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

卷:270

Article

Fulop, Tamas^1,5  Nemes, Reka²  Meszaros, Tamas¹  Urbanics, Rudolf³  Kok, Robbert Jan²  Jackman, Joshua A.⁴  Cho, Nam-Joon⁴  Storm, Gert^2,5  Szebeni, Janos^1,3,6 

[1] Semmelweis Univ, Nanomed Res & Educ Ctr, Dept Pathophysiol, Budapest, Hungary

[2] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut, POB 80082, NL-3508 TB Utrecht, Netherlands

[3] SeroScience Ltd, Nagyvarad Ter 4, H-1089 Budapest, Hungary

[4] Nanyang Technol Univ, Sch Mat Sci & Engn, 50 Nanyang Dr, Singapore 637553, Singapore

[5] Univ Twente, MIRA Inst, Dept Targeted Therapeut, POB 217, NL-7500 AE Enschede, Netherlands

[6] Univ Miskolc, Fac Hlth, Dept Nanobiotechnol & Regenerat Med, Budapest, Hungary

关键词: Complement;    Hypersensitivity reactions;    Iron;    Anaphylaxis;    CARPA;    Anaphylatoxins;    MRI;    Imaging;    Nanoparticles;    Nanomedicines;    Immune toxicity;   

DOI  :  10.1016/j.jconrel.2017.11.043

来源: Elsevier

【 摘 要 】

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 carbox-ymethyldextran-coated (ferucarbotran, Resosvist (R)) and dextran-coated (ferumoxtran-10, Sinerem (R)) 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.

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