C60 fullerene-pentoxifylline dyad nanoparticles enhance autophagy to avoid cytotoxic effects caused by the β-amyloid peptide

Many studies have focused on the neuroprotective effects of C₆₀ fullerene-derived nanomaterials. The peculiar structure of C₆₀ fullerene, which is capable of "adding" multiple radicals per molecule, serves as a "radical sponge," and it can be an effective antioxidant by reducing cytotoxic effects caused by intracellular oxidative stress. In this study, PEG-C₆₀-3, a C₆₀ fullerene derivative incorporating poly(ethylene glycol), and its pentoxifylline-bearing hybrid (PTX-C₆₀-2) were investigated against β-amyloid (Aβ)_25-35-induced toxicity toward Neuro-2A cells. PEG-C₆₀-3 and PTX-C₆₀-2 significantly reduced Aβ_25-35-induced cytotoxicity, with comparable activities in decreasing reactive oxygen species and maintaining the mitochondrial membrane potential. Aβ_25-35 treatment elicited adenosine monophosphate-activated protein kinase-associated autophagy. Cytoprotection by PEG-C₆₀-3 and PTX-C₆₀-2 was partially diminished by an autophagy inhibitor, indicating that the elicited autophagy and antioxidative activities protect cells from Aβ damage. PTX-C₆₀-2 was more effective than PEG-C₆₀-3 at enduring the induced autophagy. Our results offer new insights into therapeutic drug design using C₆₀ fullerene-PTX dyad nanoparticles against Aβ-associated diseases. From the Clinical Editor: The neuroprotective effects of C60 fullerene-derived nanomaterials are known and thought to be related to their capacity of "absorbing" multiple free radicals. In this study, another interesting property is presented: they may enhance autophagy of beta-amyloid peptide, which could minimize the damaging effects of this peptide.