Enzyme-responsive linkers

While the previous section dealt with the structural elements that define enzyme-responsive polymers, here we will introduce different methods that can be used to integrate an enzyme-responsive functionality with a polymeric material. These methods are placed into three groups. The first method deals with the preparation of enzymatically degradable polymers, the second introduces strategies to incorporate enzyme-responsive linkers into the polymer and the third explores ways to prepare enzyme-responsive polymers enzymatically. 

FIGURE 10.6 Schematic representation of selective enzyme-triggered charge-induced swelling of the enzyme-responsive hydrogels with the zwitterionic peptide linkers that are hydrolyzed by a specific enzyme. 

The introduction of enzyme-sensitive cross-links in an otherwise nonenzyme-responsive polymer such as PEG is frequently used to prepare enzyme-responsive polymer hydrogels and polymer particles. Because of their versatility and natural predisposition as enzyme substrates, short peptide sequences are almost exclusively used as cross-linkers, although dex-tran has also been used (Klinger et al., 2012). They can be readily changed to respond to a variety of proteases such as matrix metalloproteinases,plasmin or trypsin (Lutolf et al., 2003a Yang et al, 2010). In most cases, the peptides have to be modified at the termini to introduce reactive groups that are able to react with the polymer. 

To date, two main approaches have been adopted for developing enzyme-responsive materials. In the first and most common approach, the nanocarrier itself is sensitive to enzymatic transformation. This is achieved by the use of either an enzymatically degradable polymer or enzymatically sensitive linkers between the drug and the polymer. 

The A and B polypeptides in proricin are joined by a twelve-residue linking peptide. This linker sequence is excised in the protein bodies to release the A and B chains and it is noteworthy that the carboxy-terminal residue of the linker peptide is asparagine. Endoproteolytic cleavage after an asparagine residue is a feature of the processing of plant proproteins [156]. In the case of the ricin precursor, the endoproteinase which removes the linker peptide, or a related protein body enzyme, may also be responsible for the proposed post-translational N-terminal processing. 

In addition, the degradation properties of hydrogels were adjusted by incorporation of degradable linkers. By using enzyme-sensitive peptide sequences, cell-responsive biomaterials that mimic the proteolytic recognition of natural ECMs... 

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