The design of multifunctional hydrogel nanoparticles for drug delivery

The application of therapeutic proteins and small interfering RNA (siRNA) molecules for disease treatment is an important yet challenging concept in modern medicine. To date, billions of dollars have been invested in the development of various drug candidates. However, the poor pharmacological properties of those compounds continue to limit progress towards viable human therapeutics, especially when intravenous delivery routes are considered. For instance, biological macromolecules are often incapable of targeting disease sites, can be immunogenic, or they can induce toxicity at off-target tissues. In response to the shortcomings of siRNA and protein drugs, many nanoparticle carriers are being pursued. Nanoparticles are designed to encapsulate, protect, and transport therapeutics to diseased cells. To be effective in this role, the delivery vehicle must overcome a series of biological hurdles over the course of delivery. Thus, dynamic, multifunctional nanoparticles are needed that can perform multiple in vivo functions.;Hydrogel particles are a unique class of polymeric biomaterials for drug delivery applications. Depending on their diameter, particles are either categorized as nanogels (less than 100 nanometers) or microgels (up to several micrometers). Similar to macroscopic hydrogels, nanogels and microgels contain a large fraction of water within their structure, can retain their architecture despite mechanical stress, and are generally soft/pliable. Particles are composed of synthetic hydrophilic polymers, cross-linked into porous networks that are capable of encapsulating and releasing macromolecules. In addition to those features, stimuli-responsive nanogels and microgels may be synthesized by incorporating responsive polymers into the hydrogel matrix.;In this dissertation, nanogels and microgels were investigated as candidate vehicles for macromolecule therapeutics, including siRNA and proteins. Chapter 1 is provided for additional background into the physicochemical properties of the particles. The chapter also discusses the relevant biological barriers faced by the vehicles during intravenous delivery, chemistries that may improve disease targeting, and factors that govern biocompatibility. In Chapter 3, proof-of-principle experiments show the utility of multifunctional nanogels for siRNA delivery. Using simple core/shell nanogel architectures, siRNA molecules were delivered to chemosensitize drug resistant ovarian cancer cells in vitro. In Chapter 4 biodegradable nanogels were synthesized that may enable the clearance of the vehicles following repeated administration in vivo. Chapter 5 describes the detailed assessment of microgels that rapidly decompose in response to sodium periodate. The decomposition revealed key differenced in network composition for microgels composed of two different thermoresponsive polymers. In Chapter 6, charge microgels were investigated for the encapsulation of a model therapeutic protein. The loading of the protein was found to be tunable with respect to the chemistry of the hydrogel network. Chapter 7 is provided to summarize in-progress projects to modulate the loading of siRNA, and improve targeting and stealth for those vehicles. The chapter also proposes new avenues of research to improve the carriers.;New light scattering methods were developed in this dissertation to provide detailed, direct assessments of the particle properties. For example, through multiangle light scattering (MALS) the decomposition of microgels (Chapters 4 and 5) was monitored through changes in particle molar mass from network erosion. In another example, the loading of proteins within various microgels and nanogels was assessed through changes in particle molar mass (Chapter 6 and 7). To explain those methodologies, Chapter 2 is provided to briefly review some light scattering principles used in the work. Together, the chapters of this dissertation reveal nanogels and microgels as promising carriers for macromolecule drug candidates. By combining the knowledge gained throughout this work, next-generation carriers may be pursued with improved performance in the treatment of disease.