Anthracyclines are crucial in treating neoplastic diseases but can cause cardiomyopathy and brain damage. Rutin, a bioflavonoid, improves brain damage induced by doxorubicin but has limitations. Hybrid nanoparticles (H-NPs) were developed to enhance rutin's effectiveness and protect brain cells. The H-NPs were formulated using phosphatidylcholine, palmitoylethanolamide (PEA), cholesterol, poloxamers (LP and LPR) and hyaluronic acid (HA) (LPHA, LicpHA and LPHAR and LicpHAR) via the nanoprecipitation technique. PEA reduces inflammation, while HA aids in mucoadhesion and absorption enhancement. The mean size, stability size, zeta potential (ZP), morphology, thermal properties, encapsulation efficiency, drug content, and in vitro drug release and permeation were studied. The cellular uptake of LPP and LPH was investigated in cell lines. Cytotoxicity and anti-inflammatory activity were evaluated in cells. HA and PEA influenced the size of H-NPs. The mean size increased from 118 nm for LPP to 179 nm for LicpHA and further to 247 nm for LPHR. The size also increased after rutin loading, ranging from 171 nm for LPPR to 255 nm for LPHR. HA's addition influenced the ZP, shifting from -17.3 mV for LPP to -29.9 mV for LPH and finally to -35 mV for LicpHA. TEM images showed spherical shapes with irregular surfaces for all N-HPs. The total amount of rutin in the dispersion was approximately 97%, with an encapsulation efficiency of 68%. Thermal analysis indicated the presence of HA on the LPH surface. In vitro, studies demonstrated significantly improved drug permeation with both systems, higher than rutin-free solutions. LPP and LPH showed rapid cellular uptake within three hours. LPPR and LPHR significantly reduced cell death and induced inflammation. All H-NPs resulted in a greater anti-inflammatory effect compared to H-NPs without PEA.

In summary, LPH and LicpHA show potential for rutin encapsulation for different delivery routes. Additionally, rutin-loaded PEA H-NPs exhibit enhanced vasculoprotective effects.