A New Discovery In Biomimetic Pegylated Polypeptoids With Thermal-Responsive Properties

Smart polymeric materials have received extensive attention for a wide variety of applications. In particular, thermal-responsive polymers, which are able to exhibit a reversible phase, transition in a controlled manner to temperatures, which offer great potential for biomedical applications such as drug carriers, smart hydrogels, and stimuli-responsive surfaces.

It is known that a couple of polymers containing oligo (ethylene glycol/OEG) moieties exhibit thermal-responsive properties due to their hydration and dehydration of the groups. For example, the OEG-grafted (meth)acrylates copolymers show typically lower critical solution temperature (LCST) behavior with obvious tunable phase transition temperature.

The polypeptoids have been reported to exhibit good biocompatibility and biological activities due to the structural similarity to polypeptides. A large number of short peptoid oligomers with precise sequence and chain length up to 50 monomers have been synthesized by a solid-phase approach. The peptoid polymers with high molecular weights and large-scale yields can be obtained by ring-opening polymerization technique. Meanwhile, the diversity of the side-chain functionalities is confined and most of the polypeptoids merely contain alkyl side chains due to the limitation of ROP synthetic. Thus the post-modification of the well-defined polypeptoid precursors has emerged as an efficient and convenient approach to the final versatile functionalities of the polymers.

Recently, Prof. Jing Sun and Jiliang Tian in Qingdao University of Science and Technology synthesized a series of pegylated polypeptoids by a combination of ring-opening polymerization and post-modification strategy. Unlike the previously reported pegylated polypeptoids, the obtained polypeptoids show completely reversible thermal-responsive behaviors in aqueous solution after 8 heating and cooling cycles. The phase transition temperature (clouding points) is highly dependently on the degree of polymerization (DP), the side-chain length, the polymer concentration. In addition, the phase transition of the polypeptoid solutions can be very sharp (∆T < 5 ^oC), comparable to poly(N-isopropylacrylamide) (PNIPAM). It is conceivable that the thermal-responsive property arises from the thioether groups introduced by the thiol-yne click chemistry reaction that vary the hydrophilic-hydrophobic balance.

The influence of the temperature on the solution properties of HEX-PNPG_n–g-EG_2/3 samples (see figure from the article). In the typical plots, the transmittance of HEX-PNPG_n–g-EG_2/3 as a function of temperature with n ranging from 18 to 70. And the transmittance decreases from 100% to 0 % as the temperature increases from 15 to 40 ^oC as a result. Finally, the cloud point (CP) which defined as the temperature at the transmittance of 50% during the heating process was determined to be 23 ^oC. Further, the HEX-PNPG18-g-EG2 solution shows a sharp transition (∆T < 5 ^oC), comparable to the benchmark PNIPAM. Instead, the reported Poly(N-alkyl glycine) and its copolymers exhibiting a broad transition with ∆T > 10 ^oC. Increasing DP of HEX-PNPG results in increased CPs and broad transitions.

In the case of HEX-PNPG₇₀–g-EG₂, ∆T of the transition is around 10 ^oC. Note that ∆T is smaller than that of reported thermal-responsive polypeptoids containing aliphatic chains. We further plotted the CP of HEX-PNPG_n-g-EG_2/3 solutions as a function of DP (see figure from the article). In all cases, the CP of HEX-PNPG_n-g-EG_2/3 is increased as the DP of PNPG is increased. It was reported that polypeptides bearing OEG groups on the side chains show the opposite tendency. We, therefore, attribute to the absence of secondary conformation in polypeptoids, where the short polymer chains enable more exposure of hydrophobic segments to the water phase, which results in the lower CP.

The stability of the polypeptoid solution was also investigated. We performed 8 times of heating and cooling cycles between 20 and 50 ^oC. The phase transition is completely recovered, indicative of good stability to temperature (see figure from the article). The influence of salt concentration on the solution behavior of the polypeptoids was also investigated. We plotted the CP as a function of the NaCl concentration (see figure from the article). The CPs show barely visible variation by addition of NaCl, suggesting high tolerance to salts. This is possibly due to the nonionic property of the OEG residues. All these features enable the obtained polypeptoids potential candidates for next generation of smart polymeric materials.

These findings are described in the article entitled Biomimetic Pegylated polypeptoids with Thermal-Responsive Properties, published in the journal Polymer. This work was led by Prof. Jing Sun, Jiliang Tian, and Zhibo Li from Qingdao University of Science and Technology.