Using High Molecular Precision to Study Enzymatically Induced Disassembly of Polymeric Nanocarriers: Direct Enzymatic Activation or Equilibrium-Based Degradation?

Gadi Slor,Roey J Amir

doi:10.1021/acs.macromol.0c02263

Abstract

Enzyme-responsive polymers and their assemblies offer great potential to serve as key materials for the design of drug delivery systems and other biomedical applications. However, the utilization of enzymes to trigger the disassembly of polymeric amphiphiles, such as micelles, also suffers from the limited accessibility of the enzyme to moieties that are hidden inside the assembled structures. In this Perspective, we will discuss examples for the utilization of high molecular precision that dendritic structures offer to study the enzymatic degradation of polymeric amphiphiles with high resolution. Up to date, several different amphiphilic systems based on dendritic blocks have all shown that small changes in the hydrophobicity and amphiphilicity strongly affected the degree and rate of enzymatic degradation. The ability to observe the huge effects due to relatively small variations in the molecular structure of polymers can explain the limited enzymatic degradation that is often observed for many reported polymeric assemblies. The observed trends imply that the enzymes cannot reach the hydrophobic core of the micelles, and instead, they gain access to the amphiphiles by the unimer–micelle equilibrium, making the unimer exchange rate a key parameter in tuning the enzymatic degradation rate. Several approaches that are aimed at overcoming the stability–responsiveness challenge are discussed as they open the way to the design of stable and yet enzymatically responsive polymeric nanocarriers.

Highlights

Polymeric micelles of various dimensions and compositions have been widely explored as potential drug carriers for hydrophobic drug molecules
In the past few years, we have been studying polymeric amphiphiles based on linear PEG as the hydrophilic block and dendron containing enzymatically cleavable lipophilic endgroups as the hydrophobic block.[38−41] Taking advantage of the high molecular precision that emerges from using a dendron as the hydrophobic block, we studied how fine-tuning of the amphiphilicity, mostly by altering the structure of the hydrophobic dendron, affects the self-assembly and enzymatic degradation of our PEG-dendron amphiphiles
There is no doubt that enzyme-responsive polymers and their assemblies hold great potential as key materials for the design of smart drug delivery systems and other biomedical applications

Summary

■ INTRODUCTION

Polymeric micelles of various dimensions and compositions have been widely explored as potential drug carriers for hydrophobic drug molecules. Following our observation of the correlation between the increase in CMCs for amphiphiles with larger hydrophilic block and their faster enzymatically induced disassembly, which indicated an equilibrium-based enzymatic activation, we set to study the effect of changes in the hydrophobic block Toward this goal, we designed PEG-dendron amphiphiles bearing enzymatically cleavable end-groups with different degrees of hydrophobicity. It comes with two significant price tags: release of electrophilic species that are being formed during the self-degradation process and might have some toxicity and the need for custom synthesis using a relatively limited number of backbones

■ CONCLUSIONS AND FUTURE PERSPECTIVES

Corresponding Author

■ REFERENCES