Stimuli-Responsive Supramolecular Assemblies of\nLinear-Dendritic Copolymers

Abstract

With the goal of developing a pH-responsive micelle system, linear-dendritic block copolymers\ncomprising poly(ethylene oxide) and either a polylysine or polyester dendron were prepared and hydrophobic\ngroups were attached to the dendrimer periphery by highly acid-sensitive cyclic acetals. These copolymers\nwere designed to form stable micelles in aqueous solution at neutral pH but to disintegrate into unimers at\nmildly acidic pH following loss of the hydrophobic groups upon acetal hydrolysis. Micelle formation was\ndemonstrated by encapsulation of the fluorescent probe Nile Red, and the micelle sizes were determined\nby dynamic light scattering. The structure of the dendrimer block, its generation, and the synthetic method\nfor linking the acetal groups to its periphery all had an influence on the critical micelle concentration and\nthe micelle size. The rate of hydrolysis of the acetals at the micelle core was measured for each system\nat pH 7.4 and pH 5, and it was found that all systems were stable at neutral pH but underwent significant\nhydrolysis at pH 5 over several hours. The rate of hydrolysis at pH 5 was dependent on the structure of the\ncopolymer, most notably the hydrophobicity of the core-forming block. To demonstrate the potential of\nthese systems for controlled release, the release of Nile Red as a “model payload” was examined. At pH\n7.4, the fluorescence of micelle-encapsulated Nile Red was relatively constant, indicating it was retained\nin the micelle, while at pH 5, the fluorescence decreased, consistent with its release into the aqueous\nenvironment. The rate of release was strongly correlated with the rate of acetal hydrolysis and was therefore\ncontrolled by the chemical structure of the copolymer. The mechanism of Nile Red release was investigated\nby monitoring the change in size of the micelles over time at acidic pH. Dynamic light scattering measurement\nshowed a size decrease over time, eventually reaching the size of a unimer, thus providing evidence for\nthe proposed micelle disintegration.