Margarita Valero

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

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.

Complexation of the Non-steroidal Anti-inflammatory Drug Nabumetone with Modified and Unmodified Cyclodextrins

The inclusion of the anti-inflammatory drug, Nabumetone, in α-, β- and hydroxypropyl-β-cyclodextrin (CDs) is studied using UV-VIS absorption and steady-state fluorescence emission. Binding constants and thermodynamic parameters of complex formation are determined by spectrofluorimetry. The inclusion phenomena of Nabumetone with the three cyclodextrins is compared with that of the well known similar anti-inflammatory drug Naproxen. In the case of Nabumetone pronounced differences are observed in the complexation process with each cyclodextrin whereas the respective Naproxen complexes are nearly identical. 1H-NMR experiments show that the inclusion process in Nabumetone can occur either through the substituents in the -2 (butanone) or -6 (methoxy) positions in the naphthalene ring.

Rupture of Pluronic Micelles by Di-Methylated β-Cyclodextrin is not due to polypseudorotaxane formation

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.

New Insight into the Structure of CTAB Micelles in the Presence of Cyclodextrins, Using Non-Steroidic Anti-Inflammatory Agents – Nabumetone, Naproxen – as Fluorescent Probes

The structure of CTAB micelles in the presence of α-, β- and hydroxypropyl-β-cyclodextrin has been investigated by means of conductivity and spectroscopic measurements – absorption and steady state fluorescence – using Naproxen, Nabumetone and pyrene as probes. In the presence of the three cyclodextrins, two types of micelles have been detected. The first type is a pure surfactant micelle, while the other is formed by surfactant monomers complexed with cyclodextrins. The presence of cyclodextrins produces a decrease in the cmc of the pure micelle. The second type of micelle is formed at higher cmc* values, 25.6 × 10-4 M, 27.8 × 10-4 M and 38.9 × 10-4 M for α-, β-, and HPβCD respectively. A significant increase in the ionisation degree has been detected. The aggregation number is strongly increased, being 92 ± 3 , 97 ± 3 and 80 ± 2 for for α-, β-, and HPβCD respectively. The polarity of this micelle decreases, indicating that it becomes tighter and its hydrophobic region becomes less polar.

Hydrogen bonding in a non-steroidal anti-inflammatory drug—Naproxen

Photophysical properties of a non-steroidal anti-inflammatory drug, Naproxen (6-methoxy alpha-methyl-2-naphthalene acetic acid sodium salt), were investigated in solvents of different polarity, hydrogen donor ability and also in cyclodextrins. The results indicate that in all cases the emitting state is the 1L(b) singlet. In alcoholic solvents, an intermolecular hydrogen bond is responsible for the observed photophysical behaviour of the probe whereas in non-protic solvents (polar and weakly polar) an intramolecular hydrogen bond type is postulated to rationalize the data found. In water, the non-radiative rate constant has a value similar to those found in aqueous solutions of alpha- and beta-cyclodextrins where the probe form complexes. The behaviour in water is explained by a water-structure enforced hydrophobic effect. The spectroscopic results are interpreted on the basis of a multiple-parameter model that considers specific solute-solvent interactions. These were also observed in the ground state and detected by Fourier transform infrared spectroscopy. Molecular mechanics (MM) and molecular orbital (AM1) calculations also support the existence of two conformations (rotamers) in Naproxen with non-equivalent intramolecular hydrogen bond-like formation.

Selective Interaction of 2,6-Di-O-methyl-β-cyclodextrin and Pluronic F127 Micelles Leading to Micellar Rupture: A Nuclear Magnetic Resonance Study

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.

Remarkable viscoelasticity in mixtures of cyclodextrins and nonionic surfactants.

We report the effect of native cyclodextrins (α, β, and γ) and selected derivatives in modulating the self-assembly of the nonionic surfactant polyoxyethylene cholesteryl ether (ChEO10) and its mixtures with triethylene glycol monododecyl ether (C12EO3), which form wormlike micelles. Cyclodextrins (CDs) generally induce micellar breakup through a host-guest interaction with surfactants; instead, we show that a constructive effect, leading to gel formation, is obtained with specific CDs and that the widely invoked host-guest interaction may not be the only key to the association. When added to wormlike micelles of ChEO10 and C12EO3, native β-CD, 2-hydroxyethyl-β-CD (HEBCD), and a sulfated sodium salt of β-CD (SULFBCD) induce a substantial increase of the viscoelasticity, while methylated CDs rupture the micelles, leading to a loss of the viscosity, and the other CDs studied (native α- and γ- and hydroxypropylated CDs) show a weak interaction. Most remarkably, the addition of HEBCD or SULFBCD to pure ChEO10 solutions (which are low-viscosity, Newtonian fluids of small, ellipsoidal micelles) induces the formation of transparent gels. The combination of small-angle neutron scattering, dynamic light scattering, and cryo-TEM reveals that both CDs drive the elongation of ChEO10 aggregates into an entangled network of wormlike micelles. (1)H NMR and fluorescence spectroscopy demonstrate the formation of inclusion complexes between ChEO10 and methylated CDs, consistent with the demicellization observed. Instead, HEBCD forms a weak complex with ChEO10, while no complex is detected with SULFBCD. This shows that inclusion complex formation is not the determinant event leading to micellar growth. HEBCD:ChEO10 complex, which coexists with the aggregated surfactant, could act as a cosurfactant with a different headgroup area. For SULFBCD, intermolecular interactions via the external surface of the CD may be more relevant.

Modulating Pluronics micellar rupture with cyclodextrins and drugs: Effect of pH and temperature

Micelles of the triblock copolymer Pluronic F127 can encapsulate drugs with various chemical structures and their architecture has been studied by small-angle neutron scattering (SANS). Interaction with a derivative of β-cyclodextrin, namely, heptakis(2,6-di-O- methyl)-β-cyclodextrin (DIMEB), induces a complete break-up of the micelles, providing a mechanism for drug release. In the presence of drugs partitioned within the micelles, competitive interactions between polymer, drug and cyclodextrin lead to a modulation of the micellar rupture, depending on the nature of the drug and the exact composition of the ternary system. These interactions can be further adjusted by temperature and pH. While the most widely accepted mechanism for the interaction between Pluronics and cyclodextrins is through polypseudorotaxane (PR) formation, involving the threading of β-CD on the polymer backbone, time-resolved SANS experiments show that de-micellisation takes place in less than 100 ms, thus unambiguously ruling out an inclusion complex between the cyclodextrin and the polymer chains.