The Influence of molecular design on structure-property relationships of a supramolecular polymer prodrug

Supramolecular self-assemblies of hydrophilic macromolecules functionalized with hydrophobic, structure-directing components have long been used for drug delivery. In these systems, loading of poorly soluble compounds is typically achieved through physical encapsulation during or after formation of the supramolecular assembly, resulting in low encapsulation efficiencies and limited control over release kinetics that are predominately governed by diffusion and carrier degradation. To overcome these limitations, amphiphilic prodrugs that leverage a hydrophobic drug as both the therapeutic and structure-directing component can be used to create supramolecular materials with higher loading and controlled release kinetics when biodegradable or enzymatically cleavable linkers are used. Here, we report the design, synthesis, and characterization of a library of supramolecular polymer prodrugs based on poly(ethylene glycol) (PEG) and the pro-regenerative drug 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (DPCA). Structure-property relationships were elucidated through experimental characterization of prodrug behavior in both the wet- and dry-state, using scattering techniques and electron microscopy, and corroborated by coarse-grained modeling. Molecular architecture and hydrophobic-to-hydrophilic ratio of PEG-DPCA conjugates strongly influenced their physical state in water, ranging from fully soluble to supramolecular assemblies of micelles and nanofibers. Molecular design and supramolecular structure, in turn, were shown to dramatically alter hydrolytic and enzymatic release, bioactivity, and cellular transport of DPCA. In addition to potentially expanding therapeutic options for DPCA through control of supramolecular assemblies, the resulting design principles elaborated here may inform the development of other supramolecular prodrugs based on hydrophobic small molecule compounds.