Roadmap and strategy for overcoming infusion reactions to nanomedicines

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Abstract

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.

Abstract

This Perspective analyses the infusion reactions triggered by nanomedicine administration and proposes a strategy to improve their mechanistic understanding and to reduce their negative outcomes.

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Most cited references 51

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Janos Szebeni (2014)

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.

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Author and article information

Contributors

Marina A. Dobrovolskaia: marina@mail.nih.gov

Journal

Journal ID (nlm-ta): Nat Nanotechnol

Journal ID (iso-abbrev): Nat Nanotechnol

Title: Nature Nanotechnology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1748-3387

ISSN (Electronic): 1748-3395

Publication date (Electronic): 22 October 2018

Publication date (Print): 2018

Volume: 13

Issue: 12

Pages: 1100-1108

Affiliations

[1 ]ISNI 0000 0001 0942 9821, GRID grid.11804.3c, Nanomedicine Research and Education Center, Institute of Pathophysiology, , Semmelweis University, ; Budapest, Hungary

[2 ]SeroScience Ltd, Budapest, Hungary

[3 ]ISNI 0000 0001 2254 2845, GRID grid.10334.35, Department of Nanobiotechnology and Regenerative Medicine, , Faculty of Health, Miskolc University, ; Miskolc, Hungary

[4 ]ISNI 0000000121090824, GRID grid.266185.e, Translational Bio-Nanosciences Laboratory, , University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, ; Aurora, CO USA

[5 ]ISNI 0000 0001 2097 6738, GRID grid.6312.6, 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

[6 ]ISNI 0000 0004 1937 0538, GRID grid.9619.7, Department of Biochemistry, Institute for Medical Research Israel–Canada, , Hebrew University–Hadassah Medical School, ; Jerusalem, Israel

[7 ]ISNI 0000 0004 0535 8394, GRID grid.418021.e, Nanotechnology Characterization Laboratory, Cancer Research Technology Program, , Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, ; Frederick, MD USA

Article

Publisher ID: 273

DOI: 10.1038/s41565-018-0273-1

PMC ID: 6320688

PubMed ID: 30348955

SO-VID: 8e1f430c-d635-4a3c-851a-92e5d0d1a656

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.