Polymeric hydrophilic polymers in targeted drug delivery - Artificial Cells, Cell Engineering and Therapy - page 48

Temperature-responsive gelation
Xyloglucan
Xyloglucan is a polysaccharide from tamarind seeds that, when partially
degraded by -galactosidase, shows a sol to gel transition at a transition
temperature that is dependent on the degree of galactose elimination that can be
designed to be between ambient and physiologic temperatures. 62 It has been
explored for rectal, 63 oral 64 and ocular delivery of pilocarpine and timolol 62,65
with promising results, but no gelation mechanism has been hypothesized or
reported.
PNIPAAm-based systems
Copolymers based on poly(N-isopropylacrylamide) (PNIPAAm) have shown
thermoreversible in situ gelling properties that can be exploited for targeting.
Bae and coworkers 66±68 synthesized high molecular weight (~10 6 Da) co-
polymers of NIPAAm with 2±5 mol% acrylic acid, and observed four
temperature-dependent phases: clear solution, opaque solution, gel and shrunken
gel. Gelation is attributed to the collapse of portions of the polymers from
expanded coils to globules and the subsequent globule aggregation to form
physical crosslinks. The opaque solution to gel transition occurs between 30 and
34 ëC, making these copolymers suitable for injectable gelation applications.
Encapsulated islets of Langerhans from Sprague-Dawley rats showed insulin
secretion function for a month with shorter lag times and higher permeation rates
than alginate matrices more conventionally used for cell encapsulation.
In a different approach, block copolymers of PNIPAAm and poly(ethylene
glycol) (PEG) have been shown to exhibit thermoreversible gelation behavior at
low concentrations (~4%) in water. 69 The copolymers were designed with
PNIPAAm segments as the terminal aggregating blocks connected by central
PEG segments as solvating blocks. When heated, the PNIPAAm terminal
segments undergo their LCST transitions and form intermolecular aggregates
that serve as physical crosslinks connecting the PEG solvation segments.
Copolymers of various architectures can be made including two-arm linear
(PNIPAAm±PEG±PNIPAAm triblock copolymers), and four-arm and eight-arm
branched structures to modulate mechanical and mass transfer properties.
Gelation kinetics are quick and appear to be heat conduction limited. These
polymers have been used in mixtures with PNIPAAm homopolymers to form
cell encapsulating membranes. 70 The presence of PNIPAAm homopolymers
enhanced the extent of crosslinking and the resulting membranes were stable in
water or phosphate buffered saline (PBS) throughout the 60 day duration of the
study. MIN6 cells were not adversely affected by the cell encapsulation process,
and remained functional in response to glucose challenge. Wound-healing
products are under commercial development (see www.rimontherapeutics.com).