This dissertation presents research on the synthesis, functionalization and biological applications of photoluminescent silicon nanocrystals (quantum dots).
Fluorescent labeling reagents are an essential component of a huge industry built on sensitive fluorescence detection. Organic dye molecules are the typical labeling reagent; however, they fall short in some areas, such as long-term stability and simultaneous detection of multiple signals. The optical properties of quantum dots overcome some shortcomings of the organic dyes. This has led to intense research activity area in biological applications of nanotechnology. The attractive properties of the quantum dots include narrow, symmetric and bright emission, continuous excitation by any wavelength smaller than the emission wavelength, broad absorption spectrum, long lifetime, and resistance to photo bleaching. The most noted drawbacks of the better studied quantum dots (e.g. CdSe/ZnS) are the toxicity of metal chalcogenides and added size due to the inorganic and organic shells needed to protect them. Silicon quantum dots have the potential to overcome this problem because they are non-toxic and they do not need a shell prior to surface modification for biological applications.
Besides their desirable toxicity profile, silicon nanocrsytals are of extensive scientific interest to the biologic nanotechnology community because silicon is abundant, inexpensive, and can be made at high production rates. Advances reported here are made based on a mixed aerosol and solution phase method that overcomes major limitations of previous approaches, including (i) low production rates, (ii) insufficient brightness and (iii) incomplete coverage of the visible and near infrared spectrum of emission wavelengths. Highly luminescent silicon quantum dots spanning the visible spectrum were synthesized by laser pyrolysis followed by an acid etching procedure. Stabilization of the particles has been optimized by covalently linking the particles to organic compounds.
In this dissertation the full emission spectrum from blue to near infrared was demonstrated. The new contributions involve obtaining functionalized blue emitting silicon nanocrytals via oxidation of yellow emitting particles. Also reported in this study is the first observation of four spectrally distinguishable near infrared emission peaks from the silicon nanocrystals. Combined with previous work, this enables efficient and scalable preparation of silicon nanocrystals with emission spanning the visible spectrum and near infra red spectrum. Emission in the infrared spectrum (700-900 nm) is particularly desirable for biological applications because cells and tissues have minimal absorption in that region.
Biological systems are aqueous. Therefore, tailoring nanoparticles for biological applications requires that the particles form stable colloidal dispersions in water. Mixed surface functionalization of particles enabled dispersibility in aqueous and organic solvents by functionalizing particles with a mixed monolayer of carboxylic acid and alkenes. The persistent challenge of water solubility was also overcome in this work by micelle encapsulation to obtain particles that maintained their optical properties under physiological conditions of pH, temperature and salt concentrations. These particles were further characterized to determine their feasibility for biological applications.
To understand the impact of the physicochemical properties of silicon nanocrystals for biological imaging, studies of excitation at longer wavelengths were performed and the toxicity was evaluated. The excitation properties were evaluated to demonstrate that silicon nanocrytsals can undergo one-, two-and three-photon excitation. The particles maintained similar emission profiles under multiphoton excitation in water and chloroform. The cytoxicity was evaluated in vivo and in vitro to conclude that no adverse effects from silicon nanocrystals are observed, even at 10 times the concentrations used for cellular labeling and tumor imaging. With toxicity concerns addressed, the potential of the particles was explored in biological (cancer) imaging applications.
Imaging is an important tool in cancer research. Silicon nanocrystals were evaluated in some cancer imaging applications. Tumor targeted imaging, multiplex imaging, and sentinel lymph node mapping are highly important for cancer diagnosis and treatment. Bioconjugation of the micelle encapsulated silicon nanocrystals allowed for targeted imaging of pancreatic cancer in vivo and in vitro. The robust signal from the silicon nanocrystals was observed in panc-1 cancer cells targeted with silicon nanocrystals conjugated to transferrin. The signal was also observed over a 40 hr period in a tumor xenograft whose vasculature was targeted with silicon nanocrystals conjugated to cyclic RGD peptides. The particles were also used to identify the sentinel lymph node, an important procedure of significant relevance to melanoma and breast cancer patients. In vivo multiplex near infrared imaging was also demonstrated in a live mouse. Combinations of multiple imaging modalities can provide a powerful tool for cancer imaging. Toward this end, a magnetofluorescent probe was constructed by the co-encapsulation of silicon nanocryatals and iron oxide within phospholipid micelles. The particles exhibited desirable optoelectronic and superparamagnetic properties. The combined work presented in this dissertation thus takes several key steps toward making silicon quantum dots a valuable addition to the growing class of revolutionary semiconductor fluorescent probes, with unique advantages for applications where heavy metal toxicity is a concern. (Abstract shortened by UMI.)
|Advisor:||Swihart, Mark T.|
|Commitee:||Andreadis, Stelios, Ruckenstein, Eli|
|School:||State University of New York at Buffalo|
|Department:||Chemical and Biological Engineering|
|School Location:||United States -- New York|
|Source:||DAI-B 70/05, Dissertation Abstracts International|
|Keywords:||Biophotonics, Cancer applications, Luminescent, Nanocrystals, Quantum dots, Silicon nanocrystals|
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