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Review
. 2020 Sep;12(5):e1633.
doi: 10.1002/wnan.1633. Epub 2020 Apr 7.

Nonclinical regulatory immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls

Christina Giannakou  1 , Margriet V D Z Park  2 , Irene E M Bosselaers  3 , Wim H de Jong  2 , Jan Willem van der Laan  3 , Henk van Loveren  4 , Rob J Vandebriel  2 , Robert E Geertsma  2
Affiliations
Review

Nonclinical regulatory immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls

Christina Giannakou et al. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2020 Sep.

Abstract

Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 "Immunotoxicity Studies for Human Pharmaceuticals" of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH-S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory immunotoxicity assessment strategy, which considers the immunotoxicity endpoints currently missing in the ICH-S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Keywords: ICH-S8; immunotoxicity; in vitro; nanomedicinal product; regulatory.

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Conflict of interest statement

The authors have declared no conflicts of interest for this article.

Figures

FIGURE 1
FIGURE 1
Flow diagram of current regulatory immunotoxicity evaluation of nonbiological pharmaceuticals. Adapted from guideline ICH‐S8
FIGURE 2
FIGURE 2
Proposed regulatory immunotoxicity evaluation strategy of nanomedicinal products
FIGURE 3
FIGURE 3
Proposed paradigm for preclinical testing for CARPA induction by nanomedicinal products, modified from the suggested paradigm by Szebeni and Storm (2015)
FIGURE 4
FIGURE 4
Proposed paradigm for preclinical testing of effects on macrophage function after administration of nanomedicinal products
FIGURE 5
FIGURE 5
Proposed paradigm for preclinical testing of inflammasome activation after administration of nanomedicinal products
See this image and copyright information in PMC

References

    1. Accomasso, L. , Cristallini, C. , & Giachino, C. (2018). Risk assessment and risk minimization in nanomedicine: A need for predictive, alternative, and 3Rs strategies. Frontiers in Pharmacology, 9, 228 10.3389/fphar.2018.00228 - DOI - PMC - PubMed
    1. Arts, J. H. , Hadi, M. , Irfan, M. A. , Keene, A. M. , Kreiling, R. , Lyon, D. , … Landsiedel, R. (2015). A decision‐making framework for the grouping and testing of nanomaterials (DF4nanoGrouping). Regulatory Toxicology and Pharmacology, 71(2), S1–S27. 10.1016/j.yrtph.2015.03.007 - DOI - PubMed
    1. Brand, W. , Noorlander, C. W. , Giannakou, C. , De Jong, W. H. , Kooi, M. W. , Park, M. V. , … Geertsma, R. E. (2017). Nanomedicinal products: A survey on specific toxicity and side effects. International Journal of Nanomedicine, 12, 6107–6129. 10.2147/IJN.S139687 - DOI - PMC - PubMed
    1. Caron, W. P. , Lay, J. C. , Fong, A. M. , La‐Beck, N. M. , Kumar, P. , Newman, S. E. , … Zamboni, W. C. (2013). Translational studies of phenotypic probes for the mononuclear phagocyte system and liposomal pharmacology. The Journal of Pharmacology and Experimental Therapeutics, 347(3), 599–606. 10.1124/jpet.113.208801 - DOI - PMC - PubMed
    1. De Jong, W. H. , Van Der Ven, L. T. , Sleijffers, A. , Park, M. V. D. Z. , Jansen, E. H. , Van Loveren, H. , & Vandebriel, R. J. (2013). Systemic and immunotoxicity of silver nanoparticles in an intravenous 28 days repeated dose toxicity study in rats. Biomaterials, 34(33), 8333–8343. 10.1016/j.biomaterials.2013.06.048 - DOI - PubMed

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