In vitro imaging using stable, water dispersible luminescent silicon quantum dots capped with various cellular targeting agents
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This thesis presents research on the synthesis, functionalization, and biological applications of silicon nanocrystals, also called silicon quantum dots (Si QDs). Over the past 20 years, semiconductor nanocrystals (also known as quantum dots or QDs) have been investigated for applications ranging from electronic materials science to biological imaging. The outstanding optical properties of QDs, which include stable luminescence, tunable luminescence color, modifiable surface characteristics, and the potential to interface with biologically relevant molecules, have made QDs a good replacement for organic dyes in many applications. Silicon nanocrystals show many of the same useful optical properties but lower toxicity than cadmium based quantum dots for biological applications. In this thesis, I focus on the biological applications of silicon nanocrystals in fluorescent biosensing and cellular labeling applications. Conventional quantum dots have great potential in cancer-related imaging and diagnostic applications; however, these applications are limited by concerns about the inherent toxicity of their core materials (e.g. cadmium, lead). Virtually all imaging applications require conjugation of the imaging agent to a biologically active molecule to achieve selective uptake or binding. Here, we report a study of biocompatible silicon quantum dots covalently attached to biomolecules including lysine, folate, anti-mesothelin, and transferrin. The particles possess desirable physical properties, surface chemistry, and optical properties. Folate- and anti-mesothelin-conjugated silicon quantum dots show selective uptake into Panc-1 cells. This study contributes to the preclinical evaluation of silicon quantum dots and further demonstrates their potential as an imaging agent for cancer applications. Major bionanotechnology research issues in quantum dot synthesis include the stabilization of their optical properties using various coating and encapsulation strategies, and advancing the rational design of constructs containing them to optimize overall size, surface chemistry, and composition in order to minimize potential toxicity and overcome biological barriers. Conventional cadmium- and lead-based quantum dots are normally coated, because their degradation may result in the release of toxic heavy metal ions. For in vivo use, they must be cleared from the body without degradation. Freestanding silicon quantum dots are expected to biodegrade to non-toxic products (e.g. silicic acid); however they have not been evaluated in biodegradable nanocarriers. Previous work from our group has encapsulated them with non-toxic, but non-biodegradable phospholipid-polyethylene glycol surfactants. Here, we report the development of chitosan-coated silicon nanoparticles (CSi QDs). Evaluation of the physicochemical and optical properties of the CSi QDs shows that they remain optically active in aqueous media. The chitosan coating renders silicon quantum dots stable in aqueous biological media and useful for biological applications such as cellular imaging with single and two photon excitation. The particles are also degradable when incubated at physiological temperature. These results open the door for a new generation of silicon quantum dots that may have a wide variety of applications derived from the flexibility of chitosan.