Articles A New Double-Responsive Block Copolymer Synthesized via RAFT Polymerization: Poly(N-isopropylacrylamide)-block-poly(acrylic acid) Christine M. Schilli, ² Mingfu Zhang, ² Ezio Rizzardo, ‡ San H. Thang, ‡ (Bill) Y. K. Chong, ‡ Katarina Edwards, § Go1 ran Karlsson, § and Axel H. E. Mu1 ller* ,² Makromolekulare Chemie II, Universita¨ t Bayreuth, 95440 Bayreuth, Germany, CSIRO Molecular Science, Bag 10, Clayton South, Victoria 3169, Australia, and Department of Physical Chemistry, Uppsala University, Box 579, 75123 Uppsala, Sweden Received December 4, 2003; Revised Manuscript Received July 23, 2004 ABSTRACT: Poly(N-isopropylacrylamide)-block-poly(acrylic acid), PNIPAAm-b-PAA, with low polydis- persity was prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization in methanol. The block copolymers respond to both temperature and pH stimuli. The behavior of the double- responsive block copolymers in solution was investigated by dynamic light scattering, temperature-sweep NMR, cryogenic transmission electron microscopy, and IR spectroscopy. The block copolymers form micelles in aqueous solutions in dependence of pH and temperature. Cloud point measurements indicated the formation of larger aggregates at pH 4.5 and temperatures above the lower critical solution temperature (LCST) of PNIPAAm. The solution behavior is strongly influenced by hydrogen bonding interactions between the NIPAAm and acrylic acid blocks. Introduction Block copolymers consisting of poly(acrylic acid), PAA, and poly(N-isopropylacrylamide), PNIPAAm, are of interest for a variety of reasons. First of all, poly(acrylic acid) is a polymer that responds to changes in pH and ionic strength with changes in its properties; e.g., at pH < 4 precipitation occurs in aqueous solutions due to protonation of the carboxylate groups, which renders the polymer sparsely soluble in water. Poly(N-isopropyl- acrylamide), PNIPAAm, shows lower critical solution temperature (LCST) behavior in aqueous solutions, and a sharp phase transition is observed at 32 °C in water. 1 The combination of pH-responsive PAA and temper- ature-responsive PNIPAAm creates systems that re- spond to combined external stimuli. Conjugation of drugs or proteins to PNIPAAm-b-PAA generates ther- mo- and pH-responsive entities that can be addressed through external stimuli. Furthermore, PNIPAAm-b-PAA may form micelles or other aggregates depending on solvent, temperature, pH, and block lengths (cf. Figure 1). Temperature- or pH-sensitive micelles could eventually be used to confer bioadhesive properties; pH-sensitive micelles might be applied in the drug delivery to tumors, inflamed tissues, or endosomal compartments, where a pH lower than that in normal tissue is found. 2 For that reason, we synthesized the corresponding block copolymers by reversible addition-fragmentation chain transfer (RAFT) polymerization of NIPAAm in the presence of a PAA RAFT agent synthesized earlier. 3 We investigated the behavior of these block copolymers in DMF and aqueous solution using turbidimetry, dynamic light scattering, cryogenic transmission electron mi- croscopy, Raman and IR spectroscopy. Experimental Section Materials. N-Isopropylacrylamide (Aldrich, 97%) was re- crystallized twice from benzene/hexane 3:2 (v:v) and dried under vacuum prior to use. Azobis(isobutyronitrile) (AIBN, Fluka, purum) was recrystallized twice from methanol. Poly- (acrylic acid) (polymeric RAFT agent) was obtained from RAFT * Corresponding author. Fax: +49-921-553393. E-mail: axel. mueller@uni-bayreuth.de. ² Universita¨ t Bayreuth. ‡ CSIRO Molecular Science. § Uppsala University. Figure 1. Possible modes of aggregate formation for PNIPAAm-b-PAA in aqueous solution in dependence of pH and temperature. 7861 Macromolecules 2004, 37, 7861-7866 10.1021/ma035838w CCC: $27.50 © 2004 American Chemical Society Published on Web 09/21/2004