Synthetic self-assembled nano structures and their interactions with enzymes have been drawing increasing attention as part of the growing interest in biocompatible and biodegradable stimuli-responsive polymeric platforms. Utilization of enzymes as triggers that can modify the structural properties of polymeric assemblies can be highly relevant for biological applications such as controlled drug delivery, tissue engineering, etc. Many disease states are associated with a unique enzymatic over-expression, which could be exploited to induce a site specific-response of cleverly designed stimuli-responsive platforms. Our research group has recently developed a simple synthetic approach for preparation of enzyme-responsive PEG-dendron hybrids.^[1] Our molecular design included a PEG hydrophilic backbone, while the enzyme-responsive functionalities were attached to the terminal positions of a dendron unit. These amphiphilic hybrids were shown to self-assemble in aqueous media into nano-sized polymeric micelles and to disassemble in response to the designed enzymatic stimulus.^[2] In this work, we wished to expand the enzymatic trigger from a single enzyme into two activating enzymes by attaching two different enzyme-responsive end-groups to the dendron. Activation of each end-group by either one of the enzymes can cause the micelles to disassemble and release their encapsulated molecular cargo. In addition, simultaneous activation with both enzymes caused the micelles to disassemble even faster, granting a wider range of activation rates.

1. Harnoy, A; Buzhor, M; Tirosh, E; Shaharabani. R; Beck, R; Amir, R; Biomacromolecules, 2017, 18 (4), 1218–1228.

2. Harnoy, A; Rosenbaum, I; Tirosh, E; Ebenstein, Y; Shaharabani, R; Beck, R; Amir, R; J. Am. Chem. Soc., 2014, 136, 7531−7534.