Chitosan Derivatives - Chitosan Based Hydrogels: Functions and Applications - page 59

derivatives with the potential to act as surfactants. N -Lauryl- N -methylenephosphonic
chitosan is one such surfactant reported [156]. Phosphorylated chitosans are synthesized
in the phosphorus pentoxide-methanesulfonic acid system also [149].
To impart good anti-blood-coagulation properties to chitosan, modifications are carried
outwithphosphorylcholine(PC)compounds.Reactionwith2-chloro-1,3,2-dioxaphospholane
in homogeneous or heterogeneous conditions yields PC chitosan [157]. Modification of
chitosan with 2-methacryloyloxyethyl phosphorylcholine through the Michael addition
reaction has been carried out with cell adhesion studies, indicating that cell attachment
could be easily controlled by adjusting the concentration of 2-methacryloyloxyethyl phos-
phorylcholine bound to chitosan [158].
To achieve regiospecific functionalization of chitosan, Winnik and coworkers [159,160]
chose to introduce PC groups via chemical modification of the C2 amine group, thus leav-
ing intact all the hydroxyl groups that play an important role in the biological activity of
chitosan derivatives. The synthetic strategy involves two reactions carried out in sequence,
without isolation of the intermediate: (1) reductive amination of phosphorylcholine-glycer-
aldehyde by the C2 primary amine groups of chitosan and (2) reduction of the resulting
imine groups with NaCNBH 3 , a reagent extensively used in various modifications of chi-
tosan. Note that, overall, the reaction path converts primary amines into secondary amines,
a transformation that will affect, yet maintain, the polyelectrolyte properties of native chi-
tosan. These PC-substituted chitosans (PC-CH) exhibit remarkable solubility in water
under physiological pH conditions and demonstrate that the introduction of zwitterionic
PC moieties into chitosan, even with modest DSs, provides a new and effective route
toward nontoxic chitosan, while remaining soluble under neutral and even slightly alka-
line conditions. Moreover, the cytotoxicity of the polymers was evaluated, confirming the
nontoxic nature of chitosan and its PC derivatives.
The premodified chitosan can also be extended with Phosphorus-containing groups; for
example, the -COOH group of carboxymethyl chitosan was made to react with -NH 2 of
phosphatidylethanolamine giving an amphiphilic polymer [161]. This polymer was investi-
gated for its feasibility as a delivery carrier for the transfection of hydrophobic model drug
ketoprofen by forming beads on ionic cross-linking by sodium tripolyphosphate.
P-chitosan was used for the preparation of gel beads using TPP to improve the con-
trolled release system in a gastrointestinal fluid [162]. This work included the in vitro drug
release profiles monitored at various pH media at 37°C using Ib as a model drug. The
release percentages of Ib from P-chitosan gel beads were found to increase with increasing
pH of the dissolution medium. This behavior indicated that the drug release profile is pH
sensitive. The release rate of Ib at pH 7.4 was noticeably higher than the release rate at pH
1.4 due to the ionization of phosphorus groups and the high solubility of Ib at pH 7.4
[163,164] and also the electrostatic repulsion between negatively ionized carboxyl groups
of Ib and phosphate groups in P-chitosan molecules. The release rate in simulated intesti-
nal fluid (pH 7.4) was higher than that in simulated gastric fluid (pH 1.4), enabling drug
delivery or release to take place preferentially in the intestine while simultaneously avoid-
ing drug leakage in the stomach. All of these interesting features indicated that the
P-chitosan gel beads could be used as a successful drug carrier for controlled drug deliv-
ery in oral administration.
In polymeric implants used in orthopedics, the presence of a calcium phosphate over-
layer is often desirable to promote osteoconduction and to ensure bone bonding. Grafting
negatively charged functionalities, such as phosphates, is a well-known strategy for induc-
ing the deposition of apatite-like layers under simulated physiological conditions [165-168].
Recently, Amaral et al. [169] applied this approach to chitosan membranes, using the