Enzyme-Responsive Polymeric Assemblies

Profound understanding of the parameters that governs the enzymatic degradation of polymeric assemblies is crucial for the development of biodegradable materials for applications ranging from drug delivery systems to tissue engineering. It is clear that one of the key parameters that determine the enzymatic activity is the limited accessibility of the enzyme to hydrophobic substrates that may be hidden inside hydrophobic domains. In the past few years, we synthesized amphiphilic PEG-dendron hybrids with enzymatically cleavable hydrophobic end-groups to study enzymatic hydrolysis of polymeric amphiphiles and their assemblies. The monodispersity of the hydrophobic dendritic block, allowed us to demonstrate how precise minor changes of the hydrophobic blocks strongly affected their stability towards enzymatic degradation. Furthermore, I will show in vitro cellular internalization studies, which demonstrate that the micellar stability in serum can also dictate the internalization mechanism of the polymeric assemblies.

Our results together with the kinetic behavior for other enzyme-responsive assemblies, strongly supports the hypothesis that the enzyme cannot reach the core of the assembly and instead it gains excess to the non-assembled monomers, which are in equilibrium with the polymeric assemblies. This equilibrium-based mechanism and its sensitivity to minor changes in amphiphilicity may explain the often-observed poor or lack of degradability of many polymeric amphiphiles. Furthermore, the broad range of micellar stabilities, ranging from readily degradable to undegradable and the different internalization pathways due to minor changes in the hydrophobic block, highlight the great role that micellar stability and polydispersity might play in controlling degradation and release rates.