Nanoscopic characterization of the thermal phase behavior of random poly(ethylene glycol-glycidyl methyl ether) copolymers (rPEGs)

Abstract

PEGylation─linking of poly(ethylene glycol) (PEG) to a nanocarrier or active pharmaceutical ingredient to achieve stealth properties─is a key technology of nanomedicine. However, PEG has been shown to induce the formation of anti-PEG antibodies, motivating the search for alternative polymers for conjugation with nanocarriers. Recently, the concept of randomized PEG (rPEG), random copolymers of ethylene oxide and glycidyl methyl ether (GME), was introduced. These polymers are structural isomers of PEG with potential for manifold biomedical applications. To investigate their phase behavior in aqueous solution, a series of rPEGs with systematically varied monomer ratios were synthesized. Turbidimetric determination of the cloud point temperatures (Tcp) was applied to study macroscopic lower critical solution temperature behavior. Paralleling these measurements, local nanophase separation was investigated by electron paramagnetic resonance spectroscopy (EPR) using amphiphilic spin probes to address two key questions: (i) polymer hydration at nanoscopic level and (ii) to determine the temperature at which the onset of the collapse of the polymer chains occurs. The results reveal no phase separation below 96 °C for copolymers of a GME content of 35 mol % and less (26 and 0 mol % GME), while for GME content exceeding 40 mol %, cloud points of 70 °C–96 °C were observed. Comparison of both methods shows good accordance between the cloud points determined by turbidimetry and EPR with the exception of poly(glycidyl methyl ether) (PGME), for which EPR showed a lower Tcp by 5–10 °C. Combining the results with literature data, a model could be established that gives insight into the nanoscopic processes and allows for an approximation of the macroscopic cloud point temperatures in dependence of the GME content. Excellent aqueous solubility of all samples could be demonstrated in the physiological temperature range, satisfying the requirements for biomedical applications.