Polysaccharides as Nanomaterials for Therapeutics - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 138

Chemically modified alginate has also been used for the pre-
paration of nanoparticles. As with chitosan, chemical modifications
improve the physiochemical characteristics of alginate. For example,
thiolated alginate achieved by covalent attachment of cysteine
improves the mucoadhesive properties of alginate and provides
improved stability of the drug delivery system [99]. Hydrophobically
modified alginate have also been produced [100].
5.4.3 Hyaluronan-BasedNanoparticles
HA-based nanocarriers were developed using several approaches
such as HA-drug conjugates, which restore their cytotoxicity
upon cell internalization by receptor-mediated endocytosis [32],
PEC with polycations and ionically cross-linked nanoparticles.
Chemically modified HA have also been widely used for the delivery
of proteins, peptides, and nucleotides [101]. Chemical modifications
assist in prolonging HA half-life; however, beyond a certain level of
modification, HA loses the ability to bind its receptors [101].
HA-drug conjugates utilize several chemical groups
on hyaluronan: the carboxylate on the glucuronic acid, the
N -acetylglucosamine hydroxyl, the reducing end, and the acetyl group,
which can be enzymatically removed from the N -acetylglucosamine
[25]. In addition to targeting, HA conjugation has been used to
increase drug solubility. This quality was used for the delivery of
the hydrophobic antimitotic chemotherapeutic agent paclitaxel
[102-104]. HA−paclitaxel conjugates exhibited greater cytotoxicity
to CD44 overexpressing cells (HCT-116 and MCF-7) and reduced
cytotoxicity to CD44-deficient cells (NIH-3T3) in comparison with
free paclitaxel [103]. HA-drug conjugates are internalized via CD44
receptor-mediated endocytosis and drug is released mainly by
intracellular enzymatic hydrolysis [25]. Recently, HA conjugation
was used for the delivery and improved serum stability of exendin
4 [105]. Exendin 4 (exenatide) is a 39-amino acid peptide incretin
mimetic that exhibits gluco-regulatory activities [106]. Exendin
4 has been shown to induce glucose-dependent enhancement of
insulin secretion, glucose-dependent suppression of inappropriately
high glucagon secretion, slowing of gastric emptying, reduction of
food intake and body weight, and an increase in β-cell mass [105].
However, exendin 4 has a significantly short half-life, which limits its
clinical applications [105]. Conjugation to vinyl sulfone-modified HA