Abstract

Therapeutic vaccines containing aluminum adjuvants have been widely used in the treatment of tumors due to their powerful immune-enhancing effects. However, the neurotoxicity of aluminum adjuvants with different physicochemical properties have not been completely elucidated. In this study, a library of engineered aluminum oxyhydroxide (EAOs) and aluminum hydroxyphosphate (EAHPs) nanoparticles was synthesized to determine their neurotoxicity in vitro. It was demonstrated that the surface charge of EAHPs and size of EAOs did not affect the cytotoxicity in N9, bEnd.3 and HT22 cells, however, soluble aluminum ions trigger the cytotoxicity in three different cell lines. Moreover, soluble aluminum ions induce apoptosis in N9 cells, and further mechanistic studies demonstrated that this apoptosis was mediated by mitochondrial reactive oxygen species (mtROS) generation and mitochondrial membrane potential (MMP) loss. This study identifies the safety profile of aluminum-containing salts as adjuvants in the nervous system for use in a therapeutic cancer vaccine, and provides novel design strategies for their safer applications.

Significance Statement Although therapeutic cancer vaccines containing aluminum-based nanoparticle adjuvants have been widely used in the treatment of tumors due to their powerful immune-enhancing effects, the neurotoxicity of such nanoparticle adjuvants is still unclear. Thus, this work fills this gap by engineering aluminum-based nanoparticle adjuvants with different surface charges and sizes to elucidate their neurotoxicity in the context of cancer vaccines.