Molecular Imaging Using Nanoparticles and Small Molecules

This dissertation evaluates nanoparticle and small molecule strategies for molecular imaging applications. Squaraine rotaxane endoperoxide (SREP) dyes formulated into polystyrene nanoparticles produce unique chemiluminescent-fluorescent imaging agents. Encapsulating these self-illuminating SREPs within microparticle systems, permitted planar optical imaging at relatively deep tissue depths in living rats. Another fluorescent nanoparticle system bearing cationic zinc(II) dipicolylamine (ZnDPA) ligands was a liposome that binds anionic phospholipids and related phosphate containing structures in the cell wall of bacteria and cell death. Fluorescence cell microscopy studies demonstrated that the multivalent liposomes selectively target bacteria in the presence of healthy mammalian cells and caused bacterial cell agglutination. A micellar nanoparticle containing the commercially available deep-red fluorescent probe, SRFluor680 enabled non-invasive optical imaging of interscapular brown adipose tissue (BAT). Whole-body fluorescence imaging of living mice showed extensive accumulation of the fluorescent probe in the interscapular BAT and ex vivo analysis showed 3.5-fold selectivity for interscapular BAT over interscapular white adipose tissue (WAT). Multimodal PET/CT and planar fluorescence/X-ray imaging of the same living animal showed co-localization of BAT mass signal reported by the fluorescent probe and BAT metabolism signal reported by the PET agent, 18F-FDG. Three small molecule ZnDPA tracers containing 111In labels were examined for SPECT/CT imaging of bacterial infection in living mice. All three [111In]-ZnDPA tracers selectively targeted the site of a clinically relevant mouse infection model that could not be discerned by visual external inspection of the living animal. The highest target selectivity, observed with a divalent tracer equipped with two ZnDPA targeting units, compared quite favorably with the imaging selectivities previously reported for other nuclear tracers that target bacterial cell surfaces. Finally, two related optical probes that are conjugates of a ZnDPA targeting unit and a BODIPY chromophore were examined as a bacterial theranostic strategy. One probe is a microbial targeted fluorescent imaging agent, mSeek, and the other is an oxygen photosensitizing analogue, mDestroy. The fluorescent probe, mSeek, effectively labeled all tested bacteria and enabled detection at concentrations of ~100 CFU/mL for B. thuringiensis spores, ~1000 CFU/mL for S. aureus and ~10,000 CFU/mL for E. coli. The photosensitizer analogue, mDestroy, inactivated 99-99.99% of bacterial samples containing 10^6 CFU/mL.