The influence of molecular design on structure–property relationships of a supramolecular polymer prodrug

Abstract

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.

pH- and temperature-responsive supramolecular assemblies with highly adjustable viscoelasticity: a multi-stimuli binary system

“…Supramolecular assemblies have received a lot of attention from various disciplines of science and technology in the past decade. [1][2][3][4][5][6][7][8][9][10][11][12][13] Among these extensive efforts, three key thrusts have particularly been focused on: (i) the design and development of nano-/microstructures using molecular programming via the bottom-up approach, [14][15][16][17][18] (ii) understanding dynamics-structure-property relationships of supramolecular assemblies, [19][20][21][22][23][24] and (iii) the utilization and implementation of novel, functional supramolecular assemblies in contemporary and emerging applications such as sensors, 25 actuators, 26 photonics, 27 photovoltaics, 28 energy storage, 29 ferroelectrics, 30 thermoelectrics, 31 drug delivery, [32][33][34] and hydrocarbon recovery. [35][36][37] Amphiphilic molecules hold a pivotal position as fundamental building blocks in the realm of supramolecular assemblies due to their dual nature and the versatile opportunities they offer for manipulation of their self-assembly behavior through adjustments in their chain length and molecular architecture.…”

“…Supramolecular assemblies have received a lot of attention from various disciplines of science and technology in the past decade. 1–13 Among these extensive efforts, three key thrusts have particularly been focused on: (i) the design and development of nano-/micro-structures using molecular programming via the bottom-up approach, 14–18 (ii) understanding dynamics–structure–property relationships of supramolecular assemblies, 19–24 and (iii) the utilization and implementation of novel, functional supramolecular assemblies in contemporary and emerging applications such as sensors, 25 actuators, 26 photonics, 27 photovoltaics, 28 energy storage, 29 ferroelectrics, 30 thermoelectrics, 31 drug delivery, 32–34 and hydrocarbon recovery. 35–37…”

Controlling Molecular Packing in Aqueous Metallosupramolecular Self-assembly by Ligand Geometry

“…hydrogen bonding) and less directional (i.e. hydrophobic interactions and π–π stacking) inter- and/or intramolecular interactions is key to control the overall self-assembly outcomes of small molecules in solution. − In this regard, molecular design strategies have been successfully exploited to control self-assembly processes, with special focus on organic compounds. − More recently, introduction of metal ions in the molecular structure of supramolecular building blocks has further boasted the supramolecular polymer field and broadened the scope of application . The incorporation of metal ions not only enriches the systems with unique redox, optical, electronic, and magnetic properties, but also provides additional intermolecular interaction sites (i.e.…”

Construction of aggregation-induced emission photosensitizers based on supramolecular polymers for enhanced photocatalytic oxidative coupling of amines

“…Supramolecular polymers are reversible, degradable, selfhealing, easy to process and renewable, and have broad application prospects in biodegradable materials, biomedical materials, supramolecular self-healing materials, biomedical applications and so on. 3,8,[38][39][40][41][42][43][44][45][46][47] For example, Yang and coworkers reported water-dispersible fluorescent nanoparticles of hydrogen-bonded supramolecular polymers by the miniemulsion method, which could be fine-tuned by efficient excitation energy transfer in co-assemblies of the energy donor and acceptor fluorophore-based monomers and have been successfully applied in cellular imaging and fluorescent inks. 48 Zhou and coworkers prepared a dandelion-like supramolecular polymer through non-covalent host-guest coupling with a novel hierarchical self-assembly behavior, which display great potentials to construct aqueous light-harvesting system.…”