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

T.G. Fülöp, Réka Nemes, Tamás Mészáros, Rudolf Urbanics, Robbert Jan Kok, Joshua A. Jackman, Namjoon Cho, Gert Storm, János Szebeni (Corresponding Author)

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

Abstract

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 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, but not 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.

Original languageEnglish
Pages (from-to)268-274
Number of pages7
JournalJournal of controlled release
Volume270
DOIs
Publication statusPublished - 28 Jan 2018

Fingerprint

Complement Activation
Nanoparticles
Swine
Molecular Weight
In Vitro Techniques
ferumoxides
Activation Analysis
ferumoxtran-10
ferric oxide
Chitosan
Dextrans
Serum
Phosphatidylcholines
Citric Acid
Starch
Hypersensitivity
Polymers
Iron

Keywords

  • UT-Hybrid-D
  • Anaphylaxis
  • CARPA
  • Complement
  • Hypersensitivity reactions
  • Imaging
  • Immune toxicity
  • Iron
  • MRI
  • Nanomedicines
  • Nanoparticles
  • Anaphylatoxins

Cite this

Fülöp, T.G. ; Nemes, Réka ; Mészáros, Tamás ; Urbanics, Rudolf ; Kok, Robbert Jan ; Jackman, Joshua A. ; Cho, Namjoon ; 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. In: Journal of controlled release. 2018 ; Vol. 270. pp. 268-274.
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abstract = "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 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{\circledR}) and dextran-coated (ferumoxtran-10, Sinerem{\circledR}) 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, but not 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.",
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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, T.G.; Nemes, Réka; Mészáros, Tamás; Urbanics, Rudolf; Kok, Robbert Jan; Jackman, Joshua A.; Cho, Namjoon; Storm, Gert; Szebeni, János (Corresponding Author).

In: Journal of controlled release, Vol. 270, 28.01.2018, p. 268-274.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model

T2 - Correlation with physicochemical features and clinical information

AU - Fülöp, T.G.

AU - Nemes, Réka

AU - Mészáros, Tamás

AU - Urbanics, Rudolf

AU - Kok, Robbert Jan

AU - Jackman, Joshua A.

AU - Cho, Namjoon

AU - Storm, Gert

AU - Szebeni, János

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PY - 2018/1/28

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N2 - 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 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, but not 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.

AB - 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 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, but not 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.

KW - UT-Hybrid-D

KW - Anaphylaxis

KW - CARPA

KW - Complement

KW - Hypersensitivity reactions

KW - Imaging

KW - Immune toxicity

KW - Iron

KW - MRI

KW - Nanomedicines

KW - Nanoparticles

KW - Anaphylatoxins

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DO - 10.1016/j.jconrel.2017.11.043

M3 - Article

VL - 270

SP - 268

EP - 274

JO - Journal of controlled release

JF - Journal of controlled release

SN - 0168-3659

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