TY - JOUR AU - Kozma, Gergely Tibor AU - Mészáros, Tamás AU - Vashegyi, Ildikó AU - Fülöp, Tamás AU - Őrfi, Erik AU - Dézsi, László AU - Rosivall, László AU - Bavli, Yaelle AU - Urbanics, Rudolf AU - Mollnes, Tom Eirik AU - Barenholz, Yechezkel AU - Szebeni, János TI - Pseudo-anaphylaxis to Polyethylene Glycol (PEG)-Coated Liposomes: Roles of Anti-PEG IgM and Complement Activation in a Porcine Model of Human Infusion Reactions JF - ACS NANO J2 - ACS NANO VL - 13 PY - 2019 IS - 8 SP - 9315 EP - 9324 PG - 10 SN - 1936-0851 DO - 10.1021/acsnano.9b03942 UR - https://m2.mtmt.hu/api/publication/30786516 ID - 30786516 N1 - Nanomedicine Research and Education Center, Semmelweis University, Budapest, 1089, Hungary SeroScience Ltd., Budapest, 1125, Hungary Department of Pathophysiology, International Nephrology Research and Training Center, Semmelweis University, Budapest, 1089, Hungary Laboratory of Membrane and Liposome Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, 9112102, Israel Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, 0372, Norway Research Laboratory, Nordland Hospital Bodø, Faculty of Health Sciences and TREC, University of Tromsø, Tromsø, 9019, Norway Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, 7012, Norway Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, 3515, Hungary Cited By :114 Export Date: 8 February 2024 Correspondence Address: Szebeni, J.; Nanomedicine Research and Education Center, Hungary; email: jszebeni@seroscience.com LA - English DB - MTMT ER - TY - JOUR AU - Őrfi, Erik AU - Mészáros, Tamás AU - Hennies, Mark AU - Fülöp, Tamás AU - Dézsi, László AU - Nardocci, Alexander AU - Rosivall, László AU - Hamar, Péter AU - Neun, Barry W. AU - Dobrovolskaia, Marina A. AU - Szebeni, János AU - Szénási, Gábor TI - Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice JF - INTERNATIONAL JOURNAL OF NANOMEDICINE J2 - INT J NANOMED VL - 14 PY - 2019 SP - 1563 EP - 1573 PG - 11 SN - 1176-9114 DO - 10.2147/IJN.S187139 UR - https://m2.mtmt.hu/api/publication/30466738 ID - 30466738 N1 - * Megosztott szerzőség LA - English DB - MTMT ER - TY - JOUR AU - Szebeni, János TI - Mechanism of nanoparticle-induced hypersensitivity in pigs: complement or not complement? JF - DRUG DISCOVERY TODAY J2 - DRUG DISCOV TODAY VL - 23 PY - 2018 IS - 3 SP - 487 EP - 492 PG - 6 SN - 1359-6446 DO - 10.1016/j.drudis.2018.01.025 UR - https://m2.mtmt.hu/api/publication/3377436 ID - 3377436 N1 - Nanomedicine Research and Education Center, Department of Pathophysiology, Semmelweis University and SeroScience Ltd, Budapest, Hungary Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary Cited By :33 Export Date: 10 April 2023 CODEN: DDTOF Correspondence Address: Szebeni, J.; Nanomedicine Research and Education Center, Hungary; email: jszebeni@seroscience.com AB - A recent study on nanoparticle-induced hypersensitivity reactions in pigs showed robust pulmonary intravascular macrophage clearance of Polybead (R) carboxylate microspheres in mediating the adverse cardiopulmonary distress, irrespective of the ability of these particles to activate the complement (C) system in vitro. Focusing on this observation, this article highlights the controversies in projecting in vitro C assay data to in vivo conditions and applying data on polystyrene particles to therapeutic nanopharmaceuticals. Based on overwhelming evidence of a role of anaphylatoxins in hypersensitivity reactions, the need to further explore the role of C activation in the reported and other reactions is highlighted. C-activation-related and C-independent pseudoallergies (CARPA and CIPA) can proceed simultaneously, as outlined by the 'double-hit' hypothesis. LA - English DB - MTMT ER - TY - JOUR AU - Szebeni, János AU - Simberg, Dmitri AU - Gonzalez-Fernandez, Africa AU - Barenholz, Yechezkel AU - Dobrovolskaia, Marina A. TI - Roadmap and strategy for overcoming infusion reactions to nanomedicines JF - NATURE NANOTECHNOLOGY J2 - NAT NANOTECHNOL VL - 13 PY - 2018 IS - 12 SP - 1100 EP - 1108 PG - 9 SN - 1748-3387 DO - 10.1038/s41565-018-0273-1 UR - https://m2.mtmt.hu/api/publication/30473882 ID - 30473882 N1 - Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary SeroScience Ltd, Budapest, Hungary Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary Translational Bio-Nanosciences Laboratory, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States Immunology, Centro de Investigaciones Biomédicas (CINBIO), Centro de Investigación Singular de Galicia, Instituto de Investigación Sanitaria Galicia Sur (IIS-GS), University of Vigo, Vigo, Spain Department of Biochemistry, Institute for Medical Research Israel–Canada, Hebrew University–Hadassah Medical School, Jerusalem, Israel Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD, United States Cited By :18 Export Date: 1 February 2020 Correspondence Address: Dobrovolskaia, M.A.; Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer InstituteUnited States; email: marina@mail.nih.gov Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary