd G., additional, Lacle, Miangela M., additional, and Moons, Leon M.G., additional

Published
2019
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30. Routine Blood Tests Do Not Predict Survival in Patients with Glioblastoma—Multivariable Analysis of 497 Patients

Author

Maas, Sybren L.N., primary, Draaisma, Kaspar, additional, Snijders, Tom J., additional, Senders, Joeky T., additional, Berendsen, Sharon, additional, Seute, Tatjana, additional, Schiffelers, Raymond M., additional, van Solinge, Wouter W., additional, Ten Berg, Maarten J., additional, Robe, Pierre A., additional, and Broekman, Marike L.D., additional

Published
2019
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31. Development and characterization of liposomal formulation of bortezomib

Author

Afd Pharmaceutics, Pharmaceutics, Deshantri, Anil K, Metselaar, Josbert M, Zagkou, Stavroula, Storm, Gert, Mandhane, Sanjay N, Fens, Marcel H A M, Schiffelers, Raymond M, Afd Pharmaceutics, Pharmaceutics, Deshantri, Anil K, Metselaar, Josbert M, Zagkou, Stavroula, Storm, Gert, Mandhane, Sanjay N, Fens, Marcel H A M, and Schiffelers, Raymond M

Published
2019

32. A head-to-head comparison of conjugation methods for VHHs: Random maleimide-thiol coupling versus controlled click chemistry

Author

Afd Pharmaceutics, Pharmaceutics, van Moorsel, Marc V.A., Urbanus, Rolf T., Verhoef, S., Koekman, C. A., Vink, Maurice, Vermonden, T., Maas, Coen, Pasterkamp, Gerard, Schiffelers, Raymond M., Afd Pharmaceutics, Pharmaceutics, van Moorsel, Marc V.A., Urbanus, Rolf T., Verhoef, S., Koekman, C. A., Vink, Maurice, Vermonden, T., Maas, Coen, Pasterkamp, Gerard, and Schiffelers, Raymond M.

Published
2019

33. A head-to-head comparison of conjugation methods for VHHs: Random maleimide-thiol coupling versus controlled click chemistry

Author

UMC Utrecht, CDL Nanomedicine, Poli Van Creveldkliniek Medisch, Circulatory Health, Centraal Diagnostisch Laboratorium, CDL Staf Research, CDL Onderzoek Pasterkamp, dLAB Afdelingen, CDL Cluster Onderzoek en Onderwijs, Cancer, van Moorsel, Marc V.A., Urbanus, Rolf T., Verhoef, S., Koekman, C. A., Vink, Maurice, Vermonden, T., Maas, Coen, Pasterkamp, Gerard, Schiffelers, Raymond M., UMC Utrecht, CDL Nanomedicine, Poli Van Creveldkliniek Medisch, Circulatory Health, Centraal Diagnostisch Laboratorium, CDL Staf Research, CDL Onderzoek Pasterkamp, dLAB Afdelingen, CDL Cluster Onderzoek en Onderwijs, Cancer, van Moorsel, Marc V.A., Urbanus, Rolf T., Verhoef, S., Koekman, C. A., Vink, Maurice, Vermonden, T., Maas, Coen, Pasterkamp, Gerard, and Schiffelers, Raymond M.

Published
2019

34. Development and characterization of liposomal formulation of bortezomib

Author

Circulatory Health, Cancer, CDL Nanomedicine, CDL Cluster Onderzoek en Onderwijs, Deshantri, Anil K, Metselaar, Josbert M, Zagkou, Stavroula, Storm, Gert, Mandhane, Sanjay N, Fens, Marcel H A M, Schiffelers, Raymond M, Circulatory Health, Cancer, CDL Nanomedicine, CDL Cluster Onderzoek en Onderwijs, Deshantri, Anil K, Metselaar, Josbert M, Zagkou, Stavroula, Storm, Gert, Mandhane, Sanjay N, Fens, Marcel H A M, and Schiffelers, Raymond M

Published
2019

38. The Soft Side of Extracellular Vesicles

Author

Sorkin, Raya, primary, Huisjes, Rick, additional, Bošković, Filip, additional, Vorselen, Daan, additional, Pignatelli, Silvia, additional, Ofir-Birin, Yifat, additional, Leal, Joames K.F., additional, Schiller, Jürgen, additional, Roos, Wouter H., additional, Bosman, Giel, additional, Regev-Rudzki, Neta, additional, Schiffelers, Raymond M., additional, and Wuite, Gijs J.L., additional

Published
2018
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42. Liposome encapsulated berberine treatment attenuates cardiac dysfunction after myocardial infarction

Author

Allijn, Iris E., primary, Czarny, Bertrand M.S., additional, Wang, Xiaoyuan, additional, Chong, Suet Yen, additional, Weiler, Marek, additional, da Silva, Acarilia Eduardo, additional, Metselaar, Josbert M., additional, Lam, Carolyn Su Ping, additional, Pastorin, Giorgia, additional, de Kleijn, Dominique P.V., additional, Storm, Gert, additional, Wang, Jiong-Wei, additional, and Schiffelers, Raymond M., additional

Published
2017
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48. Lipid-based Transfection Reagents Exhibit Cryo-induced Increase in Transfection Efficiency

Author

Sork, Helena, primary, Nordin, Joel Z, additional, Turunen, Janne J, additional, Wiklander, Oscar PB, additional, Bestas, Burcu, additional, Zaghloul, Eman M, additional, Margus, Helerin, additional, Padari, Kärt, additional, Duru, Adil D, additional, Corso, Giulia, additional, Bost, Jeremy, additional, Vader, Pieter, additional, Pooga, Margus, additional, Smith, CI Edvard, additional, Wood, Matthew JA, additional, Schiffelers, Raymond M, additional, Hällbrink, Mattias, additional, and Andaloussi, Samir EL, additional

Published
2016
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49. An in situ gelling liquid crystalline system based on monoglycerides and polyethylenimine for local delivery of siRNAs

Author

Borgheti-Cardoso, Lívia Neves, primary, Depieri, Lívia Vieira, additional, Kooijmans, Sander A.A., additional, Diniz, Henrique, additional, Calzzani, Ricardo Alexandre Junqueira, additional, Vicentini, Fabiana Testa Moura de Carvalho, additional, van der Meel, Roy, additional, Fantini, Márcia Carvalho de Abreu, additional, Iyomasa, Mamie Mizusaki, additional, Schiffelers, Raymond M., additional, and Bentley, Maria Vitória Lopes Badra, additional

Published
2015
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50. In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior

Author

Zomer, Anoek, primary, Maynard, Carrie, additional, Verweij, Frederik Johannes, additional, Kamermans, Alwin, additional, Schäfer, Ronny, additional, Beerling, Evelyne, additional, Schiffelers, Raymond Michel, additional, de Wit, Elzo, additional, Berenguer, Jordi, additional, Ellenbroek, Saskia Inge Johanna, additional, Wurdinger, Thomas, additional, Pegtel, Dirk Michiel, additional, and van Rheenen, Jacco, additional

Published
2015
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