Hideki Matsuoka

AB-type and BAB-type betaine block copolymers composed of a carboxybetaine methacrylate and a sulfobetaine methacrylate, PGLBT-b-PSPE and PSPE-b-PGLBT-b-PSPE, respectively, were synthesized by one-pot RAFT polymerization. By optimizing the concentration of the monomer, initiator, and chain transfer agent, block extension with precise ratio control was enabled and a full conversion (~99%) of betaine monomers was achieved at each step. Two sets (total degree of polymerization: ~300 and ~600) of diblock copolymers having four different PGLBT:PSPE ratios were prepared to compare the influence of block ratio and molecular weight on the temperature-responsive behavior in aqueous solution. A turbidimetry and dynamic light scattering study revealed a shift to higher temperatures of the cloud point and micelle formation by increasing the ratio of PSPE, which exhibit upper critical solution temperature (UCST) behavior. PSPE-dominant diblocks created spherical micelles stabilized by PGLBT motifs, and the transition behavior diminished by decreasing the PSPE ratio. No particular change was found in the diblocks that had an identical AB ratio. This trend reappeared in the other set whose entire molecular weight approximately doubled, and each transition point was not recognizably impacted by the total molecular weight. For triblocks, the PSPE double ends provided a higher probability of interchain attractions and resulted in a more turbid solution at higher temperatures, compared to the diblocks which had similar block ratios and molecular weights. The intermediates assumed as network-like soft aggregates eventually rearranged to monodisperse flowerlike micelles. It is expected that the method for obtaining well-defined betaine block copolymers, as well as the relationship of the block ratio and the chain conformation to the temperature-responsive behavior, will be helpful for designing betaine-based polymeric applications.

Cationicrandom copolymers (PCm) consisting of2-(methacryloyloxy)ethyl phosphorylcholine (MPC; P) with methacroylcholinechloride (MCC; C) and anionic random copolymers (PSn) consisting of MPC and potassium 3-(methacryloyloxy)propanesulfonate(MPS; S) were prepared via a reversible addition-fragmentationchain transfer method. "m" and "n" represent the compositions (mol %) of the MCCand MPS units in the copolymers, respectively. The degrees of polymerizationfor the copolymers were 93-99. Water-soluble MPC unit containsa pendant zwitterionic phosphorylcholine group whose charges are neutralizedin pendant groups. MCC and MPS units contain the cationic quaternaryammonium and anionic sulfonate groups, respectively. The stoichiometricallycharge-neutralized mixture of a matched pair of PCm and PSn aqueous solutions resulted in the spontaneousformation of water-soluble PCm/PSn polyion complex (PIC) micelles. These PIC micelles have the MPC-richsurface and MCC/MPS core. These PIC micelles were characterized using H-1 NMR, dynamic and static light scattering, and transmissionelectron microscopic measurements. The hydrodynamic radius of thesePIC micelles depends on the mixing ratio of the oppositely chargedrandom copolymers. The charge-neutralized mixture formed maximum-sizePIC micelles.

The effect of the hydrophobicity of the core part and salt on the temperature responsiveness of polymeric micelles composed of sulfobetaine and hydrophobic blocks was investigated. Poly(sulfopropyl dimethylammonium propylacrylamide) (PSPP) was used as the sulfobetaine; poly(2-ethylhexyl acrylate) (PEHA), poly(n-butyl acrylate) (PnBA), poly(ethyl acrylate) (PEA), or poly(n-hexyl acrylate) (PnHA) was used as the hydrophobic polymer. Measurement of the transmittance revealed that the transition temperature of the sulfobetaine homopolymer could be controlled by adjusting the concentration, the degree of polymerization (DP), and the concentration of the added salt. The effect of the anionic species of the added salt due to the chemical structural properties of the sulfobetaine chain was consistent with the order of ionic species with strong structural destruction in the Hofmeister series. The temperature response and micelle formation behavior of the polymeric micelles according to the hydrophobicity of the core part and the preparation method were examined by static light scattering (SLS), fluorescence measurement with pyrene, dynamic light scattering (DLS), transmittance, and atomic force microscopy (AFM). Micelles that had EHA (solubility in water was 0.01 g/100 mL) as the core and did not show temperature responsiveness expressed temperature responsiveness at a lower hydrophobicity (solubility of nBA in water was 0.14 g/100 mL). nBA-b-SPP did not show temperature responsiveness due to the block ratio. However, when micelles were prepared by dialysis, smaller and more stable micelles could be formed in an equilibrium state, and temperature responsiveness was observed. Their transition temperature can be controlled by adjusting the ratio of the sulfobetaine blocks, the hydrophobicity of the core part, the concentration of the polymer aqueous solution, and the concentration of the added salt. Furthermore, like the sulfobetaine homopolymer, the effect depended on the anionic species of the added salt.

