posted on 2016-11-09, 00:00authored byMargarita Valero, Franca Castiglione, Andrea Mele, Marcelo A. da Silva, Isabelle Grillo, Gustavo González-Gaitano, Cécile A. Dreiss
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 (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 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.