Chitosan Derivatives - Chitosan Based Hydrogels: Functions and Applications - page 51

O

NH 2

NH 2

R Cl

O

RO O

HO

O

O O

O

0°C MeSO 3 H

OH

OR

Figure 2.13
Synthesis of O -acyl-chitosans.

urea, or NaCl) can affect TR loading on the nanoparticles. The thermal stability of TR load-
ing on nanoparticles was significantly improved compared to free TR. On the other hand,
adriamycin (ADR) has been physically entrapped in self-aggregates based on linolenic-
carboxylchitosan derivatives [41]. The drug loading (DL) experiments indicate that loading
capacity and efficiency increase with increasing concentration of ADR. ADR is slowly
released from chitosan self-aggregates for about 3 days.
Stearic acid has also been coupled to chitosan via activation with EDC for DNA and
drug delivery applications [49]. Stearic acid-chitosan oligosaccharide micelles showed a
critical micelle concentration (CMC) of 0.035 mg/mL (DS 25.4%). Due to their cationic prop-
erties, the micelles could compact the plasmid DNA to form micelle-DNA complex nano-
particles, which can efficiently protect the condensed DNA from enzymatic degradation
by DNase I. You et al. [54-56] demonstrated that stearic acid-chitosan micelles show pH-
sensitive properties, thus favoring intracellular delivery of encapsulated drug.

2.4.2 O -Acyl Chitosan

Since the amino group is more active than the two hydroxyl groups, protection is often
necessary in order to prepare N , O -acyl chitosan with a refined substitution pattern.
Nishimura et al. [80] reported the preparation of amphiphilic chitosans by using an
N -phthaloyl chitosan as an intermediate. However, this method needs several steps for the
protection and deprotection of the amine groups. Seo et al. [66] also reported a heteroge-
neous method to prepare N , O -acyl chitosan by using N -acyl chitosan as a precursor.
However, the resultant N , O -acyl chitosans had lower DSs and showed poor solubility in
organic solvents. At the same time, a new method for selective O-acylation of chitosan in
methanesulfonic acid (MSA) was proposed [64]. This method is based on the idea that the
amine groups are protonated through the formation of a salt with MSA, which is disad-
vantageous for a nucleophilic displacement reaction. As a result, the substitution occurs
preferentially on the hydroxyl groups of chitosan. O -Acyl chitosans are prepared from
acyl chlorides in the presence of MSA (MeSO 3 H) (Figure 2.13).
Acryloyl chitosan (AcCS) has been synthesized by a homogeneous reaction of chitosan
and acryloyl chloride using MSA as the solvent and catalyst [81,82]. Concentrated solutions
of AcCS/acrylic acid were investigated by polarized optical microscopy, and cholesteric
mesophase was found above the critical concentration of 45 wt%.

2.4.3 Controlled N , O -Acylation of Chitosan

The O -acyl chitosans synthesized via an MSA protection method generally dissolve in
N , N -dimethylacetamide (DMAc). Therefore, further N-acylations could be conducted on
the O -acyl chitosans in homogeneous systems using DMAc as the solvent (Figure 2.14).