STIMULI-SENSITIVE PARTICLES FOR DRUG DELIVERY - Biologically-Responsive Hybrid Biomaterials - page 161

the polymer, which in turn depends on the polymer's composition and molecular
weight. [17]
Hoffman, Stayton and coworkers characterized the pH-dependent
membrane-destabilizing activity of poly(acrylic acid) (PAA), poly(methyl acrylic
acid) (PMAA), poly(ethyl acrylic acid) (PEAA), poly(propyl acrylic acid)
(PPAA), and poly(butyl acrylic acid) (PBAA) polymers. Their results showed
that the systematic increase in the length of the hydrophobic alkyl group by one
methylene unit (CH 2 ) results in an increase in the polymer's pKa value and
consequently affects the pH at which this polymer switches from a hydrophilic
conformation to a hydrophobic and membrane-destabilizing one. This was
evident by the increase in the polymer's pKa from 6.3 for PEAA to 6.7 for PPAA
to 7.4 for PBAA, which limited the utility of PBAA as a carrier for drug delivery
because of its non-specific membrane-destabilizing activity at physiologic pH.
[18, 19] Duncan et al. showed that the pH-dependent membrane-destabilizing
activity of these polymers decreases with the decrease in polymer concentration,
which indicates that it is a concentration-dependent effect. [20] Poly(acrylic acid)
polymers have been formulated into drug-loaded particles for oral drug delivery
where they retain their therapeutic cargo in the acidic environment of the
stomach but release the encapsulated drug in the alkaline environment of the

(A) (B)

pH increase

pH decrease

Acidic pH Environment Neutral or Alkaline pH Environment

Fig. 3. A schematic drawing of a drug-loaded particle formulated using poly(acrylic acid)
polymers. (A) The pendant carboxylic acid groups are unionized in the acidic environment of the
stomach and the particle retains the loaded drug. Whereas, in neutral and alkaline environments of
the small intestine (B), the pendant carboxylic acid groups become ionized, the particle swells due
to electrostatic repulsion of the ionized groups and release the loaded drug molecules into the
surrounding medium.