title: A comparison of immunotoxic effects of nanomedicinal products with regulatory immunotoxicity testing requirements.
abstract: Nanomaterials (NMs) are attractive for biomedical and pharmaceutical applications because of their unique physicochemical and biological properties. A major application area of NMs is drug delivery. Many nanomedicinal products (NMPs) currently on the market or in clinical trials are most often based on liposomal products or polymer conjugates. NMPs can be designed to target specific tissues, eg, tumors. In virtually all cases, NMPs will eventually reach the immune system. It has been shown that most NMs end up in organs of the mononuclear phagocytic system, notably liver and spleen. Adverse immune effects, including allergy, hypersensitivity, and immunosuppression, have been reported after NMP administration. Interactions of NMPs with the immune system may therefore constitute important side effects. Currently, no regulatory documents are specifically dedicated to evaluate the immunotoxicity of NMs or NMPs. Their immunotoxicity assessment is performed based on existing guidelines for conventional substances or medicinal products. Due to the unique properties of NMPs when compared with conventional medicinal products, it is uncertain whether the currently prescribed set of tests provides sufficient information for an adequate evaluation of potential immunotoxicity of NMPs. The aim of this study was therefore, to compare the current regulatory immunotoxicity testing requirements with the accumulating knowledge on immunotoxic effects of NMPs in order to identify potential gaps in the safety assessment. This comparison showed that immunotoxic effects, such as complement activation-related pseudoallergy, myelosuppression, inflammasome activation, and hypersensitivity, are not readily detected by using current testing guidelines. Immunotoxicity of NMPs would be more accurately evaluated by an expanded testing strategy that is equipped to stratify applicable testing for the various types of NMPs.
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven; Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands.
authors.forename: Christina
authors.initials: C
authors.lastname: Giannakou
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven.
authors.forename: Margriet Vdz
authors.initials: MV
authors.lastname: Park
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven.
authors.forename: Wim H
authors.initials: WH
authors.lastname: de Jong
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven; Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven.
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Vandebriel
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Geertsma
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000009:adverse effects / Q000379:methods; D017408:Guidelines as Topic; D006801:Humans; D007107:Immune System / Q000187:drug effects*; D007108:Immune Tolerance / Q000187:drug effects; D050997:Nanomedicine / Q000331:legislation & jurisprudence / Q000379:methods*; D049329:Nanostructures / Q000009:adverse effects / Q000633:toxicity*; D013154:Spleen / Q000187:drug effects; D018675:Toxicity Tests / Q000379:methods / Q000592:standards*
keywords: immunotoxicity; nanomedicine; regulatory requirements; safety; testing methods