SeroScience Ltd, Budapest, Hungary Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary Translational Bio-Nanosciences Laboratory, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States Immunology, Centro de Investigaciones Biomédicas (CINBIO), Centro de Investigación Singular de Galicia, Instituto de Investigación Sanitaria Galicia Sur (IIS-GS), University of Vigo, Vigo, Spain Department of Biochemistry, Institute for Medical Research Israel–Canada, Hebrew University–Hadassah Medical School, Jerusalem, Israel Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD, United States Cited By :19 Export Date: 3 February 2020 Correspondence Address: Dobrovolskaia, M.A.; Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer InstituteUnited States; email: marina@mail.nih.gov Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary SeroScience Ltd, Budapest, Hungary Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary Translational Bio-Nanosciences Laboratory, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States Immunology, Centro de Investigaciones Biomédicas (CINBIO), Centro de Investigación Singular de Galicia, Instituto de Investigación Sanitaria Galicia Sur (IIS-GS), University of Vigo, Vigo, Spain Department of Biochemistry, Institute for Medical Research Israel–Canada, Hebrew University–Hadassah Medical School, Jerusalem, Israel Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD, United States Cited By :47 Export Date: 3 February 2021 Correspondence Address: Dobrovolskaia, M.A.; Nanotechnology Characterization Laboratory, United States; email: marina@mail.nih.gov Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary SeroScience Ltd, Budapest, Hungary Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary Translational Bio-Nanosciences Laboratory, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States Immunology, Centro de Investigaciones Biomédicas (CINBIO), Centro de Investigación Singular de Galicia, Instituto de Investigación Sanitaria Galicia Sur (IIS-GS), University of Vigo, Vigo, Spain Department of Biochemistry, Institute for Medical Research Israel–Canada, Hebrew University–Hadassah Medical School, Jerusalem, Israel Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD, United States Cited By :47 Export Date: 12 February 2021 Correspondence Address: Dobrovolskaia, M.A.; Nanotechnology Characterization Laboratory, United States; email: marina@mail.nih.gov Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary SeroScience Ltd, Budapest, Hungary Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary Translational Bio-Nanosciences Laboratory, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States Immunology, Centro de Investigaciones Biomédicas (CINBIO), Centro de Investigación Singular de Galicia, Instituto de Investigación Sanitaria Galicia Sur (IIS-GS), University of Vigo, Vigo, Spain Department of Biochemistry, Institute for Medical Research Israel–Canada, Hebrew University–Hadassah Medical School, Jerusalem, Israel Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD, United States Cited By :47 Export Date: 17 February 2021 Correspondence Address: Dobrovolskaia, M.A.; Nanotechnology Characterization Laboratory, United States; email: marina@mail.nih.gov AB - Infusion reactions (IRs) are complex, immune-mediated side effects that mainly occur within minutes to hours of receiving a therapeutic dose of intravenously administered pharmaceutical products. These products are diverse and include both traditional pharmaceuticals (for example biological agents and small molecules) and new ones (for example nanotechnology-based products). Although IRs are not unique to nanomedicines, they represent a hurdle for the translation of nanotechnology-based drug products. This Perspective offers a big picture of the pharmaceutical field and examines current understanding of mechanisms responsible for IRs to nanomedicines. We outline outstanding questions, review currently available experimental evidence to provide some answers and highlight the gaps. We review advantages and limitations of the in vitro tests and animal models used for studying IRs to nanomedicines. Finally, we propose a roadmap to improve current understanding, and we recommend a strategy for overcoming the problem. LA - English DB - MTMT ER - TY - JOUR AU - Zamboni, William C. AU - Szebeni, János AU - Kozlov, Serguei V. AU - Lucas, Andrew T. AU - Piscitelli, Joseph A. AU - Dobrovolskaia, Marina A. TI - Animal models for analysis of immunological responses to nanomaterials: Challenges and considerations JF - ADVANCED DRUG DELIVERY REVIEWS J2 - ADV DRUG DELIV REV VL - 136 PY - 2018 SP - 82 EP - 96 PG - 15 SN - 0169-409X DO - 10.1016/j.addr.2018.09.012 UR - https://m2.mtmt.hu/api/publication/30473881 ID - 30473881 N1 - UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, Carolina Center of Cancer Nanotechnology Excellence, the University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University and SeroScience Ltd, Nagyvárad tér 