Unravel the tangle: atomistic insight into ultrahigh curcumin-loaded poly(2-oxazoline) and poly(2-oxazine)-based micelles

Amphiphilic ABA-triblock copolymers, comprised of poly(2-oxazoline) and poly(2-oxazine) blocks, can solubilize poorly water-soluble molecules; they form micelles with exceptionally high drug loading. In previous work, experimental studies have shown that even minor structural changes can have a significant impact on the maximum loading capacity for several different drugs. In an effort to shed light on the molecular interactions underlying the structure-property-relationships we performed all-atom molecular dynamics simulations on a selection of curcumin-loaded polymer micelles that have been experimentally characterized in detail. We investigated polymer-drug interactions in different micelle compositions, i.e. different drug loadings as well as variation of polymer structures of the inner hydrophobic core and the outer hydrophilic shell. Interestingly, the system with the highest experimental loading capacity also showed the highest amount of drug molecules encapsulated by the hydrophobic core in silico. Furthermore, in systems with a lower loading capacity the outer A blocks showed a greater extent of entanglement with the inner B blocks. Our results from hydrogen bond analyses corroborate the hypotheses of previous experimental studies: poly(2-butyl-2-oxazoline) B blocks, found experimentally to have a reduced loading capacity for curcumin in comparision to poly(2-propyl-2-oxazine), established fewer but longer-lasting hydrogen bonds. This possibly results from the additional methylene group in the backbone of poly(2-propyl-2-oxazine) to allow for different sidechain conformations around the hydrophobic cargo, compared to poly(2-butyl-2-oxazoline). This was further investigated by an unsupervised clustering of monomers within smaller model systems mimicking the different micelle compartments. In addition, an exchange of the hydrophilic poly(2-methyl-2-oxazoline) A blocks with the slightly more hydrophobic poly(2-ethyl-2-oxazoline) leads to a higher percentage of A blocks interacting with hydrophobic drugs and a reduced hydration of the corona; this suggests an impairment of micelle solubility or colloidal stability. This study demonstrates how all-atom molecular dynamics simulations can help in dissecting the effects of small structural changes in poly(2-oxazoline)-based micelles; we argue that it will pave the way for a more rational a priori design based approach to the development of drug delivery systems in the future.