Computational Studies of Highly PEG-ylated Sterically Stabilized Micelles: Self-Assembly and Drug Solubilization

Abstract

Self-assembled micelles of block copolymers, containing controllable physical, chemical, and biological properties, are strong candidates for new drug delivery platforms. Here, we summarize our studies of structure, dynamics and drug solubilization in micelles self-assembled from highly PEG-ylated block copolymers. First, we examined sterically stabilized micelles (SSM) formed by self-assembled phospholipids (DSPE–PEG₂₀₀₀) in pure water and isotonic HEPES-buffered saline solution. The observed micelle sizes of 2–15 nm were shown to largely depend on the solvent and the lipid concentration used. Computational modeling showed that micelle sizes are determined by the interactions of their charged –${\text{PO}}_{4}^{ - }$ groups with the present counterions. Second, we studied solubilization of prototypical therapeutic molecules, a drug bexarotene and a vasoactive intestinal peptide (VIP), in SSM, as observed in experiments. Free energy calculations revealed that molecules of bexarotene can reside at the micellar ionic interface of the PEG corona or in the alkane core center, where several bexarotene molecules can cluster and self-stabilize. Charged molecules, such as VIP, can be stabilized at the SSM ionic interface by Coulombic coupling between their positively charged residues and the –${\text{PO}}^{ - }_{4}$ groups of the lipids. The performed studies illustrate that atomistic simulations can reveal drug solubilization character in nanocarriers and be used in efficient optimization of novel nanomedicines.