Hyaluronic acid and PEA-based Rutin-loaded nanoparticles as new cardioprotective tool against anthracycline-induced cardiotoxicity

A dual cardioprotective strategy was developed using lipid–polymer hybrid nanoparticles co-encapsulating rutin and palmitoylethanolamide (PEA), with or without hyaluronic acid (HA). This approach may enhance cardioprotection by improving the delivery of rutin, an agent with strong antioxidant and anti-inflammatory effects whose clinical application is constrained by poor solubility and low bioavailability. PEA, known for modulating the endocannabinoid system and inhibiting NLRP3 inflammasome activation, offers a complementary mechanism to reduce inflammation and oxidative stress. The LPNs were prepared via nanoprecipitation technique. The LPNs lacking HA exhibited an average size ∼171 nm, while HA-based LPNs displayed larger sizes ∼247 nm, accompanied by negative zeta potentials (from −20.13 to −29.95 mV) and surface hydrophilicity attributable to HA. Despite these variations, drug content and encapsulation efficiencies remained comparable between formulations. In vitro release and permeation (PermeaPad®) experiments demonstrated formulation-dependent differences in rutin delivery. Notably, HA and PEA-based LPNs significantly protected cardiomyocytes from DOXO toxicity, evidenced by decreased apoptosis, caspase activation, and LDH release, while upregulating protective proteins (Nrf2, SIRT1) and downregulating inflammatory mediators (NLRP3, MyD88, IL-1β, IL-6). These findings support the potential of HA and PEA-based LPNs as a targeted strategy to preserve anticancer efficacy while reducing DOXO-associated cardiotoxicity.