9.3 Chitosan-Based Nanogels
Polysaccharide-based nanogels are more advantageous than bulk polysaccharidebased hydrogels as a consequence of their high water content, functionality,
biocompatibility, tunable size from submicrons to tens of nanometers, large surface
area for multivalent bioconjugation, and interior network for the incorporation of
therapeutics. Nanogels can be defined as internally crosslinked macromolecular
systems wherein the size of hydrogel nanoparticles ranges between 10 and 200 nm
[181]. Some reviews have mainly focused on the structure and function of other
polysaccharides and give little emphasis to chitosan and their engineered nanoscale
assembly for biomedical materials [132, 182, 183]. In this section, only chitosanbased nanogels will be discussed.
Current approaches for the preparation of crosslinked micro- or nanogels can be
largely categorized into physical crosslinking, chemical crosslinking, and heterogeneous controlled/living radical crosslinking polymerization (CRCP) [182]. Several
methods such as heterogeneous polymerization, continuous extrusion for starchbased biolatex nanoparticles, precipitation in water, micromolding and microfluidic
preparation, spray drying, and supramolecular self-assembly and self complexation
have been developed for the successful preparation of micro- and nanogels. One
general method involves aqueous homogeneous gelation based on chemical and
physical crosslinking in water; the gelation is generally conducted in dilute solution
in order to prevent macroscopic gelation that leads to bulk hydrogels. As far as
physical crosslinking is concerned, it has primarily two advantages, i.e., reversibility
and no requirement for other chemicals for the connectivity of chains. In many
experiments, the electrostatic interactions of polysaccharide-based polymers with
various polyelectrolytes in water have been explored. These polyelectrolytes include
polyethyleneimine (PEI), sodium tripolyphosphate (TPP), poly(ethylene oxide)
(PEO)-b-poly(N,N,-dimethylaminoethyl methacrylate) block copolymer, and
biopolymer-based polyelectrolytes to yield chitosan-based nanogels [184–189]. To
prevent dissolution of the nanogel in the aqueous environment, chemical crosslinks
involving the formation of covalent bonds are preferred over physical crosslinking.
Chitosan-based nanogels were prepared by a covalent chemical crosslinking, based
on a carbodiimide coupling of chitosan with an oligo(ethylene glycol) dicarboxylic
acid as a water-soluble crosslinker, in water. The resulting nanogels had a diameter
of 4–24 nm, as shown by TEM [190]. Chitosan nanogels with a diameter of
70–80 nm were also prepared by the reaction of chitosan with ethylenediaminetetraacetic dianhydride (EDTAA) in water. The stable pH-responsive nanogels
enabled a reversible switch of their surface charge upon pH change so that it was
positive at pH <4.8 and negative at pH >5.2. These characteristics suggest that the
nanogels can be effective candidates for the encapsulation of pH-sensitive anticancer agents such as highly water-insoluble camptothecin [191].
In a recent study, Maggi et al. [192] reported the use of polyion complex micelles
(PIC) as nanoreactors for template crosslinking for the preparation of chitosan
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J. Dutta
Polysaccharide-based nanogels are more advantageous than bulk polysaccharidebased hydrogels as a consequence of their high water content, functionality,
biocompatibility, tunable size from submicrons to tens of nanometers, large surface
area for multivalent bioconjugation, and interior network for the incorporation of
therapeutics. Nanogels can be defined as internally crosslinked macromolecular
systems wherein the size of hydrogel nanoparticles ranges between 10 and 200 nm
[181]. Some reviews have mainly focused on the structure and function of other
polysaccharides and give little emphasis to chitosan and their engineered nanoscale
assembly for biomedical materials [132, 182, 183]. In this section, only chitosanbased nanogels will be discussed.
Current approaches for the preparation of crosslinked micro- or nanogels can be
largely categorized into physical crosslinking, chemical crosslinking, and heterogeneous controlled/living radical crosslinking polymerization (CRCP) [182]. Several
methods such as heterogeneous polymerization, continuous extrusion for starchbased biolatex nanoparticles, precipitation in water, micromolding and microfluidic
preparation, spray drying, and supramolecular self-assembly and self complexation
have been developed for the successful preparation of micro- and nanogels. One
general method involves aqueous homogeneous gelation based on chemical and
physical crosslinking in water; the gelation is generally conducted in dilute solution
in order to prevent macroscopic gelation that leads to bulk hydrogels. As far as
physical crosslinking is concerned, it has primarily two advantages, i.e., reversibility
and no requirement for other chemicals for the connectivity of chains. In many
experiments, the electrostatic interactions of polysaccharide-based polymers with
various polyelectrolytes in water have been explored. These polyelectrolytes include
polyethyleneimine (PEI), sodium tripolyphosphate (TPP), poly(ethylene oxide)
(PEO)-b-poly(N,N,-dimethylaminoethyl methacrylate) block copolymer, and
biopolymer-based polyelectrolytes to yield chitosan-based nanogels [184–189]. To
prevent dissolution of the nanogel in the aqueous environment, chemical crosslinks
involving the formation of covalent bonds are preferred over physical crosslinking.
Chitosan-based nanogels were prepared by a covalent chemical crosslinking, based
on a carbodiimide coupling of chitosan with an oligo(ethylene glycol) dicarboxylic
acid as a water-soluble crosslinker, in water. The resulting nanogels had a diameter
of 4–24 nm, as shown by TEM [190]. Chitosan nanogels with a diameter of
70–80 nm were also prepared by the reaction of chitosan with ethylenediaminetetraacetic dianhydride (EDTAA) in water. The stable pH-responsive nanogels
enabled a reversible switch of their surface charge upon pH change so that it was
positive at pH <4.8 and negative at pH >5.2. These characteristics suggest that the
nanogels can be effective candidates for the encapsulation of pH-sensitive anticancer agents such as highly water-insoluble camptothecin [191].
In a recent study, Maggi et al. [192] reported the use of polyion complex micelles
(PIC) as nanoreactors for template crosslinking for the preparation of chitosan
116
J. Dutta