A universal multi-drug encapsulation and delivery system employing supramolecular nanogels that self-assemble via dynamic sulfone bonding

Project: Research project

Project Details

Description

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 (NBM). Despite these advances, considerable challenges remain. Self-assembled NBM 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.
Three independent aims are proposed to develop and validate PPSU NBMs as a novel controlled delivery platform for biomedical applications. Aim 1: Employ molecular dynamics simulations to model PPSU self-assembly and therapeutic loading. Aim 2: Identify and enhance mechanisms of PPSU nanogel disassembly and payload delivery. Aim 3. Employ universal encapsulation by PPSU for the optimization of a model theranostic NBM vaccine formulation.
StatusActive
Effective start/end date8/1/214/30/25

Funding

  • National Institute of Biomedical Imaging and Bioengineering (1R01EB030629-01A1)

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