Optimization of micellar molecular encapsulation systems, such as drug delivery vehicles, can be achieved through fundamental understanding of block copolymer micelle structure and dynamics. Herein, we present a study of PEO−PCL block copolymer spherical micelles that self-assemble at 1% wt/vol in D 2 O−THF-d 8 mixtures. Varying solvent composition as a function of cosolvent THF-d 8 at constant polymer concentration (1% wt/vol) allows sensitive study of how small molecule additives influence micelle structure and dynamics. We conduct nuclear magnetic resonance spectroscopy and diffusometry on two block copolymer (2k series: PEO 2k −PCL 3k ; 5k series: PEO 5k −PCL 8k ) spherical micelles that show drastically different behaviors. Unimers and micelles coexist in solution from 10−60 vol % THF-d 8 for the 2k series but only coexist at 60 vol % THF-d 8 for the 5k series. At ≥ 60 vol % THF-d 8 micelles disassemble into free unimers for both series. We observe relatively flat micelle diffusion coefficients (∼1 × 10 −10 m 2 /s) with increasing THF-d 8 below 60 vol % for both 2k and 5k series, with only small changes in micelle hydrodynamic radius (≈14 nm) over this range. We compare these results to a detailed SANS and microscopy study described in a companion paper. These fundamental molecular dynamics, unimer population, and diffusion results, as a function of polymer composition and solution environment, provide critical fodder for controlled design of block copolymer self-assembly.

Block copolymer micelles enable the formation of widely tunable self-assembled structures in liquid phases, with applications ranging from drug delivery to personal care products to nanoreactors. In order to understand fundamental aspects of micelle assembly and dynamics, the structural properties and solvent uptake of biocompatible poly­(ethylene oxide-b-ε-caprolactone) (PEO–PCL) diblock copolymers in deuterated water (D2O)/tetrahydrofuran (THF-d 8) mixtures were investigated with a combination of small-angle neutron scattering, nuclear magnetic resonance, and transmission electron microscopy. PEO–PCL block copolymers, of varying molecular weight yet constant block ratio, formed spherical micelles through a wide range of solvent compositions. Varying the solvent composition from 10 to 60 vol % THF-d 8 in D2O/THF-d 8 mixtures was a convenient means of varying the core–corona interfacial tension in the micelle system. An increase in THF-d 8 content in the bulk solvent increased the solvent uptake within the micelle core, which was comparable for the two series, irrespective of the polymer molecular weight. Whereas the smaller molecular weight micelle series exhibited a decrease in aggregation number with increasing THF-d 8 content in the bulk solvent, as anticipated due to changes in the core–corona interfacial tension, the aggregation number of the larger molecular weight series was surprisingly invariant with bulk solvent composition. Differences in the dependencies of the micelle size parameters (core radius and overall micelle radius) on the solvent composition originated from the differing trends in aggregation number for the two micelle series. Incorporation of the known unimer content determined from NMR (described in the companion paper), and directly accounting for impacts of solvent swelling of the micelle core on the neutron scattering length density of the core, allowed refinement of and increased confidence in extracted micelle parameters. In summary, the two micelle series showed similar solvent uptake that was independent of the polymer molecular weight yet significantly different dependencies of their aggregation number and size parameters on the solvent composition.

Understanding molecular partitioning in solution is crucial for the design of micelle-based formulations. We investigate PEO−PPO−PEO triblock copolymer micelles and their solubilization of three hydrophobic drugs: hydrochlorothiazide, indomethacin, and paclitaxel. Using NMR diffusometry, we quantify the diffusion coefficients of different species in solution, including polymers, drug cargo molecules, and solvent molecules. Polymer concentration and drug chemistry changes cause effects such as increasing partition percentages of hydrochlorothiazide and indomethacin within micelles as the F127 concentration increases from 1 to 5% w/v. This facile methodology enables quantification of drug distribution in micelles without perturbation of the solution, thus opening opportunities to understand broader processes of cargo partitioning.

Block copolymer micelles can carry molecular cargo in a nanoscopic package that is tunable via polymer structure in combination with cargo and/or solution properties. We use NMR spectroscopy and diffusometry to investigate spherical micelles that self-assemble from diblock poly­(ethylene oxide)-b-(ε-caprolactone) (PEO–PCL) at 1% w/v in D2O–THF-d 8 mixed solvents. For two series of micelles with block masses of 2 and 3 kg/mol (PEO and PCL, respectively) and 5 and 8 kg/mol, we quantify diffusion coefficients and relative populations of micelles and free unimers over a range of temperatures (21–50 °C) and solvent compositions (10–100 vol % THF-d 8). Micelles and free unimers coexist over surprisingly large areas of these micelle–unimer phase diagrams and with a large variation of relative populations. This study provides a new avenue for understanding how inter- and intramolecular interactions fundamentally affect unimer exchange, cargo release, the thermodynamics of chain partitioning, and the tuning of micelle structure and dynamics.

Fluorescence spectroscopy was employed to characterize the kinetics of guest exchange in diblock copolymer micelles composed of poly(ethylene oxide-b-ε-caprolactone) (PEO-PCL) diblock copolymers in water/tetrahydrofuran (THF) mixtures which encapsulated fluorophores. The solvent composition (THF content) of the micelle solution was varied as a means of modulating the strength of interactions between the fluorophore and solvent as well as between the micelle core and solvent. A donor-acceptor fluorophore pair was employed consisting of 3,3′-dioctadecyloxacarbocyanine perchlorate (DiO, the donor) and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI, the acceptor). Through the process of Förster resonance energy transfer (FRET), energy was transferred from the donor to acceptor when the fluorophores were in close proximity. A micelle solution containing DiO was mixed with a micelle solution containing DiI at t=0, and the emission spectra of the mixed solution were monitored over time (at an excitation wavelength optimized for the donor). In micelle solutions containing 5 and 10 vol% THF in the bulk solvent, an increase in the acceptor peak intensity maximum occurred over time in the post-mixed solution, accompanied by a decrease in the donor peak intensity maximum, indicating the presence of energy transfer from the donor to the acceptor. At long times, the FRET ratios (acceptor peak intensity divided by the sum of the acceptor and donor peak intensities) were indistinguishable from that determined from pre-mixed micelle solutions of the same THF content (in pre-mixed solutions, DiO and DiI were encapsulated within the same micelle cores). In the micelle solution containing 20 vol% THF, the fluorophore exchange process occurred too quickly to be observed (the FRET ratios measured from the solutions mixed at t=0 were commensurate to that measured from the pre-mixed solution). A time constant describing the guest exchange process was extracted from the time-dependence of the FRET ratio through fit of an exponential decay. An increase in the THF content in the micelle solution resulted in a decrease in the time constant, and the time constant varied over five orders of magnitude as the THF content was varied from 5–20 vol%.