Poly(caprolactone-b-ethylene glycol-b-caprolactone) (PCL-PEG-PCL) triblock copolymer aqueous solution (>15 wt %) undergoes the sol-gel-sol transition as the temperature increases from 10 to 60 °C. The mechanism and structure-property relationship of the sol-gel transition were investigated. In particular, compared with the PEG-PCL-PEG triblock copolymers recently reported by our group, PCL-PEG-PCL has (1) a synthetic advantage without a hexamethylene diisocyanate coupling step, (2) a wider gel window of over 15-32 wt %, and (3) a larger gel modulus. Both PEG-PCL-PEG and PCL-PEG-PCL polymers are an important progress in the biodegradable thermogelling system in that they can be lyophilized in a powder form, are easy to handle, are easy to redissolve to a clear solution, and show little syneresis through the gel phase.

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Well-defined nanostructural control from biological motifs is gaining attention among materials scientists. We are reporting that the b-sheet structure of L-polyalanine plays a critical role in developing a fibrous nanostructure as well as the sol-to-gel transition of amphiphilic poly(ethylene glycol)-L/or DL-polyalanine diblock copolymers. L-isomers underwent transitions from random coils to b-sheets, and to nanofibers as the polymer concentration increased, whereas the DL-isomer remained as a random coil structure without developing any specific nanostructure. At high polymer concentrations, the aqueous polymer solutions underwent a sol-to-gel transition as the temperature increased, a so called reverse thermal gelation. The L-isomer with a preassembled b-sheet secondary structure facilitates the sol-to-gel transition rather than the DL-isomer with a random coil structure. Thus, only the L-isomer showed a sol-to-gel transition in the physiologically important range of 20-40 C. This report provides fundamental information on the relationship between hierarchical structures of polypeptides and the thermosensitive sol-gel transition of the polypeptide aqueous solution.

Thermosensitive poly(organophosphazenes) bearing α-amino-ω-methoxy-PEG (AMPEG) and hydrophobic l-isoleucine ethyl ester (IleOEt) as side groups have been synthesized, and their reversible sol−gel properties were investigated by means of 31P NMR spectroscopy and viscometer. In an aqueous solution, the poly(organophosphazenes) exhibited four-phase transitions with temperature gradually increasing:  a transparent sol, a transparent gel, a opaque gel, and a turbid sol. The gelation properties of the polymer were affected by several factors such as the composition of substituents, the chain length of AMPEG, and the concentration of the polymer solutions. The more hydrophilic composition of the polymers offers the higher gelation temperature. The gelation of the polymer is presumed to be attributed to the hydrophobic interaction between the side-chain fragments (−CH(CH3)CH2CH3) of IleOEt which act as the physical junction in the polymer aqueous solution.

We reported aqueous solutions of poly(caprolactone-b-ethylene glycol-b-caprolactone) (PCL−PEG−PCL) that underwent sol−gel−sol transition as the temperature increased (Macromolecules 2005, 38, 5260−5265). However, when the triblock copolymer aqueous solution (20 wt %), initially as a sol phase, was left at room temperature (20 °C), it turned into an opaque gel in 1 h. The crystallization of the PCL−PEG−PCL triblock copolymer in water was suggested to be responsible for such a kinetic aspect of the phase transition. In addition, PEG/PCL multiblock copolymers were synthesized by coupling the triblock copolymers using terephthaloyl chloride. Even though both PCL−PEG−PCL triblock and PEG/PCL multiblock copolymer aqueous solutions (20 wt %) instantaneously undergo a sol-to-gel transition upon injection into 37 °C water and their thermogels show a maximum modulus at around body temperature (35−42 °C), the multiblock copolymer shows a pronounced sol phase stability at room temperature. The fundamental difference in such phase behavior between triblock and multiblock copolymers seems to lie in their ability to form micelles at low temperature and high crystallizability of the low molecular weight PCL.

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The hydrolytic properties of the novel biodegradable thermosensitive poly(organophosphazenes) with methoxypoly(ethylene glycol) (MPEG) and amino acid esters as side groups have been studied by means of gel permeation chromatography and 31 P and 1 H NMR spectroscopy and by identification of the hydrolysis products. The polymers substituted with R-amino acid esters were hydrolyzed faster than that with β-amino acid ester. The higher content of the amino acid ester in the polymer backbone caused enhanced hydrolysis. The rate of the polymer degradation decreased in the order of methyl > ethyl > benzyl esters. The polymer hydrolysis occurred more rapidly in both acidic and basic buffer solutions than in the neutral solution. The 31 P NMR spectra of the polymers with high content of glycine ethyl ester showed that the polyphosphazene backbone underwent fragmentation mostly to small molecules after incubation in the buffer solution of pH 10 for 26 days. Phosphates and ammonia were formed as hydrolysis products in most cases. The hydrolytic behaviors of the present thermosensitive polyphosphazenes are consistent with the conventional acid-catalyzed degradation mechanism, and a detailed pathway to their hydrolytic degradation is proposed. The salt and pH effects on the thermosensitivity of the polymers were also examined by measuring their lower critical solution temperature (LCST) in aqueous solutions containing various inorganic and organic salts. When various inorganic salts were added to aqueous solutions of the polymers, their salting-in and salting-out effects were found to be mainly dependent on the anions of the salts. On the other hand, in the case of tetraalkylammonium halides which are organic salts, cations seem to play an important role: the salting-in effect is stronger with increasing alkyl chain of the ammonium salt. The aqueous solutions of the polymers showed higher LCST in the acidic solution than in the neutral and basic buffer solutions.

Poly(alanine) end-capped poly(propylene glycol)−poly(ethylene glycol)−poly(propylene glycol) (PA−PLX−PA) aqueous solutions underwent sol-to-gel transition as the temperature increased. On the basis of FTIR spectra, circular dichroism spectra, 13C NMR spectra, transmission electron microscopic images, fluorescence spectra, and dynamic light scattering studies, increases in the β-sheet conformation of the polyalanine (PA) and dehydration of the poly(propylene glycol)−poly(ethylene glycol)−poly(propylene glycol) (PLX) were suggested as the sol-to-gel transition mechanism. The sol-to-gel transition temperature could be controlled by molecular parameters of the PA−PLX−PA such as molecular weight of PA, molecular weights of PLX, and l-Ala/dl-Ala ratio. The PA−PLX−PA was significantly degraded in the subcutaneous layer of rats over 15 days; however, it was stable in phosphate buffer saline over the same period of time. Poly(propylene glycol)/poly(ethylene glycol) block copolymers suffer from short gel duration for biomedical applications, whereas the current polypeptide-based polymer is unique in that it shows prolonged (>15 days) gel duration and the sol-to-gel transition involves the secondary structural change of the polypeptide.