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, which 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 using biodegradable or enzymatically cleavable linkers. Here, we report the design, synthesis, and characterization of a library of supramolecular polymer prodrugs based on poly(ethylene glycol) (PEG) and the proregenerative 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 states using scattering techniques and electron microscopy and corroborated by coarse-grained modeling. Molecular architecture and the hydrophobic-to-hydrophilic ratio of PEG–DPCA conjugates strongly influenced their physical state in water, ranging from fully soluble to supramolecular spherical assemblies and nanofibers. Molecular design and supramolecular structure, in turn, were shown to dramatically alter hydrolytic and enzymatic release and cellular transport of DPCA. In addition to potentially expanding therapeutic options for DPCA through control of supramolecular assemblies, the design principles elaborated here may inform the development of other supramolecular prodrugs based on hydrophobic small-molecule compounds.

Ionic liquids (ILs) have emerged as versatile solvents that are facilitating advances in many industries such as energy storage, separations, and bioprocessing. Despite their great promise, the cost of many ILs remains excessively high, thus limiting their scalability and commercialization. Therefore, the aim of this paper was to develop a simple and integrated process for synthesizing protic ionic liquids (PILs) in situ, while utilizing them directly as pretreatment solvents for biomass deconstruction/biorefining. The in situ method eliminates the major steps associated with increased cost and carbon footprint, thereby yielding an economically advantaged and environmentally efficient process. The PIL hydroxyethylammonium acetate ([Eth]­[OAc]) was utilized in the pretreatment and enzymatic hydrolysis of sorghum biomass with the in situ method, which demonstrated equivalent sugar yields relative to the presynthesized [Eth]­[OAc]. Techno-economic analysis demonstrated the economic advantage of the in situ synthesis over other PIL synthesis methods, due to its reduction of production costs up to $2.9/kg, while the life-cycle assessment showed the environmental efficiency of the process, yielding >30% reduction of GHG per kilogram of PIL. Therefore, this method demonstrates an improvement in the sustainability impact for the utilization of PILs for biomass pretreatment and other IL-utilizing processes.

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.