Exploring Poly(ethylene glycol)-Polyzwitterion Diblock Copolymers as Biocompatible Smart Macrosurfactants Featuring UCST-Phase Behavior in Normal Saline Solution

Abstract

Nonionic-zwitterionic diblock copolymers are designed to feature a coil-to-globule collapse transition with an upper critical solution temperature (UCST) in aqueous media, including physiological saline solution. The block copolymers that combine presumably highly biocompatible blocks are synthesized by chain extension of a poly(ethylene glycol) (PEG) macroinitiator via atom transfer radical polymerization (ATRP) of sulfobetaine and sulfabetaine methacrylates. Their thermoresponsive behavior is studied by variable temperature turbidimetry and 1 H NMR spectroscopy. While the polymers with polysulfobetaine blocks exhibit phase transitions in the physiologically interesting window of 30-50 • C only in pure aqueous solution, the polymers bearing polysulfabetaine blocks enabled phase transitions only in physiological saline solution. By copolymerizing a pair of structurally closely related sulfo-and sulfabetaine monomers, thermoresponsive behavior can be implemented in aqueous solutions of both low and high salinity. Surprisingly, the presence of the PEG blocks can affect the UCST-transitions of the polyzwitterions notably. In specific cases, this results in "schizophrenic" thermoresponsive behavior displaying simultaneously an UCST and an LCST (lower critical solution temperature) transition. Exploratory experiments on the UCST-transition triggered the encapsulation and release of various solvatochromic fluorescent dyes as model "cargos" failed, apparently due to the poor affinity even of charged organic compounds to the collapsed state of the polyzwitterions.

The Design of Sulfobetaine Polymers with Thermoresponsiveness under Physiological Salt Conditions

“…In a recent study, Nizardo et al prepared a sulfobetaine copolymer from two sulfobetaines of DMAPS and 3-((2-methacryloyloxyethyl)dimethylammonio) propane-1-sulfate) and succeeded to retain the CP near physiological salt conditions. [16] However, sulfobetaine polymers with aromatic cations have not successfully responded in the physiological conditions. One must consider the many intermolecular interactions of the monomers and polymers and high salt concentrations to solubilize the polymers in aqueous solution.…”

Biodegradable zwitterionic nanoparticles with tunable UCST-type phase separation under physiological conditions

“…1a and 1 H NMR spectrum in Fig. S3 †) retained the UCST behavior in a biologically relevant temperature range (30-45°C) at physiological NaCl concentration 38 (Fig. 1b).…”

“…The ZB monomer was synthesized via an addition reaction according to a procedure previously reported. 38 Briefly, 5 g (31.8 mmol) of DMAEMA and 4 g (29 mmol) of TMS were respectively dissolved in 5 mL and 35 mL of acetonitrile at ambient temperature. The solutions were added to a 100 mL septum-sealed round bottom flask equipped with a magnetic stirrer and the reaction was carried out at 50°C for three days.…”

“…These studies culminated in the discovery of poly(sulfabetaine) ( pZB), which differs structurally from poly(sulfobetaine) ( pSB) by bearing a sulfate instead of a sulfonate moiety as the anionic group. 38 In this way, it is possible to obtain an ion pair of similar charge densities with respect to the original SB monomer (the anionic sulfate group and the cationic trimethyl ammonium group of the ZB monomer). Yet, this ion pair presents a stronger self-association and a lower interaction with water compared to the sulfonate/trimethyl ammonium ion pair of the SB monomer, in agreement with Collins' "law of matching water affinity".…”

Advances in thermo-responsive polymers exhibiting upper critical solution temperature (UCST)

“…Hence, PGLBT-b-PSPE formed micelles with PSPE core and PGLBT shell below UCST but this assembly disrupt upon heating above UCST [23]. Similarly, micelle formation and temperature induced disassembly of block copolymers containing derivative of poly(sulfobetaine) as one of the block were reported [28][29][30]. There are several other reports presenting the synthesis of thermoresponsive derivatives of poly(sulfobetaine) with tunable UCST, however, the application part of such polymers were sparsely explored due to the high fluctuations of UCST in the presence of electrolytes.…”