Engineering nanomaterials for molecular imaging and targeted therapy

Nanomaterials such as quantum dots and polymeric nanoparticles have found a variety of applications in biology including bioimaging and drug delivery. Despite tremendous progress, applications of these materials for disease detection and treatment are restricted by several limitations such as lack of a multiplexed platform for molecular imaging and low targeting efficiency. This thesis focuses on using advanced polymer science and nanotechnology to address some of the major challenges associated with molecular profiling and targeted drug delivery. The first goal of this thesis is to engineer quantum dot surfaces to make a quantum dot with minimal hydrodynamic size, negligible nonspecific interactions, chemical functionality and long stability for imaging cells and tissues. Toward this goal, a new polymer surface coating methodology is developed for making small (7.4-12 nm), stable (over months in storage), and bio-functional quantum dots. The approach is shown to be robust and applicable for different shapes of nanocrystals and many other types of ligands including small molecular ligands, silica and polymeric ligands with different binding groups. The structure-property relationship is investigated and surface coatings are optimized to minimize nonspecific binding to cells. Two bioconjugation strategies are introduced to efficiently attach quantum dots to a wide range of molecular targets such as DNA and proteins without altering their functions. The performance as probes for immunofluorescence staining is further optimized for anti-tubulin antibody conjugates. The combination of polyhistidine-driven self-assembly with protein A-mediated antibody immobilization yields the highest density of specific tubulin labeling. The second goal of this thesis is to understand the interaction of dextran polysaccharides with cells and tissues in the physiological state of obesity and to develop a targeted therapy for obesity-induced insulin resistance based on dextran nanocarriers. Depending on the dextran size and administration route, obesity is observed to significantly change the biodistribution pattern of dextran, shifting from liver to visceral adipose tissue. Twenty-four hours after post intraperitoneal administration of 500 kDa dextran, up to 63% of the injected dose remain in visceral adipose tissue. Further mechanistic study shows that macrophages in adipose tissue play a critical role in the uptake of dextran in obese mice. A new targeted drug delivery system is developed based on this mechanism and a single-dose treatment of anti-inflammatory dextran conjugates results in a significant decrease of pro-inflammatory markers in adipose tissue of obese mice. This study provides a promising translational nanomaterials-based delivery strategy to target adipose tissue macrophages to inhibit the origin of the comorbidities of obesity, and potentially for other inflammatory diseases of visceral organs.LimitedAuthor requested closed access (OA after 2yrs) in Vireo ETD syste