Effect of molecular architecture of hydrophobically modified poly(N-isopropylacrylamide) on the formation of thermoresponsive core-shell micellar drug carriers.

Terminal-incorporation of hydrophilic or hydrophobic groups dramatically influences the phase transition of poly(N-isopropylacrylamide) (PIPAAm) because of a critical role of the polymer chain ends in initiation of the phase transition. Incorporation of an amino or hydroxyl group to one end of PIPAAm remarkably raised the LCST (lower critical solution temperature) and slowed down the rate of the phase transition, and these effects were more pronounced as the mole fraction of hydrophilic groups increased compared to the random copolymers of PIPAAm and hydrophilic co-monomers, such as acrylic acid (AAc) or dimethylacrylamide (DMAAm). Hydrophilic effects were more remarkable for hydroxyl groups, due to stronger hydrogen bonding with water. Terminal-modification (hydrophobization) was also more effective in producing hydrophobic effects on the PIPAAm phase transition in comparison with PIPAAm copolymers that were randomly modified along the main chain with hydrophobic co-monomers. Moreover, terminal-located hydrophobic groups were able to form hydrophobic microdomains that were clearly isolated from PIPAAm chains in aqueous media by the aggregation of hydrophobic segments. As a result, the obtained micellar aqueous solution showed the same LCST as pure PIPAAm, while the PIPAAm random copolymer with hydrophobic co-monomers formed incompletely separated microdomains. The LCST for this random copolymer was reduced with increasing hydrophobic co-monomer mole fraction. Hydrophobically terminal-modified PIPAAm produced thermo-responsive core-shell structures that exhibited the same LCST and the same thermal response rate as those of free linear PIPAAm chains. Such polymeric micellar structures show reversible thermoresponsive aggregation/dispersion and deformation/reformation in heating/cooling cycles through the LCST for pure PIPAAm. These properties indicate the possibility of using such a system as a thermoresponsive drug carrier with double targeting mechanisms, in both passive and active manners.