Molecular Structure and Co-solvent Distribution in PPO–PEO and Pluronic Micelles

Abstract

The structure and properties of micelles formed by diblock and triblock copolymers containing polypropylene oxide (PPO) and polyethylene oxide (PEO) in aqueous solutions are affected by chain architecture and have important implications for applications, e.g., in the biomedical area. Using atomistic molecular dynamics simulations, we investigate and compare the molecular structure of diblock copolymer PPO 29 PEO 26 , Pluronic L64, and reverse Pluronic 17R4 micelles formed by block copolymers of the same length and composition but different distributions of PPO and PEO blocks in pure aqueous solution or with 5% (by volume) added co-solvents. We show that while the diblock copolymer forms a tightly packed mostly spherical micelle, Pluronic L64 micelles are non-spherical and contain 10−18% (by volume) water in the loosely packed PPO core partially interpenetrated by the PEO block. Reverse Pluronic 17R4 micelles are rather small but relatively well-packed. Addition of 5% (by volume) alcohol to aqueous micelle solutions results in a minimal change in the case of ethanol, while addition of butanol or hexanol leads to an increase of water content in the core and alcohol accumulation at the core−corona interface for the PPO 29 PEO 26 micelle. For L64 micelles, alcohol makes micelles more spherical but enhances defects, e.g., concentrates water in the core center or enhances PEO penetration, depending on the aggregation number. For 17R4 micelles, butanol and especially hexanol penetrate into the micelle core, swelling it. Even stronger core swelling occurs upon addition of 5% (by volume) isobutyric acid to aqueous solution of PPO 29 PEO 26 micelles. We show that the extent of co-solvent penetration and its distribution within the micelles strongly depend on co-solvent hydrophobicity, the capability of hydrogen bond formation with the polymer and micelle architecture, factors that can affect micelle properties and performance in practical applications.

Rationalizing the Design of Pluronics–Surfactant Mixed Micelles through Molecular Simulations and Experiments

“…Experimental results suggest that no micelles are found even under dilute conditions, but relatively large aggregates are formed instead, exhibiting sizes of around 200 nm and aggregation numbers of N agg > 300. − Our simulations are consistent with this behavior. Figure b shows the spherical micelles obtained in the 1% w/v DTAB aqueous solution (run 2) with average N agg = 60 and Ø = 3.4 nm, in good agreement with experimental results found in the literature. , Figure c confirms the formation of vesicles in the DDAB aqueous solution (run 3), as demonstrated by many experiments. − In fact, after 3000 ns of simulation, the DDAB formed two vesicles with average N agg ∼ 250 and a size of Ø ∼ 7 nm, in good agreement with the light scattering measurements reported by Marques et al Finally, Figure d shows the formation of poly-dispersed aggregates in the 12-2-12 aqueous solution (run 4), revealing an aggregate size distribution in the range of N agg ∼ 50/100, besides exhibiting some elongated micelles, as also observed in previous computational and experimental studies. ,− These validation tests give us the confidence that the CG model is realistically describing the self-assembly behavior of all the individual components of the system and hence can be used to infer mechanistic information and make predictions about the behavior of more complex mixtures.…”

“…This could be the reason behind the formation of smaller micelles, as also noticed in mixtures of aqueous solutions of Pluronic and ionic liquids. 19,24,61,62 According to these results, the observed behavior suggests that repulsive inter-micelle interactions that play the main role in the self-assembly, hindering the formation of larger L81 aggregates. The L81 system with 5 and 10 mM DTAB displayed micelle surface charges of 0.20 and 0.38 nm −2 , respectively, whereas 0.7 nm −2 was observed in the 30 mM mixture.…”

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

“…34 Each polymer chain was then initially relaxed by performing an energy minimization (maximum of 2000 cycles) followed by a short 600 ps-long simulation in Generalized Born implicit solvent 35 (12 Å distance cutoff) using sander from AmberTools22. 34 For each micelle, 35 polymers were then inserted in a loosely spherical orientation using packmol 18.169 36,37 (similar to other recent micelle modeling studies 38,39 ), leaving approximately 33 % of the core volume empty for solvation, assuming a placement of ~50 % of the CUR molecules in this area (the exact number of polymers constituting each micelle was not known a priori from experiments). After placement of the polymers with hydrophilic A blocks oriented towards the outside and hydrophobic B blocks towards the inside, the desired amount of CUR molecules for a [10/2] or [10/6] polymer/drug w/w ratio was inserted randomly within a sphere that spanned the volume of the hydrophobic core as well as parts of the hydrophilic corona.…”

“…While we cannot rule out the possibility of such phenomena occurring (potentially also contributing to an impairment of loading capacity of hydrophobic drugs), we would like to note that the micelle water content within the core after additional equilibration (~ 10 %) is within a similar range to what was reported recently for all-atom simulations of unloaded, triblock copolymer-based Pluronic L64 micelles (10 -18 %, also pre-assembled via packmol). 39 To investigate overall CUR mobility in the micelles, we analyzed the differences in distances of CUR molecules from the center of the micelle between the start and the end of the simulations. Values of up to 6 nm are recorded in single instances (Figure S6A), suggesting that the conducted protocol is able to capture possible movements of drug molecules across the amphiphilic structure, though a large fraction of the cargo remained rather rigid after initial compaction of the micelle and entanglement between the polymer chains (mostly values below 1 nm are recorded).…”

Study of the effect of active pharmaceutical ingredients of various classes of BCS on the parameters of thermosensitive systems based on poloxamers

“…One of the most important properties of pluronics is the ability of individual block copolymer molecules to assemble into micelles when the critical concentration of micelle formation (CMC) is reached in an aqueous solution. The PO core inside the micelles can include various lipophilic compounds due to its hydrophobicity ( Dahanayake 2022 ).…”