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.

Keywords:

• nanomedicine
• regulatory requirements
• safety
• testing methods
• immunotoxicity

Acknowledgments

This work was supported by the project E/132058 “Nanomedicine Benefits & Risks,” funded by the research program “Onderzoeksprogramma Geneesmiddelenketen,” a collaboration of Dutch governmental bodies involved in medicine evaluation, authorization, and monitoring. Dr Agnes Oomen and Dr Cornelle Noorlander are acknowledged for their critical review of the article.

Author contributions

CG drafted the manuscript. MVDZP and REG contributed to the concept and design of the article. MVDZP, REG, HvL, RJV, and WHdJ were involved in critically revising the article for important intellectual content. All authors read and approved the final article. All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.