Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model : correlation with physicochemical features and clinical information

The unique magnetic properties of superparamagnetic iron oxide nanoparticles (SPIONs) have led to their increasing use in drug delivery and imaging applications. Some polymer-coated SPIONs, however, share with many other nanoparticles the potential of causing hypersensitivity reactions (HSRs) known...

Full description

Saved in:
Bibliographic Details
Main Authors: Fülöp, Tamás, Nemes, Réka, Mészáros, Tamás, Urbanics, Rudolf, Kok, Robbert Jan, Jackman, Joshua A., Cho, Nam-Joon, Storm, Gert, Szebeni, János
Other Authors: School of Materials Science and Engineering
Format: Article
Language:English
Published: 2020
Subjects:
Online Access:https://hdl.handle.net/10356/142114
Tags: Add Tag
No Tags, Be the first to tag this record!
Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-142114
record_format dspace
spelling sg-ntu-dr.10356-1421142020-06-16T02:53:56Z Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model : correlation with physicochemical features and clinical information Fülöp, Tamás Nemes, Réka Mészáros, Tamás Urbanics, Rudolf Kok, Robbert Jan Jackman, Joshua A. Cho, Nam-Joon Storm, Gert Szebeni, János School of Materials Science and Engineering Engineering::Materials Complement Hypersensitivity Reactions The unique magnetic properties of superparamagnetic iron oxide nanoparticles (SPIONs) have led to their increasing use in drug delivery and imaging applications. Some polymer-coated SPIONs, however, share with many other nanoparticles the potential of causing hypersensitivity reactions (HSRs) known as complement (C) activation-related pseudoallergy (CARPA). In order to explore the roles of iron core composition and particle surface coating in SPION-induced CARPA, we measured C activation by 6 different SPIONs in a human serum that is known to react to nanoparticles (NPs) with strong C activation. Remarkably, only the carboxymethyldextran-coated (ferucarbotran, Resosvist®) and dextran-coated (ferumoxtran-10, Sinerem®) SPIONs caused significant C activation, while the citric acid, phosphatidylcholine, starch and chitosan-coated SPIONs had no such effect. Focusing on Resovist and Sinerem, we found Sinerem to be a stronger activator of C than Resovist, although the individual variation in 15 different human sera was substantial. Further analysis of C activation by Sinerem indicated biphasic dose dependence and significant production of C split product Bb but not C4d, attesting to alternative pathway C activation only at low doses. Consistent with the strong C activation by Sinerem and previous reports of HSRs in man, injection of Sinerem in a pig led to dose-dependent CARPA, while Resovist was reaction-free. Using nanoparticle tracking analysis, it was further determined that Sinerem, more than Resovist, displayed multimodal size distribution and significant fraction of aggregates - factors which are known to promote C activation and CARPA. Taken together, our findings offer physicochemical insight into how key compositional factors and nanoparticle size distribution affect SPION-induced CARPA, a knowledge that could lead to the development of SPIONs with improved safety profiles. NRF (Natl Research Foundation, S’pore) 2020-06-16T02:53:56Z 2020-06-16T02:53:56Z 2018 Journal Article Fülöp, T., Nemes, R., Mészáros, T., Urbanics, R., Kok, R. J., Jackman, J. A., . . . Szebeni, J. (2018). Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model : correlation with physicochemical features and clinical information. Journal of Controlled Release, 270, 268-274. doi:10.1016/j.jconrel.2017.11.043 1873-4995 https://hdl.handle.net/10356/142114 10.1016/j.jconrel.2017.11.043 29203414 2-s2.0-85038812790 270 268 274 en Journal of Controlled Release © 2017 Elsevier B.V. All rights reserved.
institution Nanyang Technological University
building NTU Library
country Singapore
collection DR-NTU
language English
topic Engineering::Materials
Complement
Hypersensitivity Reactions
spellingShingle Engineering::Materials
Complement
Hypersensitivity Reactions
Fülöp, Tamás
Nemes, Réka
Mészáros, Tamás
Urbanics, Rudolf
Kok, Robbert Jan
Jackman, Joshua A.
Cho, Nam-Joon
Storm, Gert
Szebeni, János
Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model : correlation with physicochemical features and clinical information
description The unique magnetic properties of superparamagnetic iron oxide nanoparticles (SPIONs) have led to their increasing use in drug delivery and imaging applications. Some polymer-coated SPIONs, however, share with many other nanoparticles the potential of causing hypersensitivity reactions (HSRs) known as complement (C) activation-related pseudoallergy (CARPA). In order to explore the roles of iron core composition and particle surface coating in SPION-induced CARPA, we measured C activation by 6 different SPIONs in a human serum that is known to react to nanoparticles (NPs) with strong C activation. Remarkably, only the carboxymethyldextran-coated (ferucarbotran, Resosvist®) and dextran-coated (ferumoxtran-10, Sinerem®) SPIONs caused significant C activation, while the citric acid, phosphatidylcholine, starch and chitosan-coated SPIONs had no such effect. Focusing on Resovist and Sinerem, we found Sinerem to be a stronger activator of C than Resovist, although the individual variation in 15 different human sera was substantial. Further analysis of C activation by Sinerem indicated biphasic dose dependence and significant production of C split product Bb but not C4d, attesting to alternative pathway C activation only at low doses. Consistent with the strong C activation by Sinerem and previous reports of HSRs in man, injection of Sinerem in a pig led to dose-dependent CARPA, while Resovist was reaction-free. Using nanoparticle tracking analysis, it was further determined that Sinerem, more than Resovist, displayed multimodal size distribution and significant fraction of aggregates - factors which are known to promote C activation and CARPA. Taken together, our findings offer physicochemical insight into how key compositional factors and nanoparticle size distribution affect SPION-induced CARPA, a knowledge that could lead to the development of SPIONs with improved safety profiles.
author2 School of Materials Science and Engineering
author_facet School of Materials Science and Engineering
Fülöp, Tamás
Nemes, Réka
Mészáros, Tamás
Urbanics, Rudolf
Kok, Robbert Jan
Jackman, Joshua A.
Cho, Nam-Joon
Storm, Gert
Szebeni, János
format Article
author Fülöp, Tamás
Nemes, Réka
Mészáros, Tamás
Urbanics, Rudolf
Kok, Robbert Jan
Jackman, Joshua A.
Cho, Nam-Joon
Storm, Gert
Szebeni, János
author_sort Fülöp, Tamás
title Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model : correlation with physicochemical features and clinical information
title_short Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model : correlation with physicochemical features and clinical information
title_full Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model : correlation with physicochemical features and clinical information
title_fullStr Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model : correlation with physicochemical features and clinical information
title_full_unstemmed Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model : correlation with physicochemical features and clinical information
title_sort complement activation in vitro and reactogenicity of low-molecular weight dextran-coated spions in the pig carpa model : correlation with physicochemical features and clinical information
publishDate 2020
url https://hdl.handle.net/10356/142114
_version_ 1681057313413136384