Introduction. Micelles formed from block copolymeric surfactants have recently attracted a lot of attention as drug delivery systems. When hydrophobic drugs are loaded into the core of the micelles, small reservoirs can be formed with virus-like dimensions. A few of the recently reported block copolymers for this application have a hydrophilic block consisting of poly(ethylene glycol) (PEG) and a hydrophobic block that is biodegradable, like poly(lactic acid)1-3 or poly(â-benzyl L-aspartate).4-7 In another approach, polymeric micelles have been constructed from a hydrophilic block of poly(N-isopropylacrylamide) (PNIPAAm) and a hydrophobic block of polystyrene.8 PNIPAAm is wellknown for its thermosensitive properties in water and is therefore widely applied. Below 30.9 °C, its lower critical solution temperature (LCST) in water, the polymer is soluble, whereas phase separation takes place when the temperature is raised above the LCST. The LCST of PNIPAAm can be adjusted by copolymerizing NIPAAm with acrylamide or other hydrophilic comonomers. Through copolymerization of NIPAAm with acrylic cross-linkers, hydrogels have been prepared that may be applied in the biomedical field.9-10 We here report on the synthesis of block copolymers composed of PEG-PNIPAAm as well as their micellization behavior. The design of these copolymers is based on the hydrophobic character of PNIPAAm above its LCST in water. Combined with the hydrophilic properties of PEG, thermosensitive micelles may be obtained. Such micelles may dissolve due to the loss of the micellization capacity when the temperature is decreased below the LCST of the PNIPAAm in the block copolymer. After administration and arrival of the micelles at the target in the body, for instance a tumor, a burst of a loaded drug could be achieved by local hypothermia. Results and Discussion. Block copolymers of PNIPAAm and PEG were synthesized according to the method shown in Scheme 1. A ceric ion redox system11-14 was applied for the formation of radicals at the terminal carbons of PEG. These radicals are used for the polymerization of NIPAAm, providing a direct route to A-B-A block copolymers using HO-PEG-OH and A-B block copolymers if CH3O-PEG-OH is applied. These block copolymers differ from PNIPAAm-PEG graft copolymers, which have been synthesized using an amido condensation reaction between P(NIPAAm-co(acryloxy)succinimide) and diamino-PEG.15 These graft copolymers showed thermoreversible gelation at 35 °C. To prepare the AB and ABA block copolymers, a solution of ammonium cerium(IV) nitrate in 4 mL of 1 N nitric acid was added to an aqueous solution of PEG and NIPAAm at 50 °C at an initial molar ratio of [Ce]0/ [HO end groups] of 1.2/1, to yield block copolymers with a narrow molecular weight distribution (Table 1).16 Termination of the polymerization occurs through reaction with another ceric ion. Radical recombination has not been observed.14 Aqueous solutions of PNIPAAm oligomers of at least three repeating units already exhibit a LCST, which implies that the polymer will phase separate in water above 30.9 °C. This phenomenon could be observed almost immediately after the addition of the ceric solution to the reaction mixture. The mixture turned from clear to milky, indicating the rapid formation of micelles by the growing block copolymers. The polymerization is therefore thought to occur in four stages. During the first stage a radical is formed through oxidation at the PEG-OH end group by the ceric ion and the ceric ion is reduced. In the second stage the polymerization of NIPAAm starts, whereafter in the third stage the block copolymers acquire the micellization capacity and start to form micelles. In the last stage the polymerization proceeds within the core of the micelles. To verify the occurrence of in situ emulsion polymerization, a small amount of the cross-linker ethylene glycol dimethacrylate (EGDMA) was added after 5 min reaction time. In this stage of the polymerization, phase separation has taken place, indicating that the micelles are already formed. If the propagation takes place outside the core of the micelles, the addition of a crosslinker to the reaction mixture should result in a hydrogel, whereas polymerization in the core of the micelles should result in cross-linked nanospheres. Because the mixture did not afford a hydrogel, a sample of the cross-linked micelles in the reaction mixture was taken for TEM analysis and dynamic light scattering. TEM showed separate micelles with a spherical shape of approximately 120 nm (Figure 1),17 thereby proving that the propagation takes place in the core of the micelles. When the same samples were analyzed with dynamic light scattering at 37 °C in water, particle sizes were found to be 89.0 ( 1.1 nm, whereas at 25 °C the size of the particles was 367.7 ( 10.2 nm. This expansion of the cross-linked micelles to 4 times their size when cooled below the LCST is a good indication of the thermosensitive behavior of the PNIPAAm core and shows its expansion and shrinkage according to a change in temperature. On the basis of the results of the TEM pictures, we assume that the non-cross-linked micelles will be spherical in shape as well. All block copolymers show a low critical micelle concentration (CMC) (Table 2)18 in water. No large differences were found between the CMC’s of the diblock copolymers. For the triblock copolymers a somewhat lower CMC value is observed. The presence of a small amount of diblock copolymer may account for a lower CMC value.19 The micelles formed from polymers with a Mn,PNIPAAm/Mn,PEG ratio of 1/3 exhibit reversible thermosensitive behavior (Table 1). This means that above the LCST micelles form while below the LCST the polymers completely dissolve. A similar behavior was observed for the sol-gel transition of PEG grafted copolymers described earlier by Yoshioka et al.15 Dynamic light scattering measurements revealed no ag† Department of Chemical Technology and Institute for Biomedical Technology at the University of Twente. ‡ Department of Pharmaceutics at the University of Utrecht. 8518 Macromolecules 1997, 30, 8518-8520