Design of smart nanogels that respond to physiologically relevant pH values and temperatures.

Herein, we report the synthesis and characterization of monodisperse 'smart' nanogels that exhibit a sharp volume phase transition at physiologically relevant temperatures and pH values. The nanogels were prepared by precipitation copolymerization of N-isopropylacrylamide (NIPAAm) and propylacrylic acid (PAA). Briefly, the reaction was performed using a PAA feed of between 0 and 10 mol% in the presence of a crosslinker at 70 degrees C. The size of the nanogel particles was determined as a function of pH and temperature using dynamic light scattering (DLS). At room temperature, the NIPAAm-PAA nanogels were discrete, spherical structures with diameters ranging from 200 to 250 nm. The hydrodynamic diameter of the nanogels decreased to ca. 100-150 nm when the solution temperature was increased to 37 degrees C. At 37 degrees C, when the pKa was below that of the NIPAAm-PAA (ca. 6.0), the gels collapsed and aggregated. However, at 37 degrees C and a physiological pH of 7.4, the nanogels did not fully collapse due to the charge-charge repulsion derived from the ionized carboxyl groups of the PAA. Similar phase transition behavior was observed with the corresponding linear copolymers. Thus, such nanogel particles could be useful for releasing drugs in regions of local acidosis, including sites of infection, tumors, ischemia, and intracellular endosomes.

Poly(N-isopropylacrylamide-co-propylacrylic acid) copolymers that respond sharply to temperature and pH.

Temperature- and pH-sensitive random copolymers of N-isopropylacrylamide (NIPAAm) and propylacrylic acid (PAA) were prepared using the reversible addition fragmentation chain transfer (RAFT) polymerization method. The lower critical solution temperatures (LCSTs) (or phase separation temperatures) of the NIPAAm-co-PAA copolymer solutions were measured by the cloud-point method. At slightly acidic conditions, the LCST decreased with increase in PAA content, which suggests that the hydrophobic propyl group of PAA has a greater influence on the LCST than the polar carboxylic acid group at those conditions. An increase of pH led to a significant increase in LCST of the copolymers due to the ionization of the -COOH group. The LCSTs were studied as a function of copolymer composition over the pH range from 5.0 to 7.0. Because the pK(a) of the polymers can be tuned to fall close to neutral pH, these polymer compositions can be designed to have phase transitions triggered near physiological pH or at slightly acidic pH values that fall within acidic gradients found in biology. The NIPAAm-co-PAA copolymers thus display tunable properties that could make them useful in a variety of molecular switching and drug delivery applications where responses to small pH changes are relevant.