Prof. Todd D. Giorgio
Chair of Biomedical Engineering
Professor of Biomedical Engineering
Professor of Chemical Engineering
E-mail: todd.d.giorgio [at] vanderbilt.edu
Office: SC 5824
Ph.D Chemical Engineering, Rice University (1986)
B.S. Chemical Engineering, Lehigh University (1982)
The research interests and ongoing activities of the Giorgio lab reflect an interdisciplinary range of projects spanning diagnostics, medical imaging, and therapeutics against cancer and cardiovascular pathologies. Lab members engage in projects dealing with novel metal nanoparticle designs for imaging applications, gene and cell therapy, RNAi therapeutics, and smart environmentally-responsive drug delivery systems. We collaborate heavily with other groups within the Dept. of Biomedical Engineering here at Vanderbilt, and beyond.
We have included below more detailed blurbs on our ongoing research activities.
Dual delivery of siRNA and chemotherapeutics to breast tumor cells to address multidrug resistance (MDR) in advanced breast cancer.
The effectiveness of chemotherapy in advanced breast cancer is thwarted by the rise of multidrug-resistant tumor cells. These cells display the ability to pump ingested chemotherapeutic agents back out of the cell, therby allowing MDR cells to survive the treatment.
The goal of this newly-funded project (DoD CDMRP, with Prof. Craig Duvall) is to use a smart polymeric nanoparticle platform to deliver two items intracellularly: (1) siRNA to knockdown mechanisms of MDR in the cell, and (2) potent chemotherapeutic agents. In doing so, the effectiveness of chemotherapeutics for the treatment of advanced breast cancer may be greatly improved.
Environmentally sensitive contrast agents for imaging proteolytic activity in human pathologies.
Over the past decade, a substantial body of research has produced a wide range of nanoscale contrast agents for interrogating microenvironments specific to human pathologies of interest, such as atherosclerosis and cancer. In these two cases, passive targeting of the contrast agents to sites of disease has been achieved through the enhanced permeation and retention (EPR) effect, while active targeting has been achieved using methods such as the immobilization of antibodies, peptides, or other ligands on nanoparticles.
In order to achieve further site specificity, we are working on developing novel nanomaterials that respond in the presence of specific microenvironments, such as the proteolytic environment in tumors. Our active projects seek to achieve this goal on quantum dots, dendrimers, gold nanoparticles, and iron oxide nanoparticles, in order to develop a nanoparticle toolbox for use with a wide range of imaging modalities.
Immunomodulation for the treatment of cardiovascular pathologies.
Each year, thousands of Americans receive bypass grafts to alleviate the symptoms of coronary heart disease and other similar diseases involving impaired perfusion of tissue. Naturally, the body reacts to the introduction of 'foreign material' through inflammatory pathways. Inflammation is frequently seen as a negative endpoint in host-biomaterial interactions, but recent work suggests that various inflammatory cascades are important in the regeneration of functional tissue. However, the potential therapeutic benefits of activating desirable inflammatory pathways, while deactivating undesirable ones, is uninvestigated.
In collaboration with the Sung & Duvall labs (see Collaborators link), we are working on methods to artificially modulate inflammatory pathways, using small molecule drugs, peptides, and nucleic acid-based approaches, and studying how this affects the regeneration of functional vascular tissue.
Jumpstarting the anti-cancer immune response.
Recent studies have begun to shed light on the nature and behavior of immune cells that are associated with the tumor stroma. It is becoming increasingly clear that antigen-presenting cells in the vicinity of a tumor engage in significant crosstalk with tumor cells, especially in ways that ultimately benefit the tumor. These immune cells release a wide range of signals that tell the rest of the immune system to back off, while at the same time encouraging tumor growth and invasiveness. Interestingly, these same cell types have been classically shown to be fully capable of the exact opposite behavior - having full ability to release cytotoxic, pro-inflammatory signals that ultimately result in tumor death.
In collaboration with the Duvall (BME), Yull & Blackwell labs (Vanderbilt-Ingram Cancer Center), we are developing methods to jumpstart the anti-cancer immune response.
