A quality-by-design engineering strategy for hybrid lipid–random copolymer nanoparticles optimization: methotrexate loading and effectiveness studies

The quality by design approach supports the rational development of pharmaceutical formulations. This strategy is particularly valuable in the case of hybrid nanoparticles, where complex molecular interactions pose challenges to predictability, control, and therapeutic performance. In this study, based on preliminary findings, hybrid nanoparticles were developed and optimized using 1,2-dioctadecanoyl-sn-glycero-3-phosphocholine and a statistical (random) copolymer, composed of oligo (ethylene glycol) methyl ether methacrylate and lauryl methacrylate incorporating a hydrophobic model drug-methotrexate. The effects of random copolymer concentration and drug content were investigated as critical formulation variables influencing key quality attributes. Additionally, nanoparticles stability under storage and biorelevant conditions was assessed. The most promising formulations were further evaluated for their in vitro anticancer efficacy using glioblastoma primary cells demonstrating encouraging results. It is anticipated that this research will shed light on the rational design of hybrid drug delivery systems combining well-established phospholipids and innovative random copolymers.