Differential toxicological response to positively and negatively charged nanoparticles in the rat brain

Abstract

We investigated the potential for systemic and local toxicity after administration of empty nanosized anionic and cationic PEGylated-micelles and non-PEGylated liposomes, without a ligand attached, intended for use in drug-delivery systems. The particles were administered to 5–6-week-old male rats by three intravenous (IV) administrations over a period of one week at a dose of 100 mg/kg bodyweight or after a single intracerebroventricular (ICV) injection at a dose of 50 µg. The particles were stable and well characterised with respect to size and zeta potential. ICV administration of cationic particles was associated with histological changes near the injection site (hippocampus). Here, we detected focal infiltration with phagocytic cells, loss of neurons and apoptotic cell death, which were not observed after administration of the vehicle. No significant difference was found after IV or ICV administration of the anionic micelles with regard to haematology, clinical chemistry parameters or at the pathological examinations, as compared to control animals. Our study suggests that ICV delivery of cationic particles to the brain tissue is associated with toxicity at the injection site.

Keywords::

• micelles
• liposomes
• hippocampus
• apoptosis

Acknowledgements

The excellent assistance of the Animal Facility, Section of Neurobiology and Section of Pathology & Clinical Pathology at H. Lundbeck A/S, Torben Gjetting and Jonas Rosager Henriksen from DTU Nanotech are gratefully acknowledged. This work was supported by H. Lundbeck A/S, DHI and University of Copenhagen.

Declarations of interest

The authors declare no conflicts of interest that could influence the present work.