Designing Hydrogels by ATRP - In-Situ Gelling Polymers: For Biomedical Applications - page 85

methods [ 159 ]. Furthermore, ATRP techniques have been utilized to develop
unique methodologies to synthesize and fabricate well-defined nanogels.
Nanogels can be prepared by inverse miniemulsion polymerization, an water-
in-oil (W/O) process consisting of dispersions of aqueous droplets, includ-
ing water-soluble monomers and difunctional crosslinkers, in organic media
with the aid of oil-soluble surfactants. Polymerization occurs in the aqueous
droplets upon addition of water-soluble initiators and yields colloidally-sta-
ble crosslinked hydrophilic nanogels [ 181 ]. Conducting an ATRP in inverse
miniemulsion has been reported. This method enables the preparation of well-
defined degradable nanogels crosslinked with disulfide linkages, which exhibit
reduction-responsive degradation through disulfide-thiol exchange reactions.
This methodology provides nanogels which possess a number of unique fea-
tures specifically targeted toward drug delivery applications [ 182 ]. First, the
incorporation of reduction-responsive degradability in the presence of cellular
glutathione (GSH), a tripeptide containing cysteine with a pendent thiol group,
facilitates biodegradation, enabling the enhanced release of encapsulated bio-
molecules including anticancer drugs, carbohydrate drugs, and protein drugs
while ensuring the removal of the original device after the release of drugs in
the body. Second, the retention of high chain-end functionalities enable further
chain extension to form functional block copolymers, and facile bioconjuga-
tion with cell targeting agents such as peptides, proteins, and antibodies. Third,
facile cellular internalization of the nanogels through clathrin-medicated endo-
cytosis was confirmed through laser confocal fluorescent microscopy (LCFM)
and flow cytometry experiments. Indeed, this methodology is so versatile that
it has been utilized to synthesize other advanced functional nanomaterials;
including thermoresponsive degradable magnetic microgels for hyperthermia
applications [ 183 ] green florescent protein loaded nanogels for protein-polymer
hybrids [ 106 , 184 ] dual-responsive surfactants for functional nanocapsules [ 147 ]
and OH-functionalized nanogels for nanostructured hybrid hydrogels [ 173 ].
Similarly, the ATRP technique has additionally been explored for inverse micro-
emulsion [ 185 ] dispersion [ 186 ] and precipitation polymerizations [ 187 ].
Self-assembled micellar aggregates based on amphiphilic block copolymers
(ABPs) resulted in formation of a broad range of materials that show promise as
tumor-targeting nanocarriers [ 188 , 189 ]. However, retaining colloidal stability
of physically aggregated micelles upon dilution remains a challenge. Dilution, far
below critical micellar concentration during circulation in the body, causes the
micelles to destabilize or dissociate, which in turn leads to premature release
of encapsulated drugs. Covalent crosslinking has been explored as a strategy to
improve the in vivo stability of micelles by converting aggregates to crosslinked
micelles or nanogels [ 190 ]. In this procedure, two reactive functional groups of
ABPs and/or external crosslinkers react to form new covalent crosslinks in the shell
or core of the micelles, endowing the micelles with enhanced colloidal stability.
However, the use of permanent crosslinks hampers the controlled release of encap-
sulated drugs [ 191 ]. Recently, stimuli-responsive degradation has been explored as
a smart response platform to synthesize degradable nanogels crosslinked with labile