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 cm²·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 PEG’s role in controlled
drug release and PNIPAM’s role 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.