Elucidating the Molecular Interactions of Encapsulated Doxorubicin within a Nonionic, Thermoresponsive Polyester Coacervate

Thermoresponsive polymers that display a lower critical solution temperature (LCST) are attractive drug delivery systems (DDSs) due to their potential to encapsulate and release therapeutics in a sustained manner as a function of temperature input. To attain the full potential of such DDSs, methods that illustrate the details of drug–polymer interactions are necessary. Here, we synthesized a nonionic, coacervate-forming, thermoresponsive polyester to encapsulate doxorubicin (Dox) and used solution state NMR spectroscopy and fluorescence microscopy techniques to probe the interactions between the polymer and Dox at the molecular level. The incomplete dehydration provides a matrix for encapsulation of sensitive therapeutics and preserving their activity, while the low hysteresis property of the polyester provides rapid transition from soluble to coacervate phase. Saturation transfer difference (STD) NMR revealed the Dox–polymer interactions within the coacervates. ¹H–¹H nuclear Overhauser effect spectroscopy (NOESY) cross-peak differences of Dox confirmed the Dox–polymer interactions. Diffusion-ordered spectroscopy (DOSY) revealed the slower diffusion rate of Dox in the presence of polyester coacervates. These studies illustrate how the state of the polyester (below and above LCST) affects the polyester–Dox interactions and offers details of the specific functional groups involved in these interactions. Our results provide a framework for future investigations aimed at characterizing fundamental interactions in polymer-based DDSs.