Controlling the Enzymatic Dissociation-Rates of Micelles Using Minimal Structural Changes

Programmed release of encapsulated biomolecules at the target location is highly desired, yet very challenging. Enzymes show great promise as triggers for disassembly of nanocarriers, thanks to their observed over-expression in specific diseases. Our group has developed a highly modular design of amphiphilic polymer-dendron hybrids, composed of linear hydrophilic polyethyleneglycol (PEG) block and a hydrophobic enzyme-responsive dendron.¹ Herein, we applied this platform to prepare a set of hybrids with highly precise structural-changes, in order to examine how small changes in the length of the hydrophobic dendritic end-groups would affect the self-assembly and enzymatic degradation of the formed polymeric micelles. Taking advantage of this modular and well-defined system, we were able to demonstrate that small changes in the hydrophobic dendron block, can lead to dramatic changes on the rate of disassembly of the nanoparticle. Moreover, to further examine the selectivity of the enzymatic hydrolysis to the structural changes, we prepared a mixture of hybrids with two lengths of hydrophobic end-groups. The mixture gave a remarkable demonstration of the effect of the minor changes between the mixed hybrids on their enzymatic degradation. This detailed molecular study enhanced our fundamental understanding of enzyme-responsive platforms, which can potentially be applied to create smart drug delivery platforms with controllable degradation rates using minimal structural modifications.²

(1) Rosenbaum, I.; Harnoy, A. J.; Tirosh, E.; Buzhor, M.; Segal, M.; Frid, L.; Shaharabani, R.; Avinery, R.; Beck, R.; Amir, R. J. J. Am. Chem. Soc. 2015, 137 (6), 2276–2284.

(2) Segal, M.; Avinery R.; Buzhor M.; Shaharabani R.;Harnoy A. J.; Tirosh E.; Beck R.; Amir R. J. submitted.2016.