University of Illinois at Urbana-Champaign
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Research Projects

Nanotechnology is rapidly transforming our ability to study biology and to detect and treat disease. Unlike everyday tools and devices, the miniature tools of nanotechnology have length dimensions near 1-100 nanometers, a scale over which strange but useful properties emerge: semiconductors have tunable colors, metals have collective charge oscillation, magnets become ‘superparamagnetic,’ and crystals disperse in liquids in which they are not soluble. Importantly, nanometer-scale materials are similar in size to proteins and nucleic acids, the fundamental building blocks of cells and life, and thus we have an opportunity to directly integrate synthetic nanomaterials within life itself. Nanoparticle tools are now being developed to ‘sense’ the presence and state of individual molecules within cells and to correct deleterious cellular behaviors that underlie disease. The major goals of the Smith Lab are to use interdisciplinary science and engineering principles to create new nanoparticle-based sensors and imaging agents, and to use these materials to study processes underlying cancer at the finest level of detail.

Nanoparticle bioimaging probes

A primary focus of our lab is in the engineering of nanoscale imaging agents with precisely controlled physical structure and optical properties. Quantum dots (QDs) are a prime example. QDs are nanocrystals made out of semiconductor materials for which color can be tuned by the crystal size. When prepared under the right conditions, these particles are the same size as proteins with exceptionally bright fluorescent light emission. This makes them outstanding probes for monitoring molecular behaviors, such as the binding of a ligand to a receptor, or the delivery of a drug to a diseased cell. A key feature of QDs is their resistance to degradation; their stability is unmatched by any other type of fluorescent probe that can be integrated into biology, which has made them indispensible for imaging individual molecules in cells and tissues at high excitation powers that would rapidly degrade normal organic dyes and fluorescent proteins.

Structurally, quantum dots are multi-domain composite particles incorporating crystalline semiconductor materials as well as flexible organic coatings. The crystalline core provides the optical properties and the coating serves as the point of contact with the surrounding medium. This coating can be chemically fused to a protein or nucleic acid, providing a light-emitting tag with a distinct color that can be tracked in the noisy environment of a cell, a tissue, or a living organism. We engineer the core materials to maximize light output and to increase the number of distinct colors for monitoring multiple events simultaneously. We also engineer the surface to maintain a compact size and to precisely attach biological molecules. QDs are just one type of nanoparticle; we also generate constructs composed of metallic, magnetic, and organic materials, which can then be assembled together as building blocks for multifunctional sensors.

Imaging living cells and living animals

We use nanoparticle probes to solve a number of problems in biomedicine. Our major drive is to understand the molecular mechanisms of cancer: how it develops, how metastasis and invasion occur, and why chemotherapeutic drugs initially work and why they ultimately fail. We observe and analyze solid tumors at all biological scales, from living animals (via wide-field optical imaging and multiphoton confocal intravital microscopy) down to individual molecules in tumor cells (epi-fluorescence and total internal reflectance fluorescence microscopy). A major goal is to connect biomolecular behavior with macroscopic pathophysiology of whole tumors. Crucial details derive from single-molecule studies, where so little is currently known, and for which there is a major need for more precise sensors and probes.

Tissues transition from healthy and functional to cancerous due to internal changes within cells (genetic mutations) that alter cellular behavior. But internal changes alone do not determine whether a mutated cell will spread to distant locations in the body; cellular behavior is also dictated by cues from the ‘microenvironment.’ The microenvironment is the local surroundings of a cell, consisting of extracellular matrix with varying mechanical properties, a diverse mix of chemicals and biomolecules that are soluble or bound to the matrix, as well as abutting cells that each interact with their own microenvironment. These assorted cues serve as inputs that a cell will process and integrate to yield a net behavior. Small alterations to the cell’s information-processing networks and machinery due to cancer-related mutations destabilize this system, causing erratic behavior in microenvironments that are normally benign such that quiescent, immobile cells rapidly proliferate and invade surrounding tissue. Compared to normal tissue, tumors are heterogeneous and chaotically organized, resulting in wide diversity in microenvironments; we think that only a small number of these microenvironments are to blame for the malignant features of cancer and our goal is to identify their characteristic features and patterns so that we can specifically target them with drugs.

nanoparticle
Electron micrograph of a single quantum dot with 12-nanometer diameter.
Probes
Schematic structure of a quantum dot bioimaging probe.
CdSe
5 sizes of CdSe quantum dots: (Top) Liquid dispersions in vials. (Bottom) Fluorescence spectra.
Multi-scale imaging
Multi-scale imaging of cancer at the scale of (clockwise from top left) animals, living tissue, cultured cells, and cellular receptors.
Single molecule imaging.
Single molecule imaging of individual proteins (red) binding to receptors on living cancer cells (left) and a map of their diffusional freedom (right)