Chitosan Derivatives - Chitosan Based Hydrogels: Functions and Applications - page 54

With the proper selection of the reactant ratio, that is, with equimolar quantities of glyoxy-
lic acid and amino groups, the product is in part N-monocarboxymethylated (0.3), N,N-
dicarboxymethylated (0.3), and N-acetylated depending on the starting chitosan (0.08-0.15)
[92]. N -Carboxymethyl chitosan is not only soluble in water, but has unique chemical,
physical, and biological properties such as high viscosity, large hydrodynamic volume and
film, and gel-forming capabilities, all of which make it an attractive option in connection
with its use in food products and cosmetics [93]. Carboxymethyl chitosan is used in the
development of different protein drug delivery systems as superporous hydrogels, pH-
sensitive hydrogels, and cross-linked hydrogels [94-97]. N , N -Dicarboxymethyl chitosan
has been shown to possess good chelating abilities and its chelate with calcium phosphate
favored osteogenesis while promoting bone mineralization [85].
N -Phthaloyl-carboxymethyl chitosan (CMPhCS) has been successfully prepared by react-
ing N -phthaloylchitosan with chloroacetic acid in isopropyl alcohol [98]. CMPhCS existed
as a flexible chain in the aqueous solution and aggregated gradually to form sphere aggre-
gates in the mixture solution of H 2 O-DMF. Micelles were self-assembled from N -phthaloyl-
carboxymethylchitosan (CMPhCS) in a DMF-H 2 O mixture solution, and they were used to
evaluate drug deliveries of levofloxacine hydrochloride (Lfloxin). The results indicated that
the CMC of CMPhCS in aqueous solution was 0.20 mg/mL. Moreover, Lfloxin and BSA
could be controlled for release within 72 h in sodium phosphate buffer (pH 7.4) [99].
Sashiwa et al. applied the Michael reaction of various acryl reagents with chitosan [100].
With the application of water-soluble acryl reagents for this reaction, novel types of func-
tional groups were introduced by a simple procedure. The reagents tried are hydroxyethyl
acrylate, hydroxypropyl acrylate, acrylamide, acrylonitrile, and poly(ethylene glycol)
(PEG)-acrylate. Reaction of chitosan with acrylonitrile gives cyanoethyl chitosan, whereas
reaction of chitosan with ethyl acrylate in aqueous acidic medium gives an N -carboxyethyl
ester intermediate that can be easily hydrolyzed to free acid or used as an intermediate to
substitute with various hydrophilic amines, without requiring protecting groups [101].
2.6 Sulfated Chitosan
Chemical modification of the amino and hydroxyl groups of chitosan with sulfate can
generate products for pharmaceutical applications. Sulfonation reactions of polysaccharides
can give rise to a structural heterogeneity in polymer chains, but on the other hand
some structures that emerge from random distribution can reveal good features for biologi-
cal functions. Sulfated chitosans, which represent the nearest structural analogs of the
natural blood anticoagulant heparin, show anticoagulant, antisclerotic, antitumor, and
antiviral activities [102-106]. Chitosan derivatives having N - and/or O -sulfate groups either
alone or in conjunction with other substituents have been widely examined as potential
heparinoids. Vikhoreva et al. [107] synthesized chitosan sulfates by sulfation of low-molec-
ular-weight chitosan ( M W 9000-35,000 Da). They used oleum as sulfating agent and dimeth-
ylformamide as medium, and demonstrated that chitosan sulfates with reduced molecular
weight show a regular increase of anticoagulant activity, for example, heparins.
The sulfation of chitin was reported as far back as 1954 [108]. Over the following several
decades, effort was extended to prepare N - and/or O -sulfated-chitins and chitosans using
various reaction conditions and sulfating reagents ( Table 2.2). Wolfrom and Shen-Han
[109], Horton and Just [110], Nishimura et al. [111], Terbojevich et al. [112], Gamzazade et al.