Observation of Dynamic Aggregation Behavior in Thermoresponsive Micro- and Nanoparticles via Diffusion-Ordered NMR Spectroscopy

Stimuli-responsive drug delivery systems have expanded the diversity of potential cargos by protecting payloads, extending circulation, and controlling payload release. However, quantitative characterization methods that accurately describe these complex systems are needed to accelerate their translation to the clinic. To this extent, degradable, thermoresponsive polyesters were developed through the ring-opening copolymerization of maleic anhydride and an oligo(ethylene glycol)-functionalized epoxide. The resulting polymers possess a lower critical solution temperature such that they are soluble in aqueous solutions at low temperatures (4-7 °C) but assemble into particles above room temperature (25 °C). The particle size and morphology were tunable through the selection of polymer initiator, forming nanoparticle (ca. 162 nm) and microparticle (ca. 1.85 μm) assemblies using macromolecular polyethylene glycol and small molecule propargyl alcohol initiators, respectively. Diffusion-ordered NMR spectroscopy (DOSY) was used over a range of temperatures to develop molecular weight calibrations using certified poly(ethylene glycol) standards. DOSY was able to monitor the dynamic self-assembly behavior of the thermoresponsive polymers in aqueous solutions, and through distinct diffusion constant shifts, quantify the aggregation number of particle intermediates within the nano- and microparticles.