Multistrata Nanoparticles for Multimodal Imaging.
Emerging materials and methods in biomedical imaging and biophotonics are improving patient outcomes. However, optical, magnetic resonance imaging (MRI), and computed tomography (CT) based imaging contrast of pathologic tissues, therapeutic localization at the site of action at the cellular level, and the inability to unite diagnosis and treatment into a single entity continue to limit the practical power and application of these technologies. In order to relieve these limitations and couple diagnostics and therapeutics into a single theranostic material, we have prepared an enhancement technology via the synthesis of a novel, multi-functional, multilayered nanomaterial. The MultiStrata nanoparticle (MSNP) is inspired by the material characteristics of its predecessors, the FeOx/Au nanoparticle and Au-Nanomatryushka. Designed to exhibit MRI contrast, X-ray contrast for CT, photonic contrast for optical coherence tomography (OCT), absorbance in the near-infrared (NIR) specrum for photothermal therapy (PTT), tunability of extinction characteristics during fabrication, theranostic potential, easy surface modulation for cellular targeting and biocompatibility and a nanostructure diameter of 60nm to support vascular extravasation ability, the fabrication of each ‘primary’ and ‘subsidiary’ strata – or functional layer – must be carefully controlled through fabrication methods. We have previously reported our preliminary findings regarding the multi-step fabrication and initial characterization of the MSNP. Furthermore, we specify methods necessary to fabricate extremely thin shells (as small as 1-2 nm; to maintain an overall particle diameter less than 60 nm) and to ensure magnetic material retention throughout the fabrication process. Relaxometry characterization, suggesting MRI contrast capacity, was also previously reported. We currently are working to elucidate the specific strata:strata geometric ratios which govern optical and magnetic properties as well as investigating the theranostic capacity of the MultiStrata nanoparticle.
Optimization of polyplex-based delivery of genes and siRNA to tumor cells.
Gene therapy has the potential to be an integral part of cancer treatment in the future by replacing mutated genes with the functional sequences. For example, the p53 gene is a tumor suppressor gene that often has a disrupted pathway in human cancers. p53 prevents damaged DNA from being replicated and passed on to daughter cells by either inducing apoptosis or by inhibiting the cell cycle. A mutation in this gene allows damaged DNA to be maintained and replicated, and therefore encouraging tumor growth.
Plasmid localization to the cell nucleus is a low probability event that contributes to inefficient transgene expression following nonviral gene delivery. To increase the specific delivery of plasmids, much effort has been devoted to the identification of nuclear targeting ligands. Currently reported nuclear targeting ligands are not tissue-specific. It is generally known that when a cell phenotype changes to malignant, the protein expression is modified. Our projects take advantage of this mechanism to identify nuclear targets specific for breast cancer cells.
The Vanderbilt research scene is defined by lots of collaboration. Only in a select few institutions across the nation can you really toss a rock from a window in the BME dept and literally break a window in the medical center (and even in a number of other science and engineering departments!). Therefore, below is a small sampling of the people who we either currently collaborate with or have collaborated with especially closely.
David E. Cliffel, Dept. of Chemistry @ Vanderbilt University [link]
James H. Dickerson, Dept. of Physics @ Vanderbilt University [link]
Craig L. Duvall, Dept. of Biomedical Engineering @ Vanderbilt University [link]
Jeffrey A. Hubbell, Integrative Biosciences Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland [link]
Jay Jerome, Dept. of Pathology @ Vanderbilt University Medical Center [link]
David J. Maron, School of Medicine @ Vanderbilt University [link]
Lynn M. Matrisian, Dept. of Cancer Biology @ Vanderbilt-Ingram Cancer Center [link]
J. Oliver McIntyre, Dept. of Cancer Biology @ Vanderbilt-Ingram Cancer Center [link]
Hak-Joon Sung, Dept. of Biomedical Engineering @ Vanderbilt University [link]
John P. Wikswo, Dept. of Biomedical Engineering / Dept. of Physics @ Vanderbilt University [link]
Fiona E. Yull, Dept. of Cancer Biology @ Vanderbilt-Ingram Cancer Center [link]