Plasma Protein Association with High Drug-Loaded Polymer Micelles: An Atomistic Molecular Dynamics Study

Abstract

Abstract Polymeric micelles are widely studied drug delivery platforms whose interactions with plasma proteins influence in vivo performance. However, the combined effects of non-pEG hydrophilic coronas and high drug loading on protein adsorption remain poorly understood. We performed all-atom molecular dynamics (MD) simulations to investigate the association of three plasma proteins: apolipoprotein E (ApoE), human serum albumin (HSA), and immunoglobulin G (IgG), with curcumin-loaded ABA triblock copolymer micelles. To isolate corona effects, micelles shared an hydrophobic core chemistry and differed only in the hydrophilic A-block: poly(ethylene glycol) (pEG), poly(N,N-dimethylacrylamide) (pDMAA), or poly(sarcosine) (pSAR). Two drug loadings (20% and 60% drug/polymer mass ratio) were examined. Binding was assessed via contact areas, hydrogen bonds, and interaction energies. pEG micelles showed the strongest protein association. pDMAA and pSAR exhibited weaker, surface-limited interactions. These simulations provide molecular-level insight into protein adsorption on drug-loaded polymeric micelles and compare alternative hydrophilic A-blocks to pEG.