Association of Octyl-Modified Poly(acrylic acid) onto Unilamellar Vesicles of Lipids and Kinetics of Vesicle Disruption

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Abstract
Water-soluble polymers containing a few hydrophobic anchors are known to bind onto lipid vesicles and are used as stabilizers of liposome-based formulas. In contrast, polymers with high hydrophobicity destabilize the lipid bilayers. With macromolecules of intermediate hydrophobic/hydrophilic balance, a gradual sweep of the stabilization-destabilization capacity can be achieved and is considered as promising triggered systems for drug release, although the mechanism of permeabilization and membrane breakage using polymers is essentially conjectural to date. As a model system, we used short octyl-modified poly(acrylic acid)s (MW 8000 g/mol) sensitive to pH, temperature, and ionic strength in conjunction with small unilamellar vesicles mainly comprised of DPPC or egg-PC. Kinetics of vesicle fragmentation was followed using static and dynamic light scattering. Polymer adsorption was studied by nonradiative energy transfer between pyrene-labeled lipids and a naphthalene-modified polymer. The permeability of the vesicles was characterized by calcein leakage experiments. The key findings were (i) the lack of coupling between the density of bound polymer and the rate of disruption and (ii) the qualitative difference depending on whether the polymer contains or not isopropyl side groups. Point i relates to the increase of the rate of polymer adsorption with increasing bulk polymer concentration, while the breakage is essentially unaffected. Point ii relates to the stabilization of large membrane fragments (Stokes radius ca. 40 nm) in the presence of a polymer with no isopropyl side groups, while micelle-like assemblies (Stokes radius 8 nm) containing the lipids are obtained with an isopropyl-containing polymer of similar hydrophobicity. Both polymers display similar efficiency at disrupting small vesicles. The mechanism of polymer-induced disruption appears to differ markedly from the disruption steps now recognized for conventional (molecular) surfactant and is discussed on the basis of data obtained with different membrane fluidity, polymer structure, concentration, and hydrophilicity.