Ghaderi, S; (2012) Development of Fluorescent Nanoparticles ‘Quantum Dots’ for Biomedical Application. Doctoral thesis , UCL (University College London).

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Abstract

Quantum dots (QDs) are semiconductor nanocrystals (<100 nm), which are emerging as a novel class of multifunctional fluorescent probes for many potential biological and medical applications. In comparison to conventional organic fluorescent probes (organic dyes), QDs have substantial advantages, such as, bright fluorescence, narrow emission, broadband excitation, photostability and extended half-life. Imaging with diagnostic assessment, plays an important part in clinical settings for determining disease (cancer) progression and therapy. However, current imaging techniques have certain limitations, and they include insufficient sensitivity to detect low numbers of cancer cells at primary or metastatic sites and appropriate probes to detect specific cancer cell surface markers. To address these limitations, studies were conducted (1) to develop an aqueous synthesis of a series of near infrared (NIR) QDs, incorporating cadmium (Cd), tellurium (Te), cobalt (Co) and mercury (Hg) in its core (2) to minimize its potential toxicities, by developing coating strategies with a novel coating nanomaterial, mercaptopolyhedral oligomeric silsequioxane (MPOSS) while maintaining strong emission, stability and biocompatibility, (3) to apply conjugated NIR QDs as probes in targeting and detecting immunogenic apoptosis in cancer cells in vitro and mapping biodistribution in vivo. The inclusion of mercury (Hg (ClO4)2) and cobalt (Co) to the QD core resulted in NIR emission at 800 nm with paramagnetic properties. Characterization by transmission electron microscopy (TEM) confirmed size of the QDs. Detoxification of QDs was demonstrated, by toxicity studies, using two different vital stains, Alamar Blue and Neutral Red on human umbilical vein endothelial cells (HUVECs), human breast cancer cells (MCF-7), colorectal cancer cells (SW620) and prostate cancer cells (PC3). A short synthetic peptide to calreticulin (CRT) was chemically synthesised and antibodies generated against the peptide (Anti-CRT) with specificity to the native CRT protein (a cancer cell immunogenic apoptosis marker). The presence of functional groups on the coatings of QDs provided an additional advantage for conjugation to Anti-CRT for targeting, and carbon nanotubes (CNT) for thermal strategy. QDs conjugated to Anti-CRT showed specificity to cancer cells in vitro undergoing apoptosis when exposed to the following: 1) Doxorubicin (an anticancer drug), 2) cadmium and 3) QD-CNT (photothermal effect). Characterization by Fourier Transform Infrared Spectrophotometry (FTIR) confirmed conjugation of QDs to Anti-CRT. Confocal microscopy images further confirmed targeted and non-targeted QDs in vitro, and NIR sensitive camera for in vivo imaging. These studies and findings demonstrate the feasibility of applying these engineered nanocrystals for clinical diagnostics, drug delivery and therapy.

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