Dynamic Self-Assembly Behavior of Degradable, Thermally Responsive Polymers as a Versatile Drug Delivery Platform

Abstract

Stimuli-responsive drug delivery systems have enhanced the efficacy of diverse 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 °C) but assemble into particles above ambient temperature (25 °C). The particle size was tunable through selection of polymer initiator, forming nanoparticle and microparticle assemblies using macromolecular and small molecule initiators, respectively. Diffusion-ordered NMR spectroscopy was used to monitor the dynamic self-assembly behavior of the thermoresponsive polymers in deuterium oxide, and through distinct diffusion constant shifts, quantify the aggregation number of particle intermediates within the nano- and microparticles. Polymers were functionalized with cationic moieties to facilitate binding of macromolecular payloads such as nucleic acids. By blending charged and uncharged polymers in various aqueous buffers, we demonstrated precise control over the polymer lower critical solution temperature, self-assembled particle size, and particle charge. Finally, the designed polymer was 3D printed to fabricate bulk gels for use as an implantable drug depot. The thermal response of the gels mimicked that of the polymer resin, as characterized via swelling experiments in water, and maintained mechanical integrity from 4-37 °C.