Polymeric hydrophilic polymers in targeted drug delivery - Artificial Cells, Cell Engineering and Therapy - page 55

grafted PEG chains were used to make a pH-sensitive oral delivery system for
calcitonin; release was found to be swelling-controlled zeroth order. 184,185
pH-sensitive crosslinked hydrogels that swell at neutral pH to release a drug
are also a common physical form for oral delivery, 186 which is sometimes
combined with enzymatic degradation to further enhance targeting to the colon.
Bajpai and Saxena 187,188 made interpenetrating starch/PAA hydrogels. At
pH 2.0, minimal swelling and therefore minimal drug release was observed due
to complex formation. At pH 7.4, the hydrogel swells, more rapid drug release is
observed which is accelerated in the presence of amylase that enzymatically
degrades the starch component of the hydrogel. Hydrogels have also been made
by crosslinking with azoaromatic groups that are susceptible to degradation by
azoreductase in the colon. pH-responsive hydrogels crosslinked in this way are
collapsed in the stomach, swollen in the small intestine, and degraded in the
colon to localize drug targeting to the colon. 50,51 To optimize swelling and
release characteristics, the concept has been further refined to include inter-
penetrating networks of an enzymatically degradable network and a non-
degradable network. 189 Azo-polysaccharide gels have also been made for colon
delivery applications. 190

Intracellular targeting

An exciting application of pH-responsive polymers is in intracellular targeting,
particularly for gene delivery to the nucleus. Endocytosed drug carriers are
enclosed in endosomes, which have acidic environments and must escape the
endosomes into the cytoplasm before uptake by the nucleus can occur. 191 One
approach exploits the pH-dependent protonation of polybasic polymers of the
appropriate pK b ; protonation of these polymers at endosomal pH results in
enhanced interaction with negatively charged membrane phospholipids and
membrane disruption. 192,193 A more extensively investigated approach is based
on pH-responsive acidic polymers. Hoffman, Stayton and coworkers 194 have
designed two types of pH-responsive acidic polymers that are hydrophobic and
insert into and disrupt lipid membranes in the low pH environment of endosomal
compartments, but have no membrane disruptive activity in the neutral pH
environment of the cytoplasm. The polymers in the first class have both
carboxylate and hydrophobic groups in their backbone. Hemolytic studies with
red blood cells with a number of such polymers showed that membrane
disruption activity and the pH of maximum activity can be controlled by
tailoring the molecular structure of the polymer. 195 A physical mixture of
poly(propylacrylic acid) (PPAA) along with a cationic lipid dioeyltrimethyl-
ammonium propane (DOTAP) and pCMV plasmid DNA was shown to
significantly enhance gene expression and fraction of transfected NIH3T3
fibroblast cells compared with the DOTAP/pCMV plasmid DNA control
group. 196 Incubation of Jurkat T-cell lymphoma cell line with a fluorescently