A universal multi-drug encapsulation and delivery system employing supramolecular nanogels that self-assemble via dynamic sulfone bonding - PROJECT SUMMARY
Significance: Nanostructure formation by supramolecular self-assembly primarily involves the
hydrophobic/hydrophilic equilibrium of amphiphiles within aqueous environments. The biocompatibility and
chemical versatility permitted by block copolymer amphiphiles have allowed the fabrication of a wide range of
nanoscale biomaterials (NBMs). Despite these advances, considerable challenges remain. Self-assembled
NBMs experience substantial difficulties with the encapsulation of molecules, with many (often difficult to express
or expensive) proteins and hydrophilic small molecules achieving low encapsulation efficiencies well below 20%.
Furthermore, the multicomponent structure of these amphiphiles often requires employment of complex block
copolymer chemistries, which can present difficulties when scaling up synthesis and purification for practical
clinical testing and translation.
Innovation: A novel means of supramolecular self-assembly that employs a single, simple, water-soluble
homopolymer that achieves >90% encapsulation efficiency universally for multiple hydrophilic (and hydrophobic)
small molecules and biologics simultaneously will be modeled, optimized and validated. The unique network
self-assembly of poly(propylene sulfone) (PPSU) homopolymers, which are simultaneously both soluble and
crystallizable in water, has not been previously reported. By adjusting solvent polarity, intra- and interchain
segments of noncovalent sulfone-sulfone bonds form along the PPSU backbone, biomimetic of DNA
hybridization and leucine zippers in proteins. Preliminary experiments and simulations of this process revealed
dynamic sulfone-sulfone interactions to form an interconnected physical gel network that can solidify into either
macroscale hydrogels or collapse into nanogels of diverse morphologies. Using this rapid and scalable
methodology, uniform populations of diverse nanogel morphologies can be specified, including spheres, vesicles
and filamentous bundles. Importantly, drugs (regardless of their physicochemical properties) are efficiently and
universally captured within PPSU nanogels during network collapse. This novel mechanism of molecular
encapsulation demonstrates an exceptionally high loading efficiency for all molecules tested and combinations
thereof, including proteins, DNA, RNA, fluorophores, contrast agents and small molecule drugs.
Two independent aims are proposed to optimize and validate PPSU NBMs as a novel controlled delivery platform
for biomedical applications. Aim 1: Employ molecular dynamics simulations and analytical nanoscale
microscopy to mechanistically understand PPSU self-assembly and therapeutic loading. Aim 2: Develop
universal molecular encapsulation by PPSU as a tool for the optimization of a model NBM vaccine formulation.