4, Budapest, 1089, Hungary Laboratory of Animal Sciences Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, United States Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, United States Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary Cited By :6 Export Date: 1 February 2020 CODEN: ADDRE Correspondence Address: Zamboni, W.C.; UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, Carolina Center of Cancer Nanotechnology Excellence, the University of North Carolina at Chapel HillUnited States; email: zamboni@email.unc.edu UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, Carolina Center of Cancer Nanotechnology Excellence, the University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University and SeroScience Ltd, Nagyvárad tér 4, Budapest, 1089, Hungary Laboratory of Animal Sciences Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, United States Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, United States Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary Cited By :6 Export Date: 3 February 2020 CODEN: ADDRE Correspondence Address: Zamboni, W.C.; UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, Carolina Center of Cancer Nanotechnology Excellence, the University of North Carolina at Chapel HillUnited States; email: zamboni@email.unc.edu UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, Carolina Center of Cancer Nanotechnology Excellence, the University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University and SeroScience Ltd, Nagyvárad tér 4, Budapest, 1089, Hungary Laboratory of Animal Sciences Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, United States Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, United States Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary Cited By :17 Export Date: 12 January 2021 CODEN: ADDRE Correspondence Address: Zamboni, W.C.; UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, Carolina Center of Cancer Nanotechnology Excellence, the University of North Carolina at Chapel HillUnited States; email: zamboni@email.unc.edu UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, Carolina Center of Cancer Nanotechnology Excellence, the University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University and SeroScience Ltd, Nagyvárad tér 4, Budapest, 1089, Hungary Laboratory of Animal Sciences Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, United States Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, United States Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary Cited By :18 Export Date: 12 February 2021 CODEN: ADDRE Correspondence Address: Zamboni, W.C.; UNC Eshelman School of Pharmacy, United States; email: zamboni@email.unc.edu AB - Nanotechnology provides many solutions to improve conventional drug delivery and has a unique niche in the areas related to the specific targeting of the immune system, such as immunotherapies and vaccines. Preclinical studies in this field rely heavily on the combination of in vitro and in vivo methods to assess the safety and efficacy of nanotechnology platforms, nanoparticle-formulated drugs, and vaccines. While certain types of toxicities can be evaluated in vitro and good in vitro-in vivo correlation has been demonstrated for such tests, animal studies are still needed to address complex biological questions and, therefore, provide a unique contribution to establishing nanoparticle safety and efficacy profiles. The genetic, metabolic, mechanistic, and phenotypic diversity of currently available animal models often complicates both the animal choice and the interpretation of the results. This review summarizes current knowledge about differences in the immune system function and immunological responses of animals commonly used in preclinical studies of nanomaterials. We discuss challenges, highlight current gaps, and propose recommendations for animal model selection to streamline preclinical analysis of nanotechnology formulations. (C) 2018 Elsevier B.V. All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Wibroe, PP AU - Anselmo, AC AU - Nilsson, PH AU - Sarode, A AU - Gupta, V AU - Urbanics, R AU - Szebeni, János AU - Hunter, AC AU - Mitragotri, S AU - Mollnes, TE AU - Moghimi, SM TI - Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes JF - NATURE NANOTECHNOLOGY J2 - NAT NANOTECHNOL VL - 12 PY - 2017 IS - 6 SP - 589 EP - 594 PG - 6 SN - 1748-3387 DO - 10.1038/nnano.2017.47 UR - https://m2.mtmt.hu/api/publication/3330122 ID - 3330122 N1 - N1 Funding details: R01HL129179, NIH, National Institutes of Health N1 Funding text: S.M.M. acknowledges financial support by the Danish Agency for Science, Technology and Innovation (Det Strategiske Forskningsrad), reference 09-065746. T.E.M. acknowledges financial support from the European Communitys Seventh Framework Programme under grant agreement no. 602699 (DIREKT). S.M. acknowledges support from the National Institutes of Health (R01HL129179). Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen Ø, DK-2100, Denmark Department of Chemical Engineering, Center for Bioengineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, 0372, Norway K.G. Jebsen IRC, University of Oslo, Oslo, 0372, Norway Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, 391 82, Sweden College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States Nanomedicine Research and Education Center, Semmelweis University, Budapest and Sero Science Ltd, Budapest, Hungary Leicester School of Pharmacy, De Montfort University, Gateway, Leicester, LE1 9BH, United Kingdom Reserach Laboratory, Nordland Hospital, Bodø, 8092, Norway K.G. Jebsen TREC, University of Tromsø, Tromsø, 9037, Norway Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, 7491, Norway Nano-Science Center, University of Copenhagen, Universitetsparken 5, Copenhagen Ø, DK-2100, Denmark School of Medicine, Pharmacy and Health, Durham University, Queen's Campus, Stockton-on-Tees, TS17 6BH, United Kingdom Cited By :85 Export Date: 12 February 2021 Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen Ø, DK-2100, Denmark Department of Chemical Engineering, Center for Bioengineering, University of California at Santa Barbara, Santa Barbara, CA 93106, United States Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, 0372, Norway K.G. Jebsen IRC, University of Oslo, Oslo, 0372, Norway Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, 391 82, Sweden College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States Nanomedicine Research and Education Center, Semmelweis University, Budapest and Sero Science Ltd, Budapest, Hungary Leicester School of Pharmacy, De Montfort University, Gateway, Leicester, LE1 9BH, United Kingdom Reserach Laboratory, Nordland Hospital, Bodø, 8092, Norway K.G. Jebsen TREC, University of Tromsø, Tromsø, 9037, Norway Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, 7491, Norway Nano-Science Center, University of Copenhagen, Universitetsparken 5, Copenhagen Ø, DK-2100, Denmark School of Medicine, Pharmacy and Health, Durham University, Queen's Campus, Stockton-on-Tees, TS17 6BH, United Kingdom Cited By :85 Export Date: 17 February 2021 AB - Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation. Specifically, we show that delaying particle recognition by macrophages within the first few minutes of injection overcomes adverse reactions in pigs using two independent approaches. First, we changed the particle geometry from a spherical shape (which triggers cardiopulmonary distress) to either rod-or disk-shape morphology. Second, we physically adhered spheres to the surface of erythrocytes. These strategies, which are distinct from commonly leveraged stealth engineering approaches such as nanoparticle surface functionalization with poly(ethylene glycol) and/or immunological modulators, prevent robust macrophage recognition, resulting in the reduction or mitigation of adverse cardiopulmonary distress associated with nanopharmaceutical administration. LA - English DB - MTMT ER - TY - JOUR AU - Dézsi, László AU - Fülöp, Tamás AU - Mészáros, Tamás AU - Szénási, Gábor AU - Urbanics, R AU - Vázsonyi, C AU - Őrfi, Erik AU - Rosivall, László AU - Nemes, R AU - Kok, RJ AU - Metselaar, JM AU - Storm, G AU - Szebeni, János TI - Features of complement activation-related pseudoallergy to liposomes with different surface charge and PEGylation: Comparison of the porcine and rat responses JF - JOURNAL OF CONTROLLED RELEASE J2 - J CONTROL RELEASE VL - 195 PY - 2014 SP - 2 EP - 10 PG - 9 SN - 0168-3659 DO - 10.1016/j.jconrel.2014.08.009 UR - https://m2.mtmt.hu/api/publication/2745559 ID - 2745559 AB - Pigs are known to provide a sensitive model for studying complement (C) activation-related pseudoallergy (CARPA), a hypersensitivity reaction to liposomal and many other nanomedicines that limits their clinical use. The utility of rats as a CARPA model has, however, not been analyzed to date in detail. The present study compared the two models by inducing CARPA with i.v. bolus injections of two reactogenic liposomes that differed from each other in surface properties: one was AmBisome, a strong anionic, free-surface small unilamellar liposome (SUV), while the other was neutral, polyethylene glycol (PEG)-grafted SUV wherein the 2 kDa-PEG was anchored to the membrane via cholesterol (Chol-PEG). Both in pigs and rats AmBisome caused significant consumption of C3, indicating C activation, along with paralleling massive changes in blood pressure, white blood cell, platelet counts and in plasma thromboxane B2 levels, indicating CARPA. These processes were similar in the two species in terms of kinetics, but significantly differed in the doses that caused major hemodynamic changes (~ 0.01 and ~ 22 mg phospholipid (PL)/kg in pigs and rats, respectively). Pigs responded to AmBisome with pulmonary hypertension and systemic hypotension, and the reaction was not tachyphylactic. The major response of rats was systemic hypotension, leukopenia followed by leukocytosis, and thrombocytopenia. Chol-PEG liposomes caused