Modular engineering of multifunctional hydrogels for molecular recognition and precision medicine

Clegg, John Robert
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The precision medicine initiative was launched by the Obama administration in 2015. Major technological challenges exist, however, preventing the clinical realization of precision medicine. This dissertation specifically addresses two of these challenges, namely the need to engineer materials with specific affinity for protein analytes, and the need for customizable nanocarriers that target individual patients’ ailments.

To address the first challenge, I developed multifunctional, molecularly imprinted hydrogels for protein recognition. Molecular imprinting within anionic microparticles increased their capacity to load high isoelectric point proteins, but failed to impart single-protein specificity. To further understand the impact of material composition on protein adsorption, I constructed a library hydrogel microparticles comprised of hydrophilic, anionic, and hydrophobic components. Analysis of model protein adsorption to each of these formulations elucidated the interaction between Coulombic attraction, hydrophobic contact, and size exclusion in dynamic protein-hydrogel interfaces.

This analysis was the first to characterize an affinity-permeability tradeoff, where moieties that increase solute affinity simultaneously decrease the maximum solute partitioning. I also uncovered the critical role of solvent-accessible arginine content in the affinity of high isoelectric point proteins for amphiphilic, anionic copolymers.

In the second portion of the dissertation, I describe the fabrication of tunable nanoscale hydrogels by inverse emulsion polymerization. A base poly(methacrylic acid-co-acrylamide) formulation was modified by altering the composition of the monomer feed or completing bioconjugation reactions off of acid moieties. Modified polymer conjugates included poly(methacrylic acid-co-acrylamide) with pendant aromatic moieties, cationic groups, fluorophores, peptide oligomers, and proteins.

Modified nanogels’ physicochemical properties determined their cytocompatibility, environmental responsiveness, and solute affinity. They facilitated combination therapies (i.e. chemotherapy delivery and photothermal therapy) for precision medicine, and exhibited predictable biodegradation kinetics. As proof-of-concept, I concluded with a tailored peptide-modified nanogel that promoted carrier uptake by colorectal tumor cells.

In the future, we will design formulations that bind, sequester, or deliver biomolecules reliably by applying known relationships governing protein-biomaterial interactions in physiological fluids. Furthermore, diverse and modular nanomaterial platforms will enable the rapid and rational construction of patient or pathology-specific drug delivery devices.