The research interests and ongoing activities of the Giorgio lab reflect an interdisciplinary range of projects spanning diagnostics, medical imaging, and therapeutics against cancer, cardiovascular pathologies, and bacterial infections. Lab members engage in projects dealing with novel metal nanoparticle designs for imaging applications, gene and cell therapy, RNAi therapeutics, smart environmentally-responsive drug delivery systems, and bacterial separation systems. We collaborate heavily with other groups within the Department of Biomedical Engineering here at Vanderbilt, and beyond.
Colistin-functionalized Magnetic Nanoparticles for Microfluidic A. baumannii Separation from Blood
Acinetobacter baumannii infections are an important cause of morbidity and mortality in combat settings, especially Iraq and Afghanistan, and also in the intensive care units of VA hospitals, placing a considerable burden on the health of our Armed Forces. Consequently, it is critical to develop improved strategies for the treatment of A. baumannii infections in military populations.
The goal of this project (DoD) is to develop novel nanoscale materials to be used in conjunction with mesofluidic devices for magnetic hemodepletion of A. baumannii from blood. Superparamagnetic nanoparticles decorated with A. baumannii surface-targeting ligands enable the magnetic isolation of these pathologic bacteria from blood, thereby reducing or eliminating A. baumannii infection. This approach will enable more military service members and veterans to survive A. baumannii sepsis.
Developing a Raman-Based Biosensor to Identify Circulating Tumor Cells Using Functionalized Zinc Oxide Nanowires
The ability to detect circulating tumor cells (CTCs) has particular application for treating metastases, which are the primary cause of most cancer-related deaths. Low, clinically relevant CTC concentrations are difficult to reliably detect in a time- and cost-efficient manner, however. Most solid tumors are also of epithelial origin, so distinguishing between cancerous and healthy epithelial cells is immensely important, but further complicates CTC detection. Near-infrared Raman spectroscopy can be employed to differentiate CTCs from healthy epithelial cells, However, CTCs have a very small optical cross-section, which limits Raman spectroscopy’s ability to detect them.
High quality, highly faceted ZnO nanowires can be grown via a modified vapor-solid method as a platform for biosensing with Raman spectroscopy. These nanowires can be uniformly coated with metal nanoparticles to enhance the Raman signal from target cells through plasmonic effects, allowing differentiation of CTCs from healthy epithelial cells. The Raman signal can be further enhanced by epitaxially coating the nanowires with specific thicknesses of MgO, chosen using COMSOL simulations, to induce a cavity mode resonance condition. The functionalized ZnO nanowire biosensing platform can be incorporated into a microfluidic channel to include such advantages as small sample volumes and high throughput, which are vital for clinical diagnostic applications.
Improving in vivo stability and circulation time of core-optimized polymer-siRNA polyplexes by altering hydrophilic corona structure.
Nucleic-acid based therapeutics like siRNA have great promise for the treatment of diseases for which there are no effective drugs, but delivery of these treatments poses many challenges. One of the most important challenges is ensuring that gene carriers circulate in blood for long periods of time, avoiding uptake by macrophages in the liver and spleen. Traditionally, poly(ethylene) glycol [PEG] has been used as a biocompatible, hydrophilic coating that protects nanoparticles from opsonization by proteins, but many alternative hydrophilic coronas are currently being investigated. In order to optimize corona chemistry, we coupled an optimized, pH responsive core polymer composed of dimethylaminoethyl methacrylate (DMAEMA) and butyl methacrylate (BMA), to various types of hydrophilic coronas. Our comparative study aims to determine which hydrophilic corona structure provides optimal stability, circulation time, and efficacy.
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.
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.
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.
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]