severe reaction in pigs at 0.1 mg/kg, while the reaction they caused in rats was mild even at 300 mg PL/kg. Importantly, the reaction to Chol-PEG in pigs was partly tachyphylactic. These observations highlight fundamental differences in the immune mechanisms of porcine and rat CARPA, and also show a major impact of liposome surface characteristics, determining the presence or absence of tachyphylaxis. The data suggest that rats are 2-3 orders of magnitude less sensitive to liposomal CARPA than pigs; however, the causes of these differences, the PEG-dependent tachyphylaxis and the massive reactivity of Chol-PEG liposomes remain unclear. © 2014 Elsevier B.V. All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Szebeni, János TI - Complement activation-related pseudoallergy: A stress reaction in blood triggered by nanomedicines and biologicals JF - MOLECULAR IMMUNOLOGY J2 - MOL IMMUNOL VL - 61 PY - 2014 IS - 2 SP - 163 EP - 173 PG - 11 SN - 0161-5890 DO - 10.1016/j.molimm.2014.06.038 UR - https://m2.mtmt.hu/api/publication/2748955 ID - 2748955 N1 - Cited By :144 Export Date: 3 February 2021 CODEN: IMCHA Correspondence Address: Szebeni, J.; Nanomedicine Research and Education Center, Semmelweis University, Budapest and Department Nanobiotechnology, Miskolc University, Miskolc, Hungary; email: JSzebeni@seroscience.com Cited By :145 Export Date: 10 February 2021 CODEN: IMCHA Correspondence Address: Szebeni, J.; Nanomedicine Research and Education Center, Semmelweis University, Budapest and Department Nanobiotechnology, Miskolc University, Miskolc, Hungary; email: JSzebeni@seroscience.com Cited By :145 Export Date: 12 February 2021 CODEN: IMCHA Correspondence Address: Szebeni, J.; Nanomedicine Research and Education Center, Semmelweis University, Budapest and Department Nanobiotechnology, Miskolc University, Miskolc, Hungary; email: JSzebeni@seroscience.com Cited By :145 Export Date: 17 February 2021 CODEN: IMCHA Correspondence Address: Szebeni, J.; Nanomedicine Research and Education Center, Semmelweis University, Budapest and Department Nanobiotechnology, Miskolc University, Miskolc, Hungary; email: JSzebeni@seroscience.com AB - Intravenous injection of a variety of nanotechnology enhanced (liposomal, micellar, polymer-conjugated) and protein-based (antibodies, enzymes) drugs can lead to hypersensitivity reactions (HSRs), also known as infusion, or anaphylactoid reactions. The molecular mechanism of mild to severe allergy symptoms may differ from case to case and is mostly not known, however, in many cases a major cause, or contributing factor is activation of the complement (C) system. The clinical relevance of C activation-related HSRs, a non-IgE-mediated pseudoallergy (CARPA), lies in its unpredictability and occasional lethal outcome. Accordingly, there is an unmet medical need to develop laboratory assays and animal models that quantitate CARPA. This review provides basic information on CARPA; a short history, issues of nomenclature, incidence, classification of reactogenic drugs and symptoms, and the mechanisms of C activation via different pathways. It is pointed out that anaphylatoxin-induced mast cell release may not entirely explain the severe reactions; a "second hit" on allergy mediating cells may also contribute. In addressing the increasing requirements for CARPA testing, the review evaluates the available assays and animal models, and proposes a possible algorithm for the screening of reactogenic drugs and hypersensitive patients. Finally, an analogy is proposed between CARPA and the classic stress reaction, suggesting that CARPA represents a "blood stress" reaction, a systemic fight of the body against harmful biological and chemical agents via the anaphylatoxin/mast-cell/circulatory system axis, in analogy to the body's fight of physical and emotional stress via the hypothalamo/pituitary/adrenal axis. In both cases the response to a broad variety of noxious effects are funneled into a uniform pattern of physiological changes. © 2014 Elsevier Ltd. All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Van, Den Hoven JM AU - Nemes, R AU - Metselaar, JM AU - Nuijen, B AU - Beijnen, JH AU - Storm, G AU - Szebeni, János TI - Complement activation by PEGylated liposomes containing prednisolone JF - EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES J2 - EUR J PHARM SCI VL - 49 PY - 2013 IS - 2 SP - 265 EP - 271 PG - 7 SN - 0928-0987 DO - 10.1016/j.ejps.2013.03.007 UR - https://m2.mtmt.hu/api/publication/2502607 ID - 2502607 N1 - Dept. Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, Netherlands Dept. Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, Netherlands Dept. Targeted Therapeutics, MIRA Institute, University of Twente, PO Box 217, 7500 AE Enschede, Netherlands Dept. Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Budapest, Hungary Nanomedicine Research and Education Center, Semmelweis University, Bay Zoltan Ltd., Budapest, Hungary Cited By :38 Export Date: 3 February 2021 CODEN: EPSCE Correspondence Address: Van Den Hoven, J.M.; Dept. Pharmacy and Pharmacology, Louwesweg 6, 1066 EC Amsterdam, Netherlands; email: Jolanda.vandenHoven@slz.nl Dept. Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, Netherlands Dept. Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, Netherlands Dept. Targeted Therapeutics, MIRA Institute, University of Twente, PO Box 217, 7500 AE Enschede, Netherlands Dept. Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Budapest, Hungary Nanomedicine Research and Education Center, Semmelweis University, Bay Zoltan Ltd., Budapest, Hungary Cited By :38 Export Date: 10 February 2021 CODEN: EPSCE Correspondence Address: Van Den Hoven, J.M.; Dept. Pharmacy and Pharmacology, Louwesweg 6, 1066 EC Amsterdam, Netherlands; email: Jolanda.vandenHoven@slz.nl Dept. Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, Netherlands Dept. Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, Netherlands Dept. Targeted Therapeutics, MIRA Institute, University of Twente, PO Box 217, 7500 AE Enschede, Netherlands Dept. Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Budapest, Hungary Nanomedicine Research and Education Center, Semmelweis University, Bay Zoltan Ltd., Budapest, Hungary Cited By :38 Export Date: 12 February 2021 CODEN: EPSCE Correspondence Address: Van Den Hoven, J.M.; Dept. Pharmacy and Pharmacology, Louwesweg 6, 1066 EC Amsterdam, Netherlands; email: Jolanda.vandenHoven@slz.nl Dept. Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, Netherlands Dept. Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, Netherlands Dept. Targeted Therapeutics, MIRA Institute, University of Twente, PO Box 217, 7500 AE Enschede, Netherlands Dept. Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Budapest, Hungary Nanomedicine Research and Education Center, Semmelweis University, Bay Zoltan Ltd., Budapest, Hungary Cited By :38 Export Date: 17 February 2021 CODEN: EPSCE Correspondence Address: Van Den Hoven, J.M.; Dept. Pharmacy and Pharmacology, Louwesweg 6, 1066 EC Amsterdam, Netherlands; email: Jolanda.vandenHoven@slz.nl AB - Infusion of PEGylated liposomes can give rise to hypersensitivity reactions (HSRs) in a relatively large number of patients. Previously it has been shown that these reactions can be caused by activation of the complement (C) system by a negative charge on the anchor molecule of PEG at the liposomal surface. In this study it is tested whether the activation of the C system by PEG-liposomes could be significantly reduced to values comparable to nonreactive liposomal formulations, by changing the PEGylation-profile on the liposomal surface. Therefore, the formation of C activation markers SC5b-9, C3a, C4d and Bb in normal human serum by both prednisolone loaded and empty liposomes with a variation of PEG chain length, PEG surface concentration, PEG anchor molecule and liposomal size was determined using in vitro assays. The tested liposomes caused no or only mild (30%) activation of C except for one formulation wherein the PEG2000 was anchored to cholesterol (CHOL-PEG2000). The latter liposomes caused paralleling rises in SC5b-9 and Bb levels, suggesting excess activation of the alternative pathway. While the relative safety of weak C activator liposomes remains to be confirmed in vivo, the unique, non-charge and non-antibody-mediated direct conversion of C3 by CHOL-PEG2000 liposomes (although argues against the clinical development of these vesicles) opens new opportunities to understand liposomal C activation at the molecular level. © 2013 Elsevier B.V. All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Baranyi, L AU - Szebeni, János AU - Sávay, S AU - Bodo, Mihaly AU - Basta, M AU - Bentley, T B AU - Bunger, R AU - Alving, C R TI - Complement-Dependent Shock and Tissue Damage Induced by Intravenous Injection of Cholesterol-Enriched Liposomes in Rats JF - JOURNAL OF APPLIED RESEARCH: IN CLINICAL AND EXPERIMENTAL THERAPEUTICS J2 - J APPLIED RES VL - 3 PY - 2003 IS - 3 SP - 221 EP - 231 PG - 11 SN - 1537-064X UR - https://m2.mtmt.hu/api/publication/1303884 ID - 1303884 N1 - Tradenames: sq 30741 Megjegyzés-20898438 Chemicals/CAS: 7 [3 [(2 heptanamidoacetamido)methyl] 7 oxabicyclo[2.2.1]hept 2 yl] 5 heptenoic acid, 107332-47-8; cholesterol, 57-88-5; cobrotoxin, 12584-83-7, 8001-03-4; thromboxane A2, 57576-52-0 Tradenames: sq 30741 UR: http://www.scopus.com/inward/record.url?eid=2-s2.0-0142188069&partnerID=40&md5=6ae8ef85f4d189c0f5ef15252fdea570 Megjegyzés-20899146 Chemicals/CAS: 7 [3 [(2 heptanamidoacetamido)methyl] 7 oxabicyclo[2.2.1]hept 2 yl] 5 heptenoic acid, 107332-47-8; cholesterol, 57-88-5; cobrotoxin, 12584-83-7, 8001-03-4; thromboxane A2, 57576-52-0 Tradenames: sq 30741 UR: http://www.scopus.com/inward/record.url?eid=2-s2.0-0142188069&partnerID=40&md5=6ae8ef85f4d189c0f5ef15252fdea570 AB - A single intravenous injection of 4 to 8 mg/kg of large, multilamellar, cholesterol-enriched lipid vesicles (containing 71% cholesterol; HC-MLV) induced marked bradycardia, arrhythmia, and transient