STIMULI-SENSITIVE PARTICLES FOR DRUG DELIVERY - Biologically-Responsive Hybrid Biomaterials - page 162

small intestine due to ionization of the carboxylic acid groups and swelling of the
polymer matrix (Figure 3).
Poly(acrylic acid) copolymers incorporating hydrophobic methyl
methacrylate (MMA) or butyl methacrylate (BMA) monomers were synthesized
where the chemical structure and percentage of the hydrophobic monomer
influenced the polymer's pKa value. For example, Barba et al. synthesized a
range of poly(MMA- co -AA) copolymers with an increasing volumetric ratio of
MMA monomer (0, 25, 30, 40, 50, 60, 70, 75, 100%) and examined their
dissolution at different pH values. Her results showed that the increase in MMA
content in a given polymer increased the pH necessary to dissolve this polymer
(pH 4.0 - 6.8; co-polymers with 75% and higher MMA content were not
soluble), which indirectly indicates the increase in the polymer's pKa with the
increase in MMA content. [7]
Another study by Licea-Claverie et al. showed that the insertion of a variable
number of methylene groups in a poly(MMA) polymer increases the polymer's
pKa (1 - 10 CH 2 spacers; MW range: 43 - 90 KDa; pKa range: 3.8 - 7.3) due to
the formation of hydrophobic microdomains that act as a cross-linker that
minimizes the polymer's dissolution and swelling. [21] One example that clearly
indicates the effect of solution pH on poly(acrylic acid) polymers is reported by
Guan et al. who utilized poly(acrylic acid-9-aminoacridine- co -acrylamide) as a
pH sensor in biological applications. This application depends on the polymer's
(MW 3.5 KDa) ability to change its fluorescence intensity as it transitions from
double to single protonation to amino and finally imino forms as a function of
environment pH (pH 0 - 13.71). [22]
The second group of pH-sensitive polymers with acidic functional groups
includes poly(sulfonic acid) polymers and their derivatives. These polymers have
pendant sulfonate groups (-SO 3 H) with pKa values of 2-3 thus become ionized
over a wide pH range. [23] Polysulfonates are often used as cross-linking agents
of other polymers such as styrene and vinyl-based polymers to tune the pKa of
the formulated particles for a specific application. For example, McCormick et
al. synthesized hydrogel-based particles using 3-[ N -(2-methacroyloyethyl)- N,N-
dimethylammonio] propanesulfonate (MW 49 KDa; polydispersity index (PDI) =
1.04) via controlled polymerization techniques. These particles were synthesized
using an aqueous salt solvent system, which is an unconventional method for
synthesis of acrylic-based polymers that typically require an organic solvent.
These particles are attractive for drug delivery applications due to their
biocompatibility, ease of production in aqueous salt solvent systems, and narrow
distribution of molecular weight. [24]