The behavior of micelle formation in the sulfobetaine-containing entirely ionic block copolymer/ionic homopolymer system and its functional expression (temperature responsivity) were investigated. Poly(sulfopropyl dimethylammonium propylacrylamide) was used as the sulfobetaine, poly[3-(methacrylamido)propyl trimethylammonium chloride] was used as the cationic polymer, and poly(p-styrenesulfonic acid sodium salt) was used as the anionic polymer. The changes in transition temperature with the concentration and the behavior of micelle formation in the block-/cationic homopolymer and block-/anionic homopolymer system were compared and examined by transmittance, dynamic light scattering, atomic force microscopy, and ¹H nuclear magnetic resonance. Only block-/cationic homopolymer systems with a core–shell (polyion complex–sulfobetaine) structure showed temperature responsivity of upper critical solution temperature type, and the responsiveness was dependent on the concentration. On the other hand, the block-/anionic homopolymer system had a core–shell structure at a concentration of 0.05 wt %, but temperature responsiveness was not observed at this concentration. At higher concentrations, electrostatic attraction caused the anionic homopolymer and block copolymer to interact as a whole, resulting in a loss of responsiveness. When the ionic homopolymer had a higher degree of polymerization than the sulfobetaine, it could not form a core–shell structure by interacting with the sulfobetaine and ionic polymer moieties of the block copolymer, thus resulting in the loss of responsiveness. The block-/ionic homopolymer system prepared by the reforming method through dialysis formed uniform and small micelles but lost responsiveness due to morphological stability and electrostatic interaction between the block copolymer and ionic homopolymer.

Temperature-responsive polyion complex (PIC) micelles were prepared by using two diblock copolymers composed of a sulfobetaine chain (poly(sulfopropyldimethylammonium propylacrylamide), PSPP) and ionic chains (poly(sodium styrenesulfonate), PSSNa, or poly(3-(methacrylamido)propyltrimethylammonium chloride), PMAPTAC). Because the core is PIC and the shell is sulfobetaine with UCST-type temperature response, the corona expands and contracts in response to temperature. To control the size and uniformity of the PIC micelles, the collapse of PIC micelles by salt addition and the reforming behavior by dialysis were investigated by transmittance, DLS, TEM, AFM, and ¹H NMR measurements. Investigation of the ionic species dependence of the added salt in the collapse behavior of PIC micelles revealed that it was dependent on the anionic species, although no dependence on the cationic species was observed. Its effectiveness was in the order of I^– > Br^– > Cl^– > F^–, which is in agreement with the order of ionic species with strong structural destruction in the Hofmeister series. Heterogeneous and large PIC micelles were formed by the simple mixing method. They collapsed by salt addition and were reformed by the dialysis method to form uniform and smaller PIC micelles. This is considered to be because a uniform and smaller micelle is formed to reform in equilibrium state by dialysis. The temperature response of PIC micelles formed by the simple mixing method and PIC micelles reformed by dialysis showed nearly the same temperature–transmittance curves. These results indicate that the temperature response of PIC micelles is affected by the concentration rather than the hydrodynamic radius. Furthermore, the stability of PIC micelles was found to be affected by the concentration temperature (the temperature at the time of concentration).