decrease in systemic blood pressure in rats. A single higher dose (15-20 mg/kg), or repeated injections of 4 to 8 mg/kg HC-MLV, resulted in severe pulmonary hemorrhage and edema (ARDS-like histologic changes), systemic microthrombus formation, hemorrhage in the kidneys and liver, as well as early signs of diffuse myocardial damage. Complement depletion with cobra venom factor, or the use of thromboxane A2 receptor inhibitor (SQ30741), prevented these adverse reactions, pointing to the involvement of C activation and TXA2 release in the pathomechanism. The likely role of C activation was supported by the demonstration of strong C activation by HC-MLV in rat serum in vitro, along with the binding of natural IgG and IgM antibodies to these vesicles. The C activation by HC-MLV seems to proceed by way of the classic pathway mediated by natural antilipid antibodies. These studies present a novel, powerful method for inducing anaphylactoid shock and other C activation-related pathologic changes providing a model for multiple organ failure, semicrystalline cholesterol embolism, and C activation-related pseudoallergy. LA - English DB - MTMT ER - TY - JOUR AU - Chanan-Khan, A AU - Szebeni, János AU - Savay, S AU - Liebes, L AU - Rafique, N M AU - Alving, C R AU - Muggia, F M TI - Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil®): Possible role in hypersensitivity reactions JF - ANNALS OF ONCOLOGY J2 - ANN ONCOL VL - 14 PY - 2003 IS - 9 SP - 1430 EP - 1437 PG - 8 SN - 0923-7534 DO - 10.1093/annonc/mdg374 UR - https://m2.mtmt.hu/api/publication/1303883 ID - 1303883 N1 - PubMed ID: 12954584 Tradenames: doxil, Alza, United States Manufacturers: Alza, United States UR: http://www.scopus.com/inward/record.url?eid=2-s2.0-0141725521&partnerID=40&md5=84156a7a12b8b8086b1afdf6e2d9280b Megjegyzés-20897273 PubMed ID: 12954584 Chemicals/CAS: cimetidine, 51481-61-9, 70059-30-2; diphenhydramine, 147-24-0, 58-73-1; doxorubicin, 23214-92-8, 25316-40-9; hydrocortisone, 50-23-7; ondansetron, 103639-04-9, 116002-70-1, 99614-01-4; tropisetron, 89565-68-4; Antibiotics, Antineoplastic; Doxorubicin, 23214-92-8 Tradenames: doxil, Alza, United States Manufacturers: Alza, United States UR: http://www.scopus.com/inward/record.url?eid=2-s2.0-0141725521&partnerID=40&md5=84156a7a12b8b8086b1afdf6e2d9280b Megjegyzés-20897315 PubMed ID: 12954584 Chemicals/CAS: cimetidine, 51481-61-9, 70059-30-2; diphenhydramine, 147-24-0, 58-73-1; doxorubicin, 23214-92-8, 25316-40-9; hydrocortisone, 50-23-7; ondansetron, 103639-04-9, 116002-70-1, 99614-01-4; tropisetron, 89565-68-4; Antibiotics, Antineoplastic; Doxorubicin, 23214-92-8 Tradenames: doxil, Alza, United States Manufacturers: Alza, United States UR: http://www.scopus.com/inward/record.url?eid=2-s2.0-0141725521&partnerID=40&md5=84156a7a12b8b8086b1afdf6e2d9280b Megjegyzés-20898439 PubMed ID: 12954584 Chemicals/CAS: cimetidine, 51481-61-9, 70059-30-2; diphenhydramine, 147-24-0, 58-73-1; doxorubicin, 23214-92-8, 25316-40-9; hydrocortisone, 50-23-7; ondansetron, 103639-04-9, 116002-70-1, 99614-01-4; tropisetron, 89565-68-4; Antibiotics, Antineoplastic; Doxorubicin, 23214-92-8 Tradenames: doxil, Alza, United States Manufacturers: Alza, United States UR: http://www.scopus.com/inward/record.url?eid=2-s2.0-0141725521&partnerID=40&md5=84156a7a12b8b8086b1afdf6e2d9280b Megjegyzés-20900136 PubMed ID: 12954584 Chemicals/CAS: cimetidine, 51481-61-9, 70059-30-2; diphenhydramine, 147-24-0, 58-73-1; doxorubicin, 23214-92-8, 25316-40-9; hydrocortisone, 50-23-7; ondansetron, 103639-04-9, 116002-70-1, 99614-01-4; tropisetron, 89565-68-4; Antibiotics, Antineoplastic; Doxorubicin, 23214-92-8 Tradenames: doxil, Alza, United States Manufacturers: Alza, United States UR: http://www.scopus.com/inward/record.url?eid=2-s2.0-0141725521&partnerID=40&md5=84156a7a12b8b8086b1afdf6e2d9280b Megjegyzés-20900283 PubMed ID: 12954584 Chemicals/CAS: cimetidine, 51481-61-9, 70059-30-2; diphenhydramine, 147-24-0, 58-73-1; doxorubicin, 23214-92-8, 25316-40-9; hydrocortisone, 50-23-7; ondansetron, 103639-04-9, 116002-70-1, 99614-01-4; tropisetron, 89565-68-4; Antibiotics, Antineoplastic; Doxorubicin, 23214-92-8 Tradenames: doxil, Alza, United States Manufacturers: Alza, United States UR: http://www.scopus.com/inward/record.url?eid=2-s2.0-0141725521&partnerID=40&md5=84156a7a12b8b8086b1afdf6e2d9280b Megjegyzés-20897254 PubMed ID: 12954584 Chemicals/CAS: cimetidine, 51481-61-9, 70059-30-2; diphenhydramine, 147-24-0, 58-73-1; doxorubicin, 23214-92-8, 25316-40-9; hydrocortisone, 50-23-7; ondansetron, 103639-04-9, 116002-70-1, 99614-01-4; tropisetron, 89565-68-4; Antibiotics, Antineoplastic; Doxorubicin, 23214-92-8 Tradenames: doxil, Alza, United States Manufacturers: Alza, United States UR: http://www.scopus.com/inward/record.url?eid=2-s2.0-0141725521&partnerID=40&md5=84156a7a12b8b8086b1afdf6e2d9280b AB - Background: Pegylated liposomal doxorubicin (Doxil®) has been reported to cause immediate hypersensitivity reactions (HSRs) that cannot be explained as IgE-mediated (type