Nanoscale Investigation of Elasticity Changes and Augmented Rigidity of Block Copolymer Micelles Induced by Reversible Core-Cross-Linking

Drug-delivery systems have attracted considerable attention due to their potential to increase the bioavailability of certain drugs and mitigate side effects by enabling targeted drug release. Reversibly core-cross-linked block copolymer micelles providing a hydrophilic and potentially nonimmunogenic shell and a hydrophobic core suitable for the uptake of hydrophobic drugs are frequently considered because of their high stability against environmental changes and dilution. Ultimately, triggering core-de-cross-linking enables the implementation of strategies for targeted drug release, which requests insights into the impact of varying nanomechanical properties on the stability of individual micelles. Here, atomic force microscopy nanoindentation in aqueous media is applied to intact α-allyl-PEG₈₀-<i>b</i>-P(<i>t</i>BGE₅₂-<i>co</i>-FGE₁₂) micelles to quantify changes in their nanomechanical properties induced by dithiobismaleimidoethane (DTME)-mediated Diels-Alder cross-linking of furfuryl moieties and sequential de-cross-linking by reduction of its disulfide bond by tris(2-carboxyethyl)phosphine. As a result of crosslinking by DTME, the apparent Young's modulus of the micelles roughly doubles to 1.18 GPa. Changes to the Young's modulus can be largely reversed by de-cross-linking. Cross-linked and de-cross-linked micelles maintain their structural integrity even in diluted aqueous media below the critical micelle concentration, in contrast to the micelles prior to crosslinking. Understanding the structure-property relationships associated with the observed augmented mechanical stability in native environments is crucial for improving the efficiency of drug encapsulation and introducing refined temporal and spatially controlled drug-release mechanisms.