Synthesis and Characterization of Lipid-Polyzwitterion Diblock Copolymers for Optimizing Micelle Formation to Enhance Anticancer Drug Delivery in 2D and 3D Cell Cultures

Amphiphilic polymers with distinct polarity differences, known as sharp polarity contrast polymers (SPCPs), have gained much attention for their ability to form micelles with low critical micelle concentrations (CMCs) and potential in anticancer drug delivery. This study addresses the limited research on structure-property relationships of SPCPs by developing various SPCPs and exploring their physicochemical properties and biological applications. Specifically, the superhydrophobic aliphatic palmitoyl (Pal) was coupled to the superhydrophilic zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC) to form Pal-pMPC diblock copolymers. Adjusting the lengths of hydrophilic chains allowed the creation of structures with varying hydrophilic-hydrophobic ratios for micelle formation. Comprehensive evaluations were carried out, including particle size, CMC, chain exchange rates, cellular uptake efficiency, and anticancer effectiveness. Our findings indicate that micelles with optimal hydrophilic-hydrophobic ratios significantly enhanced cellular uptake and cytotoxicity in both two-dimensional (2D) and three-dimensional (3D) tumor models, offering valuable insights for designing SPCPs for anticancer drug delivery.