The associative structures between F127 Pluronic micelles and four drugs, namely, lidocaine (LD), pentobarbital sodium salt (PB), sodium naproxen (NP), and sodium salicylate (SAL), were studied by small-angle neutron scattering (SANS). Different outcomes for the micellar aggregates are observed, which are dependent on the chemical nature of the drug and the presence of charge or otherwise: the micelles grow with LD, are hardly modified with PB, and decrease in size with both NP and SAL. The partition coefficient, determined by fluorescence spectroscopy, is directly correlated to the amount of charge, following NP approximately SAL < PB < LD. All drugs are found to lie at the interfacial layer, with a slightly deeper localization of LD and more superficial for PB. All drugs can form inclusion complexes with heptakis(2,6-di-O-methyl) beta-cyclodextrin (hep2,6 beta-CD). Hep2,6 beta-CD, as shown in previous studies (Joseph, J.; Dreiss, C. A.; Cosgrove, T. Langmuir, 2008, 24, 10005-10010; Dreiss, C. A.; Nwabunwanne, E.; Liu, R.; Brooks, N. J. Soft Matter, 2009, 5, 1888-1896), is also able to form a complex with F127, resulting in micellar breakup. In the ternary mixtures, a fine balance of forces is involved, which results in drastic micellar changes, as observed from the SANS patterns. Depending on the ratio of drug, polymer, and hep2,6 beta-CD and the nature of the interactions (which is directly linked to the drug chemical structure), the presence of drug either hinders micellar breakup by beta-CD (at high enough concentration of LD or PB) or leads to micellar growth (NP). These effects are mainly attributed to a preferential drug/beta-CD interaction (except for PB), which, at least in the conditions studied here, explains the higher beta-CD concentration needed for micellar breakup to occur.

Polymeric micelles, in particular PEO-PPO-based Pluronic, have emerged as promising drug carriers, while cyclodextrins (CD), cyclic oligosaccharides with an apolar cavity, have long been used for their capacity to form inclusion complexes with drugs. Dimethylated β-cyclodextrin (DIMEB) has the capacity to fully breakup F127 Pluronic micelles, while this effect is substantially hindered if drugs are loaded within the micellar aggregates. Four drugs were studied at physiological temperature: lidocaine (LD), pentobarbital sodium salt (PB), sodium naproxen (NP), and sodium salicylate (SAL); higher temperatures shift the equilibrium toward higher drug partitioning and lower drug/CD binding compared to 25 °C ( Valero, M.; Dreiss, C. A. Growth, Shrinking, and Breaking of Pluronic Micelles in the Presence of Drugs and/or β-Cyclodextrin, a Study by Small-Angle Neutron Scattering and Fluorescence Spectroscopy . Langmuir 2010 , 26 , 10561 - 10571 ). The impact of drugs on micellar structure was characterized by small-angle neutron scattering (SANS), while their solubilization locus was revealed by 2D NOESY NMR. UV and fluorescence spectroscopy, Dynamic and Static Light Scattering were employed to measure a range of micellar properties and drug:CD interactions: binding constant, drug partitioning within the micelles, critical micellar concentration of the loaded micelles, aggregation number (N). Critically, time-resolved SANS (TR-SANS) reveal that micellar breakup in the presence of drugs is substantially slower (100s of seconds) than for the free micelles (<100 ms) ( Valero, M.; Grillo, I.; Dreiss, C. A. Rupture of Pluronic Micelles by Di-Methylated β-Cyclodextrin Is Not Due to Polypseudorotaxane Formation . J. Phys. Chem. B 2012 , 116 , 1273 - 1281 ). These results combined together give new insights into the mechanisms of protection of the drugs against CD-induced micellar breakup. The outcomes are practical guidelines to improve the design of drug delivery systems as well as a better understanding of competitive assembly mechanisms leading to shape and function modulation.

Spectroscopic measurements (uv/vis absorbance and fluorescence) and time-resolved small-angle neutron scattering experiments (TR-SANS) were used to follow the breakdown of Pluronic micelles by heptakis(2,6-di-O-methyl)-β-cyclodextrin (DIMEB) over time in order to elucidate the mechanism of micellar rupture, generally attributed to polypseudotorotaxane (PR) formation between the cyclodextrin and the central hydrophobic PPO block. The spectroscopic measurements with two different probes (methyl orange and nile red) suggest that very rapid changes (on the order of seconds) take place when mixing DIMEB with F127 Pluronic and that no displacement of the probe from the cyclodextrin cavity occurs, which is in disagreement with PR formation. TR-SANS measurements demonstrate for the first time that the micelles are broken down in less than 100 ms, which categorically rules out PR formation as the mechanism of rupture. In addition, the same mechanism is demonstrated with other Pluronics, P85 and P123. In the latter case, after micellar rupture, lamellar structures are seen to form over a longer period of time, thus suggesting that after the instantaneous micellar disruption, further, longer-scale rearrangements are not excluded.

The triblock-copolymer poly(ethylene oxide)-poly(propyleneoxide)-poly(ethylene oxide) (PEO-PPO-PEO), referred to as Pluronic, is widely studied for its unique aggregation properties and its applications in drug delivery and targeting. In previous studies [Dreiss, C. A.; et al. Soft Matter 2009, 5, 1888-1896], we showed that the interaction of heptakis (2,6-di-O-methyl)-β cyclodextrin (DIMEB) with the triblock-copolymer Pluronic F127 in solutions above the CMC led to complete disruption of the polymeric micelles, while similar β cyclodextrins (βCD) derivatives, heptakis (2,3,6-tri-O-methyl)-βCD (TRIMEB), hydroxypropyl-βCD (HPBCD), and hydroxyethyl-βCD (HEBCD), did not induce micellar break-up. In this work, nuclear magnetic resonance spectroscopy experiments were used to elucidate the nature of the interactions leading to break-up and highlight differences between the four βCD derivatives studied, which could explain the very different outcome observed. Intermolecular nuclear Overhauser enhancements (NOEs) show that both DIMEB and TRIMEB interact selectively with the PPO methyl groups of F127 in a similar way. The interaction is mainly with the external methyl groups in the 6-position of the glucopyranose units of cyclodextrins. However, a weak but detectable interaction with the inner cyclodextrins protons is also observed. These interactions, both with the external surface and with the cavity of βCD, suggest the formation of a loose complex, rather than the widely invoked pseudorotaxane type of inclusion. In addition, these interactions seem to be necessary but not sufficient to induce micellar break-up. Diffusion measurements show decreased diffusivity of DIMEB in the presence of F127 to a larger extent than the other CD derivatives, thus confirming the unique behavior of DIMEB toward F127 polymer. From the diffusion coefficients, an average of 1 DIMEB molecule per 4.2 PO groups of F127 is determined for the highest concentration of DIMEB considered (11 wt % DIMEB dissolved in 5 wt % F127). Micellar break-up is complete at a concentration as low as 1 DIMEB molecule per 8.2 PO units.

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