I) allergy. Previous in vitro and animal studies indicated that activation of the complement (C) system might play a causal role in the process, a proposal that has not been tested in humans to date. Patients and methods: Patients with solid tumors (n = 29) treated for the first time with Doxil were evaluated for HSRs and concurrent C activation. HSRs were classified from mild to severe, while C activation was estimated by serial measurement of plasma C terminal complex (SC5b-9) levels. Increases in SC5b-9 were compared in patients with or without reactions, and were correlated with Doxil dose rate. Results: Moderate to severe HSRs occurred in 45% of patients. Plasma SC5b-9 at 10 min after infusion was significantly elevated in 92% of reactor patients versus 56% in the non-reactor group, and the rise was greater in reactors than in non-reactors. We found significant association between C activation and HSRs, both showing direct correlation with the initial Doxil dose rate. Conclusions: C activation may play a key role in HSRs to Doxil. However, low-level C activation does not necessarily entail clinical symptoms, highlighting the probable involvement of further, as yet unidentified, amplification factors. LA - English DB - MTMT ER - TY - JOUR AU - Szebeni, János AU - Spielberg, H AU - Cliff, R O AU - Wassef, N M AU - Rudolph, A S AU - Alving, C R TI - Complement activation and thromboxane secretion by liposome-encapsulated hemoglobin in rats in vivo: Inhibition by soluble complement receptor type 1 JF - ARTIFICIAL CELLS BLOOD SUBSTITUTES AND IMMOBILIZATION BIOTECHNOLOGY J2 - ARTIFICIAL CELLS BLOOD SUBSTITUTES AND IMMOBILIZATION BIOTECHNOLOGY VL - 25 PY - 1997 IS - 4 SP - 347 EP - 355 PG - 9 SN - 1073-1199 DO - 10.3109/10731199709118925 UR - https://m2.mtmt.hu/api/publication/1303902 ID - 1303902 AB - Intravenous administration of liposome-encapsulated hemoglobin (LEH) in rats led to an early (within 15 min) decline of hemolytic complement (C) activity in the plasma along with a significant, parallel rise in thromboxane B2 (TXB2) levels. The TXB2 response was inhibited by co-administration of soluble C receptor type 1 (sCR1) with LEH, as well as by C depletion with cobra venom factor. These observations provide evidence for a causal relationship between LEH-induced C activation and TXB2 release, and suggest that sCR1 could be useful in attenuating the acute respiratory, hematological and hemodynamic side effects of LEH described earlier in the rat. Intravenous administration of liposome-encapsulated hemoglobin (LEH) in rats led to an early (within 15 min) decline of hemolytic complement (C) activity in the plasma along with a significant, parallel rise in thromboxane B2 (TXB2) levels. The TXB2 response was inhibited by co-administration of soluble C receptor type 1 (sCR1) with LEH, as well as by C depletion with cobra venom factor. These observations provide evidence for a causal relationship between LEH-induced C activation and TXB2 release, and suggest that sCR1 could be useful in attenuating the acute respiratory, hematological and hemodynamic side effects of LEH described earlier in the rat. LA - English DB - MTMT ER - TY - JOUR AU - Szebeni, János AU - Wassef, N M AU - Spielberg, H AU - Rudolph, A S AU - Alving, C R TI - Complement activation in rats by liposomes and liposome-encapsulated hemoglobin: Evidence for anti-lipid antibodies and alternative pathway activation JF - BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS J2 - BIOCHEM BIOPH RES CO VL - 205 PY - 1994 IS - 1 SP - 255 EP - 263 PG - 9 SN - 0006-291X DO - 10.1006/bbrc.1994.2658 UR - https://m2.mtmt.hu/api/publication/1303911 ID - 1303911 N1 - PubMed ID: 7999033 UR: http://www.scopus.com/inward/record.url?eid=2-s2.0-0027997521&partnerID=40&md5=35337c061fab337b45e18f66eca5a964 AB - Intravenous injection of hemoglobin-containing liposomes (LEH) caused a significant reduction in plasma hemolytic complement activity in rats on a time scale of minutes. Liposomes without hemoglobin also caused complement consumption, but less than LEH, while free hemoglobin was without effect. Consistent with complement activation, the LEH-induced drop in plasma hemolytic complement activity was closely paralleled by an increase in plasma thromboxane B2 level. Studies to determine the mechanism of complement activation demonstrated the presence of natural antibodies in rat serum against all lipid components of LEH, thus, the potential for classical pathway activation. Yet, in vitro incubation of LEH with rat serum showed that: 1) EGTA/Mg++, which inhibits complement activation through the classical pathway, did not inhibit complement consumption of LEH, and 2) the use of serum preheated at 50°C, which inhibits C activation through the alternative pathway by selectively depleting factor B, effectively reversed the complement-consuming effect of LEH. Consequently, LEH-induced complement activation in rat serum seems to involve primarily the alternative pathway. LA - English DB - MTMT ER -