Developing novel carbon nanomaterials for tumor imaging and photothermal therapy [electronic resource]

Reliable, unambiguous cancer detection is important for successful cancer treatment. Current imaging modalities lack either the resolution or signal-to-background to reliably identify tumors below 1 mm3. Positron emission tomography (PET), Magnetic resonance imaging (MRI), and fluorescence imaging all attempt to image a contrast agent which is overly abundant at the site of a tumor while present at significantly lower levels in healthy, cancer-free tissue. Ideally, this contrast agent could serve, not only to identify cancer, but as a non-invasive treatment to eliminate the cancer. In this work, we present single-walled carbon nanotubes (SWNTs) as a potential diagnostic/therapeutic 'theranostic' agent that addresses many of the issues that face other contrast agents. SWNTs possess many unique optical properties; they have intrinsic fluorescence in the Near-Infrared (NIR) with a several hundred nanometer Stokes shift. The ability to excite SWNTs between 700-1000 nm (NIR-I) allows for superior depth penetration in vivo because of the minimal absorption of light by biological tissue and water in this region. SWNTs emit fluorescence between 1000-1400 nm (NIR-II), a region with low scattering by endogenous tissues, which enables rapid, sub 100 micron resolution whole-animal imaging. Because of the large Stokes shift, filter sets can be coordinated to eliminate virtually all auto-fluorescence. Utilizing these techniques, we present data supporting the superiority of SWNTs as in vivo fluorophors because they allow for images with a higher combined resolution and depth penetration than most other currently available modalities. In order to be useful for cancer imaging, however, an imaging contrast agent must be able to achieve high accumulation at the site of the cancer compared with non-specific uptake. By tailoring and optimizing the size and composition of the surfactant coating in this work, SWNTs achieved the highest tumor uptake of any intravenously injected nanoparticle. The high tumor accumulation of SWNTs is visually represented by crisp, well-defined images of tumors in vivo with little to no signal in other organs or skin. The speed of fluorescent imaging allowed us to take 100 ms frame-rate videos of SWNTs after intravenous injection; a mathematical technique called Principal Component Analysis (PCA) is used to separate the components of the SWNT fluorescence over time. Due to differential blood flow through cancerous and healthy tissue, we clearly identified tumor masses within minutes of injecting the SWNTs using PCA, as opposed to waiting for hours or days for typical contrast agents to have significant tumor accumulation. While SWNTs have sufficient light absorption in NIR-I for fluorescent imaging, the majority of the light absorbed (> 99%) undergoes non-radiative relaxation, resulting in heat generation. By irradiating mice with a relatively low power of 808 nm laser light, SWNTs heated and ablated tumors with no observable damage to healthy tissue. This approach to cancer therapy, known as photothermal therapy, has had a recent push into using nanoparticles, specifically gold nanorods/nanoparticles as photothermal agents. Our SWNTs, because of their higher light absorption and tumor accumulation, are able to use 70% lower laser power and 90% lower dose than the previous standard for photothermal therapy, which is important when considering toxicity and the safe limit for human exposure to laser light. Additional nanomaterials that share optical and pharmacokinetic properties with SWNTs are explored in this work as well. We synthesized the first examples of biocompatible graphite oxide and graphene oxide. These low cost, industrially scalable two-dimensional carbon-based nanomaterials maintain SWNTs high light absorption in the Near-Infrared region. We selectively targeted graphene oxide to cancer cells followed by subsequent photothermal destruction of the cancerous cells, making this an economical alternative to SWNTs for photothermal therapy. Near-Infrared Quantum Dots, composed of a silver sulfide core surrounded with a branched Poly(ethylene glycol) coating, are optically similar to SWNTs, with large Stokes shift, NIR-I excitation, and NIR-II fluorescence emission. These quantum dots were shown to have ultra-high tumor accumulation and minimal accumulation in other organs. Preliminary excretion and retention studies in this work indicated that, most likely because of their smaller hydrodynamic radius, these quantum dots are more easily able to 'escape' the liver and spleen and be excreted quicker than SWNTs. The final thrust of this work lies in separating bulk SWNTs into their single-chiralities. This holds enormous potential for lowering the dose of SWNTs necessary for biomedical treatment; by removing the SWNTs that do not contribute to the optical absorption/fluorescence for NIR imaging (> 90%) the dose for imaging and photothermal therapy can be further lowered by an order of magnitude, minimizing toxicity concerns.

Keywords: Chemistry
Advisor: Dai Hongjie
Andersen Hans
Chidsey Christopher E. D. (Christopher Elisha Dunn)