Control of the Solubility Transition in Novel Temperature-Responsive Linear Polymers Comprising α-Amino Acid Diamide Derivatives

Abstract

The present study was designed so as to control the temperature with the solubility change of temperature-responsive linear polymers through a modification of the hydrogen bonding of residues linked to the hydrocarbon backbones of polymers. Poly(N-isopropylacrylamide) (PNIPAAm), a well-known temperature-responsive polymer, 1 dissolves in water at below 32˚C and precipitates at over 32˚C. This polymer may be considered to be a pseudopeptide with numerous Nisopropylamide moieties grafted onto the backbone of the alkyl chain and, accordingly, the transition is similar to the thermal denaturation of peptides, the only difference being that the solubility change of the polymer is reversible. This transition, whose temperature is called the lower critical solution temperature (LCST), occurs when the hydrogen bonds between the amide units in the polymer and bulk water are cleaved at temperatures exceeding LCST. A desolvation of the polymer chains results in their aggregation with each other and eventual precipitation in water.Because the aggregation and extension of PNIPAAm related to the water solubility is reversible, the polymer is useful for drug delivery systems, 2,3 a scaffold in cell culturing, 4 thermoresponsive separation in solid extraction 5 and chromatography. 6,7 The regulation of LCSTs of temperature-responsive polymers must be desired for these applications. The most general approaches to LCST control are the co-polymerization of Nisopropylacrylamide with various monomers. Substitution of the N-isopropylamide moieties to butyl ester increases the hydrophobicity of the polymer and lowers LCST. 8,9 On the other hand, substitution to acrylamide increases the hydrophilicity of the polymer and heightens LCST. 10 The temperature-responsive polymers presently available, except for PNIPAAm, require a large temperature shift for complete precipitation. A rational procedure not only for controlling LCST of polymers, but also for making the temperature shift for precipitation small, should thus be developed.In this study, novel vinyl group-terminated monomers having amino acid diamide moieties were prepared, and an examination was made to determine how LCST changes by the Nmethylation of two different amide units and the changes in the α-substituents of the amino amide derivatives.N-Acryloylated L-amino amide monomers were prepared from L-alanine and L-valine both possessing the least hydrophobicity of all natural and chiral amino acids. Substitution of the two amide units in N-terminal amide and C-terminal amide with the N-methyl group should make possible regulation of LCST of polymers derived from L-alanine and L-valine. Either Nmethylation renders an amide hydrogen bond donor. Such chemical substitution significantly reduces the polymer capacity to form hydrogen bonds with the bulk aqueous phase or interresiduary hydrogen bonds, with consequent chain aggregation. A hydrophobic environment shielded from a bulk aqueous solution is thus produced. The inclusion and release of pharmaceuticals for drug delivery syste...