Water‐Soluble Thermoresponsive α‐Helical Polypeptide with an Upper Critical Solution Temperature: Synthesis, Characterization, and Thermoresponsive Phase Transition Behaviors

Abstract

Water‐soluble polypeptides bearing 1‐alkylimidazolium (methyl or n‐butyl) and various counter‐anions (i.e., Cl−, I− or BF4−) are prepared by ring‐opening polymerization of γ‐4‐chloromethylbenzyl‐l‐glutamate‐based N‐carboxyanhydride (3), post‐polymerization of poly(γ‐4‐chloromethylbenzyl‐l‐glutamate) (4), and ion‐exchange reaction. Circular dichroism (CD) analysis reveals that the resulting polypeptides adopt an α‐helical conformation in water with a fractional helicity in the range of 30%–56% at 20 °C and exhibit good conformational stability against temperature variations. The polypeptides exhibit lower critical solution temperature (LCST)‐type or upper critical solution temperature (UCST)‐type transitions in organic solvents or in water. The UCST‐type transition temperature (Tpt) in water is independent on the molecular weight, yet it decreases upon addition of NaCl and increases upon addition of NaI or NaBF4, suggesting a mainly electrostatic interaction mechanism.

Synthesis, Characterization, and thermoresponsive properties of Helical Polypeptides Derivatized from Poly(γ−4‐(3‐chloropropoxycarbonyl)benzyl‐L‐glutamate)

“…The f H values was in the sequence of I − > Cl − , suggesting that counter‐anions with smaller ionic radius and higher charge density may further increase the charge repulsions between adjacent imidazolium groups and subsequently destabilize the α ‐helical conformation. This result was consistent with our previous work …”

“…The T U s were independent with the polymeric main‐chain length and dramatically decreased at low concentration (e.g., 4 mg mL −1 ), suggesting a mechanism of the electrostatic interactions at the transition temperatures [Fig. (b–e)] . In methanol, PBLG 58 ‐OEG 2 , and PBLG 58 ‐OEG 3 with different OEG side‐chains showed reversible UCST‐type phase transition behaviors at 40.2 and 33.1 °C, respectively, at the concentration of 1 mg mL −1 [Fig.…”

“…For example, high molecular weight polymethacrylamides used in long‐circulating delivery systems were not able to eliminate from the organisms (e.g., kidney), thus, they accumulated in the body and lead to toxic side effects . Recently, thermoresponsive polypeptides have gained significant attention due to their promising properties including biodegradability, biocompatibility and considerable chemical diversity with regard to the numerous amino acids (e.g., L ‐glutamic acid, L ‐lysine, and L ‐cysteine) . The covalent modification of polymers using poly(ethylene glycol) (PEG), namely peglation, has achieved interesting properties, such as nontoxicity and thermoresponsive property .…”

“…For example, Li and co‐workers reported the LCST‐type phase transition behaviors of peglated poly( L ‐glutamates) or poly( L ‐cysteine) prepared from ring‐opening polymerization of peglated N ‐carboxyanhydrides (NCAs) . Our recent work has demonstrated that helical polypeptides bearing 1‐butylimidazolium groups and I – or counter anions exhibited UCST‐type transitions in water . Nevertheless, the structure–property relationship between thermoresponsive polypeptides and their solution phase transition behaviors still remains unclear.…”

Thermoresponsive Polymers with Lower Critical Solution Temperature‐ or Upper Critical Solution Temperature‐Type Phase Behaviour Do Not Induce Toxicity to Human Endothelial Cells

“…However, to the best of our knowledge, there is lacking information about thermoresponsive polymers on endothelial injury and inflammatory responses. In this study, we selected some of our recently synthesized thermoresponsive polymers with LCST-and/or UCST-type phase behaviour [10,11] and tested the toxicity of the polymers to human vein endothelial cells (HUVECs). Cytotoxicity and inflammatory response were considered as the main endpoints.…”