We investigated the kinds of complexes sulfobetaine surfactant and ionic polymer formed using lauramidopropyl hydroxysultane (LAPHS) as a sulfobetaine surfactant, poly(sodium styrenesulfonate) (PSSNa) as the anionic polymer and poly[3-(methacrylamido)propyl trimethylammonium chloride] (PMAPTAC) as the cationic polymer. The fundamental properties of LAPHS at various salt concentrations were estimated by various measurements, and it was confirmed that the LAPHS micelles alone did not show temperature responsiveness. The presence of large aggregates in addition to LAPHS micelles was confirmed in the aggregates prepared by adding PSSNa to LAPHS at a charge ratio of 1:0.5, 1:1, and 1:2. However, the aggregates could not be formed when the salt concentration was high or when a monomer was added instead of the polymer. This revealed that the cation part of sulfobetaine, which is the shell of LAPHS micelles, and the anion part of PSSNa electrostatically interacted with each other to form a large aggregate. On the other hand, unlike the case of LAPHS micelles alone and the aggregate consisting of LAPHS micelles and PSSNa, the aggregate of LAPHS micelles and PMAPTAC showed an unprecedented phenomenon of “clear → opaque → clear” with increasing concentration in the concentration range above CMC. The change in the transition temperature due to the change of concentration was a factor. Additionally, we confirmed that the transition temperature was lowered when the concentration was higher than CMC or the salt concentration was increased, and the transition temperature was increased when the PMAPTAC with a high degree of polymerization was added. These results suggested that the LAPHS micelles and the ionic polymer form an aggregate, and the temperature responsivity can be expressed by the interaction with the cationic polymer.

Sulfobetaine, a type of zwitterionic polymer, is a highly biocompatible polymer with temperature responsiveness of the upper critical solution temperature (UCST) type. The objective of this research was to construct polyion complex (PIC) micelles in the shell of sulfobetaine that had these properties. We used poly(sulfopropyl dimethylammonium propylacrylamide) (PSPP) as sulfobetaine, poly(sodium styrenesulfonate) (PSSNa) as the anionic polymer and poly[3- (methacrylamido)propyl trimethylammonium chloride] (PMAPTAC) as the cationic polymer. The fundamental properties of the sulfobetaine-containing polymer and the complex were investigated in order to construct micelles in which corona expands and contracts in response to temperature change. Changes in cloud point were observed from transmittance for sulfobetaine homopolymers with different degrees of polymerization and concentration and aqueous solution of temperatureresponsive diblock copolymers with different concentrations. The concentration and degree of polymerization dependencies on temperature responsivity were determined. Then we mixed two diblock copolymer aqueous solutions which did not have temperature responsivity so that the charge numbers of anions and cations became equal, and the temperature responsivity and the formation of micelles were confirmed from 1H NMR, DLS and transmittance. This confirmed the formation of PIC micelles with temperature responsivity. The diblock copolymer did not have temperature responsivity due to the influence of block ratio by introduction of ionic chain. However, it is considered to have temperature responsivity because the ionic chain becomes the core when PIC micelles are formed. Furthermore, the PIC micelles with temperature responsivity also had a degree of polymerization and concentration dependencies.

The solution behavior of the double polybetaine block copolymer poly(2-((2-(methacryloyloxy)ethyl)dimethylammonio)acetate)-block-poly(3-((2-(methacryloyloxy)¬ethyl)dimethylammonio)propane-1-sulfonate (PGLBT-b-PSPE) in sodium halide aqueous solutions was investigated. In the presence of salt ions, the unimer-to-micelle transition of PGLBT-b-PSPE that originated by Coulombic attraction between PSPE motifs was suppressed and shifted to much lower temperatures. The transition was more hindered by increases in the salt concentration due to additional counterion binding on the ionized site of PGLBT-b-PSPE chains which screens the dipole-dipole attractions. The specific ion effect was investigated on four different halides, Cl-, Br-, I- and F-. Cl- and two chaotropes (Br- and I-) apparently prevented micelle formation, and the hindering effectiveness on the PSPE pairing followed the general Hofmeister series of anions: I- > Br- > Cl-. More chaotropic anions strongly maintained the polymer chains in a fully hydrated state when the same amount of salts was incorporated. However, F-, which is classified as kosmotrope, only did small contribution on lowering the transition point and led to abrupt transition without showing a gradual phase change prior to the transition. The variations of hydrodynamic radius and zeta potentials of unimers and micelles gave hints of the solvation state of salt-incorporated PGLBT-b-PSPEs in each state. These results suggest that chaotropes tend to exist in the vicinity of the diblock polybetaine chain surface thus prominently influenced the thermoresponsive solution behavior, whereas kosmotropes prefer water molecules and cause minor changes in the PGLBT-b-PSPE aqueous solution.