Amphiphilic Alternating Copolymers with an Adjustable Lower Critical Solution Temperature (LCST) and Correlation with Nonspecific Protein Adsorption

Thermoresponsive polymers, exhibiting a lower critical solution temperature (LCST), are of diverse interest in designing stimuli-responsive materials. Most such systems are limited to poly(N-isopropylacrylamide) (PNIPAM)-derived macromolecules or others having a C-C backbone. This article reveals the synthesis of thermoresponsive alternating copolymers based on a segmented polyurethane (PU) scaffold. These polymers contain a hydrocarbon backbone, periodically grafted with a hydrophilic oligo-oxyethylene (OE) wedge. In water, they adopt a pleated conformation, driven by intrachain H-bonding (among the urethane groups), which by hierarchical assembly produces hollow capsules capable of sequestering hydrophilic guests. They exhibit a LCST with tunable cloud points in the range of ∼19 to 52 °C, depending on the degree of polymerization (DP) or hydrophobic/hydrophilic balance. With the same hydrophobic/hydrophilic content, the cloud point decreases by ∼10 °C with the increase in the DP from 7 to 16, which can be attributed to the difference in the free volumes caused by the polymer chains and solvent molecules. On the other hand, by decreasing the hydrophobic content (two -CH2 units in a repeating unit), the cloud point increases by ∼30 °C. For a given candidate, the thermodynamics of nonspecific protein (BSA) adsorption on the surface of the capsule was correlated with the LCST by isothermal titration calorimetry studies. At T < LCST, protein adsorption was largely governed by favorable entropy contribution due to the freeing of the surface-bound water molecules. In contrast, the enthalpy contribution became more prominent above the LCST, suggesting a dominant role of the hydrophobic interaction with the already dehydrated OE chains. Considering excellent biocompatibility (>85% cell viability with up to 500 μg/mL polymer after 72 h incubation with HeLa cells), degradable backbone, container property, tunable LCST, and temperature-dependent stealth effect, this polymeric system appears promising as a delivery vehicle for biomedical applications.