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

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.

Stimuli-Induced Architectural Transition as a Tool for Controlling the Enzymatic Degradability of Polymeric Micelles

“…At the same time, micelles must also disassemble once they reach their target site to release their therapeutic cargo. − Furthermore, micellar degradation and disassembly are crucial for traceless clearance of the DDSs from the body after delivering their payload . The high specificity and overexpression of disease-associated enzymes in diseased tissues make enzymes highly promising stimuli for triggering the selective release of drugs from micellar nanocarriers. , Unlike stimuli-responsive micelles that respond to dimensionless stimuli such as light , or temperature, enzymatically degradable micelles show a reverse correlation between micellar stability and their responsiveness to the activating enzymes . Once micellar stability reaches a certain threshold, they become unreactive toward the activating enzyme.…”

Dendron–Polymer Hybrids as Tailorable Responsive Coronae of Single-Walled Carbon Nanotubes

“…Amphiphilic PEG-dendrons are known to self-assemble into polymeric micelles, whose stability is dependent on their hydrophilic/hydrophobic ratio. − The ester group connecting the hydrophobic end groups to the dendritic branches is susceptible to enzymatic cleavage by porcine liver esterase (PLE), which can cleave off naphthol, naphthoic acid, pentanol, and hexanoic acid end groups (Figure a). In addition to the release of these cleaved end groups, the enzymatic cleavage should yield carboxylic acid or alcohol moieties on the dendritic block, decreasing its hydrophobicity and, thus, resulting in PEG-dendrons with a substantially higher hydrophilic/hydrophobic ratio. , The overall degradation rate of the PEG-dendrons in micellar assemblies was previously shown to depend on the equilibrium between “monomeric” PEG-dendrons and their micellar assemblies . Translated to the SWCNT@PEG-dendrons, we expect their degree of enzymatic degradation to depend on the noncovalent binding interactions between the nanotubes and the hydrophobic end groups of the PEG-dendrons.…”

“…63,65 The overall degradation rate of the PEG-dendrons in micellar assemblies was previously shown to depend on the equilibrium between "monomeric" PEG-dendrons and their micellar assemblies. 66 Translated to the SWCNT@PEG-dendrons, we expect their degree of enzymatic degradation to depend on the noncovalent binding interactions between the nanotubes and the hydrophobic end groups of the PEG-dendrons. Changes in the corona phase, by detaching and/or cleavage of the wrapping amphiphiles, should induce changes in the dielectric environment of the nanotubes, which can be monitored via their NIR-fluorescence emission.…”

Dendron-Polymer Hybrids as Tailorable Coronae of Single-Walled Carbon Nanotube

“…55,57 The overall degradation rate of the PEG-dendrons in micellar assemblies was shown to depend on the equilibrium between 'monomeric' PEG-dendrons and their micellar assemblies. 58 Translated to the SWCNT@PEG-dendrons, we expected their enzymatic degradation to depend on the non-covalent binding interactions between the nanotubes and the hydrophobic end-groups of the PEG-dendrons. Changes in the corona phase, by detaching and/or cleavage of the wrapping amphiphiles, should induce changes in the dielectric environment of the nanotubes, which can be monitored via their nIR-fluorescence emission 10,28,53,59 .…”