Development of near infrared semiconductor quantum dots for in vivo imaging
Saeboe, Alexander M.
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Quantum dots (QDs) are semiconductor nanoparticle fluorophores with size tunable emission wavelengths and large absorption cross sections, making QDs ideal optical imaging agents. Optical imaging has seen considerable academic and commercial interest, particularly for preclinical imaging. This interest stems from the capacity to multiplex, i.e., the detection of multiple independent imaging probes simultaneously, the accessibility of optical imaging equipment, and the absence of ionizing radiation. Since multiple in vivo targets can be imaged simultaneously, multiplexing is particularly appealing for targeted molecular imaging. In oncology, where a myriad of receptors can be used as targets for personalized medicine, multiplexed imaging would improve rapid receptor status profiling. Given their flexible design, QDs can be engineered for use as targeted contrast agents. To meet the needs of this application, the QDs must 1) emit in the near or short wavelength infrared (NIR/SWIR) wavelength regime to mitigate absorption of light by tissues, 2) be biocompatible, and 3) enable functionalization with targeting agents, such as antibodies or small molecules. In this thesis, the first requirement was addressed by synthesizing an inverted Type-I ZnSe/InP/ZnS system, which is the first InP based system with tunable emission past 750 nm. Biocompatibility of the InP system was confirmed with in vivo toxicity studies of the ZnSe/InP/ZnS QDs. The third requirement was addressed by the development of bioconjugation and functionalization schemes resulting in active QD targeting to the biologically interesting cellular targets human epidermal growth factor receptor 2 (HER2) and folic acid receptor alpha. In addition to developing the new contrast agent, the imaging approach was also refined to address concerns of non-specific labeling of the tumor. To discern between targeted and untargeted binding in vivo, a dual tracer approach using both an untargeted and targeted imaging probe, paired with a corresponding image processing algorithm, was implemented and validated. Identifying the limitations of this approach in NIR-I imaging, resulting from tissue auto fluorescence and light attenuation, laid the groundwork for future imaging work in the SWIR. In order to explore the utility of SWIR for dual tracer approaches, PbS/CdS QDs emitting throughout the SWIR wavelength regime were synthesized. The PbS/CdS QDs were used to generate pilot in vivo SWIR imaging data in collaboration with the National Research Council of Canada. The pilot data demonstrate that tissue attenuation and autofluorescence will not be an issue in the SWIR wavelength regime. By pairing SWIR emitting QDs with dual tracer imaging principles, future studies may be able to discern tumor biomarker status at tissue depth. Such an approach would allow researchers to determine how tumors respond to targeted therapies, furthering the development of personalized medicine.