Designing enzymatically degradable polymeric amphiphiles with high molecular precision

Deeper understanding of the molecular factors governing the enzymatic degradation of polymeric assemblies is crucial for the design of biodegradable materials with tunable degradation rates, for applications ranging from tissue engineering to drug delivery systems. It is clear that the limited access of enzymes to the hydrophobic substrates, which are hidden inside the hydrophobic domains, is an important factor in determining the enzymatic degradation rates. Our group designs amphiphilic PEG-dendron hybrids with enzymatically cleavable lipophilic end-groups and study their self-assembly and enzymatic hydrolysis. The monodispersity of the dendritic block, allows us to study how minor alternations of the hydrophobic dendrons affect the enzymatic degradation of polymeric assemblies. Recently, we demonstrated in in vitro cellular internalization studies that the micellar stability in serum and internalization mechanism of the polymeric assemblies can adjusted by fine-tuning of the hydrophobic end-groups.

The kinetic results for our polymers and other enzyme-responsive assemblies, strongly support the hypothesis that the cores of the assemblies are not accessible to the enzymes and hence the degradation occurs through the non-assembled monomers, which are in equilibrium with the polymeric assemblies. The wide range of degradation rates from readily degradable to undegradable polymeric micelles and the diverse internalization pathways due to minor changes in the hydrophobic block, highlight the important role that polydispersity plays in controlling micellar stability towards enzymatic degradation. These insights into the degradation mechanism can explain the poor enzymatic degradability that is often reported for many polymeric assemblies, which may limit their further development into clinically approved delivery vehicles.