Competitive and synergistic interactions between polymer micelles, drugs, and cyclodextrins: The importance of drug solubilization locus

Abstract

[EN]Polymeric micelles, in particular PEO-PPObased 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 (Nagg). 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 CDinduced 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.