Biomedical Engineering Reference
In-Depth Information
amino residue of Dox to HA [22]. There are also several reports
on HA-peptide/protein conjugates where the carboxylate group
of HA is conjugated to primary amine groups of lysine residue.
The limitation of this method however, lies in the need of lysine
amino acids for conjugation, which sometimes are less available in
natural proteins/peptides [23].
8.3.1.2 Hydrazide Modified Hyaluronic Acid
One of the highly explored modifications is hydrazide modification of
HA. This is typically achieved by conjugating ADH by carbodiimide
coupling and has been evaluated for various bioconjugation
applications like conjugation of drugs or peptides using hydrazone
linkages [15]. Luo-Luo and co-workers have successfully utilised
ADH modified HA derivatives for drug delivery and hydrogel
applications [24]. The hydrazone chemistry using the HA-ADH
derivative is a fast and quantitative and catalyst-free reaction, which
is cleavable under acidic pH. This is advantageous for drug delivery
applications, where the drug is cleaved from the prodrug upon
endocytosis, in the endolysosomal compartment of the cell. However,
this is also a drawback in applications where a stable conjugation
is desired as the hydrazone linkage is labile and sensitive to pH
change. This drawback is circumvented by using CDH derived HA,
as this hydrazone linkage is found to be 15-times more stable than
other hydrazone linkages under acidic pH (pH 5.0) [25]. This was
explored to develop stable hydrogels, which is discussed in detail in
the hydrogel section (
Section 8.6
).
8.3.1.3 Thiol Modified Hyaluronic Acid
Thiol modified HA is generally prepared by conjugation with a disulfide
containing molecules such as cystamine or a 3,3′-dithiopropionic acid
dihydrazide that is coupled to HA using EDC chemistry. Reduction
of disulfide bonds by dithiothreitol yields the desired thiol derivative.
The thiol derivatives of HA has been extensively used to develop
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