Fine-Tuning Hydrophilic-Hydrophobic Balance in Stimuli-Responsive PEGPNIPAM Micelles for Controlled Drug Delivery

Abstract: Temperature-responsive polymeric micelles have great potential in drug delivery, enhancing therapeutic efficacy while minimizing systemic toxicity. This study investigates the self-assembly of poly(ethylene glycol)-poly(N-isopropylacrylamide) (PEG-PNIPAM) block copolymers as nanocarriers for Doxorubicin (DOX) using coarse-grained molecular dynamics (CG-MD) simulations. We systematically examined the effects of polymer chain length and hydrophilic/hydrophobic balance on micelle formation, stability, and drug encapsulation efficiency. PEG-PNIPAM copolymers self-assembled above the lower critical solution temperature (LCST), forming stable micelles with varying morphologies. Our findings revealed that PEG enhances micelle hydration and stability, while PNIPAM improves drug retention but may hinder controlled release. Increasing PNIPAM or PEG length significantly increased micelle size, with DOX preferentially localizing in the PEG-rich outer shell, enhancing solubility and preventing aggregation. The DOX diffusion coefficient ranged from $10^{-8}$ to $10^{-9}$ cm$^{2}$s$^{-1}$, reflecting drug release dynamics. Structural and thermodynamic analyses confirmed spontaneous DOX encapsulation, with PEG-PNIPAM micelles providing a favorable environment for drug loading. Mean square displacement (MSD), radial distribution function (RDF), and solvent-accessible surface area (SASA) analyses highlighted the role of PEG in controlled drug release and PNIPAM in drug binding. These molecular-level insights underscore the potential of fine-tuning PEG-PNIPAM compositions for enhanced drug delivery, paving the way for precision cancer therapies.