Thermoresponsive Polypeptides from Pegylated Poly-l-glutamates

Abstract

The synthesis and characterization of new thermoresponsive pegylated poly-L-glutamate (poly-L-EG(x)Glu) are described. The obtained polypeptides display low critical solution temperature (LCST) behaviors in water, and the LCST can be tuned via copolymerization of different amino acid monomers at varied molar ratio. This is the first example of thermoresponsive polypeptide made from ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs). Circular dichroism characterizations reveal that the secondary structure of poly-L-EG(x)Glu depended on the chain length of the side chain.

Role of Side-Chain Molecular Features in Tuning Lower Critical Solution Temperatures (LCSTs) of Oligoethylene Glycol Modified Polypeptides

“…By comparison, analogs of α-helical thermoresponsive polypeptides that possess disordered conformations, which have much greater entropy of mixing with water, are fully water soluble and do not have LCSTs. 13 Similar behavior was also observed here for a sample of 2b prepared from racemic poly(DL-methionine) (i.e. rac-2b, see SI Figures S1 and S4).…”

“…8 Initial efforts in this area focused on polymethacrylates and polyacrylates containing OEG side-chain groups, [9][10][11][12] and now this motif has been used to prepare other types of thermoresponsive polymers, such as OEG containing polypeptides. [13][14][15][16][17][18][19][20][21][22][23] Thermoresponsive polypeptides are desirable compared to other polymers since they can degrade in living systems, which is advantageous for biological and medical applications. OEG containing thermoresponsive polypeptides have been prepared using a variety of methods, using different core amino acid residues, and also with a wide range in number of ethylene glycol (EG) repeats and means of their attachment to different residues.…”

“…OEG containing thermoresponsive polypeptides have been prepared using a variety of methods, using different core amino acid residues, and also with a wide range in number of ethylene glycol (EG) repeats and means of their attachment to different residues. [13][14][15][16][17][18][19][20][21][22][23] While many thermoresponsive polypeptides have been described that possess LCSTs, there is limited understanding of how the molecular features of different side-chain structures affect solution properties. For most thermoresponsive polypeptides, LCST is mainly adjusted by variation of the number of side-chain EG repeats, with less attention given to the components of different linkages.…”

“…For most thermoresponsive polypeptides, LCST is mainly adjusted by variation of the number of side-chain EG repeats, with less attention given to the components of different linkages. [13][14][15][16][17][18][19][20][21][22][23] Hence, it can be difficult to understand the differences in thermoresponsive properties of OEG containing polypeptides prepared using different amino acids and side-chain linkages. Here, we have utilized a recently developed synthetic methodology that allows facile modification of polypeptide sidechains 24,25 to prepare a series of thermoresponsive OEG containing polypeptides, where the number of EG repeats, EG terminal groups, and linkage groups were all systematically varied in order to obtain insights on how these molecular features affect LCST behavior ( Figure 1).…”

“…All of the non-ionic OEG-Hcy samples described above were found to adopt predominantly α-helical conformations in deionized water at 22 °C (except for water insoluble 2c, which was measured in MeOH at 22 °C), as determined by circular dichroism (CD) spectroscopy (see SI Figure S1) We envisioned that most of these OEG-Hcy derivatives would be thermoresponsive similar to OEG containing polypeptides reported by ourselves and other workers. [13][14][15][16][17][18][19][20][21][22][23] The significance of this new series of polymers is the incorporation of precise side-chain structural modifications, which enable systematic study of the effects of different functionalities on the properties of the materials. Figure 2 shows the results obtained from analysis of aqueous solutions of all the different OEG-Hcy homopolymers at concentrations of 3.0 mg/ml.…”