27 | Polymeric nanoparticles as a favorable delivery system to enhance the anti-inflammatory action of n-palmitoylethanolamide, an endocannabinoid-like molecule

E. Maretti¹, C. Rustichelli¹, B. Recchia¹, G. Battaglia, E. de Nicola¹, C. Fuoco², A. Votta³, C. Gargioli², E. Ferraro³, E. Leo¹, Susanna Molinari¹ | ¹Dept. of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; ²Dept. Of Biology, Tor Vergata Rome University, Rome, Italy; ³Dept. of Biology, University of Pisa, Pisa, Italy.

Abstract

Chronic low-grade inflammation is linked to age-related muscle loss (sarcopenia), highlighting the potential of daily anti-inflammatory strategies. A growing body of evidence suggests that N-palmitoylethanolamide (PEA), a natural endocannabinoid-like compound with anti-inflammatory properties, could represent a safe therapeutic option to counteract sarcopenia. However, the low solubility of PEA significantly limits its systemic bioavailability. To overcome this limitation, our work was aimed to develop a nanoparticle-based delivery system intended to enhance its systemic availability. We compared two nanoparticle formulations: solid lipid nanoparticles (SLNs) and poly-(lactic-co-glycolic acid) (PLGA) polymeric nanoparticles. These delivery systems were evaluated in terms of cellular uptake, cytotoxicity, and impact on myogenic differentiation. Our results indicate that PLGA nanoparticles exhibit superior cellular internalization compared to SLNs, display lower cytotoxicity, and do not substantially interfere with the myogenic differentiation process in cell culture. Furthermore, PEA encapsulated within PLGA nanoparticles effectively activated its canonical target, peroxisome proliferator-activated receptor alpha (PPAR-α), and protected muscle cells from lipopolysaccharide (LPS)-induced cytotoxicity in vitro. These findings represent a critical step toward the preclinical evaluation of PEA as a potential therapeutic agent for counteracting sarcopenia, using murine models of age-related muscle wasting.

Funding: European Union Next Generation EU” n. P2022LSW98 (PRIN-PNRR 2022 from Italian "Ministero dell'Università e della Ricerca".