The central focus of our laboratory is image-guided drug delivery, combining nanovehicles, imaging techniques and methods to enhance delivery. A great challenge in cancer therapy is to deliver efficacious doses of drug to diseased tissue with minimal systemic toxicity. Another challenge is in the development of high-quality imaging protocols for identification of cancerous lesions as well as visualization of drug circulation and accumulation. We approach these problems through image-guided therapy strategies that include multiple imaging modalities (PET, CT, Ultrasound), delivery vehicle designs, targeting approaches, and release mechanisms. By encapsulating cancer therapeutics in particles designed to be stable in circulation and targetable to diseased tissue, we are able to minimize systemic toxicity and maximize drug efficacy in cancer treatment. Ultrasound has proven to be an invaluable tool in our efforts. We have shown that in addition to using ultrasound for obtaining high target-to-background images of delivery vehicles within cancerous lesions, we can use insonation to increase drug release in these localized regions. By merging these technologies, we will develop a translational imaging and therapy capability that will allow us to visualize small metastatic lesions, map tumors and their margins, and combine this imaging with ultrasound-enhanced drug release.
The Ferrara laboratory is one of several groups collaborating on the National Heart, Lung, and Blood Institute’s (NHLBI) Programs for Nanotechnology Research. This research is aimed at creating nanotechnology solutions for cardiovascular disease. Our lab is involved in efforts to develop nanoparticle-based tools to image and deliver therapeutics to atherosclerotic plaque and to enhance stem cell repair of damaged heart tissue. We are creating VCAM-1 targeted liposomes and peptide complexes and testing binding and internalization of these vehicles in static conditions and under shear stress, as well as assessing intracellular peptide trafficking as a function of cell-penetrating motif. In addition, UCDavis laboratories will combine efforts with the Jo laboratory at Emory to optimize siRNA therapies for atherosclerosis using peptide-targeted nano-vehicles and optimizing their delivery. (back to top)
The ability to quantitatively assess therapeutic response is a critical element of cancer treatment and research. Our lab is working on the development of repeatable, operator-independent methods for quantitative evaluation of therapeutic response using ultrasound. We have embedded methods for real-time quantitative parametric ultrasound imaging of vascular volume/density and flow rate in a clinical scanner. Our goal is to obtain real-time, on-scanner measurements of these parameters, and to use the feedback in conjunction with histology to evaluate treatment effects and to optimize treatment with a cocktail of appropriate drugs. We are also working on enhancing therapeutic efficacy by using ultrasound to increase vascular permeability and delivery vehicle accumulation. Our initial studies have shown that insonation with a low thermal dose increases accumulation by three-fold in tumors and by up to ten-fold in muscle or lymph nodes compared to tissue not receiving ultrasound. Our project involves a determination of the biological mechanism for enhanced permeability.(back to top)
Ultrasound imaging can spatially map small temperature changes resulting from hyperthermia. In our laboratory we release drugs from vehicles using mild hyperthermia. We are developing methods for real-time measurement of temperature using ultrasound and applying these methods in image-guided drug delivery. Further, in order to predict and plan treatments we have developed graphics processing unit (GPU) code to rapidly map the applied ultrasound pressure field. (back to top)
Our overall goals in this project are to create safe and effective targeted ultrasound imaging strategies for a range of vascular receptors and to incorporate targeted imaging in cancer diagnostics and therapies. