Think beyond the core: The impact of the hydrophilic corona on the drug solubilization using polymer micelles.

Polymeric micelles are typically characterized as core-shell structures. The hydrophobic core is considered as depot for hydrophobic molecules and the corona forming block acts as stabilizing and solubilizing interface between core and aqueous milieu. Tremendous efforts have been made to tune the hydrophobic block to increase drug loading and stability of micelles, while the role of hydrophilic blocks is rarely investigated in this context with poly(ethylene glycol) being the gold standard of hydrophilic polymers. To better understand the role of the hydrophilic corona, a small library of structurally similar A-B-A type amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s is investigated by varying the hydrophilic block A utilizing poly(2-methyl-2-oxazoline) (pMeOx; A) or poly(2-ethyl-2-oxazoline) (pEtOx; A*). In terms of hydrophilicity, both polymers closely resemble poly(ethylene glycol). The more hydrophobic block B bear either a poly(2-oxazoline) and poly(2-oxazine) backbone with C3 (propyl) and C4 (butyl) side chains. Surprisingly, major differences in loading capacities from A-B-A > A*-B-A > A*-B-A* were observed for formulation with the two poorly water-soluble compounds curcumin and paclitaxel, highlighting the importance of the hydrophilic corona of polymer micelles used for drug formulation. The formulations are also characterized by various NMR spectroscopy methods, dynamic light scattering, cryogenic transmission electron microscopy and (micro) differential scanning calorimetry. Our findings suggest that the interaction between the hydrophilic block and the guest molecule should be considered an important but previously largely ignored factor for the rational design of polymeric micelles.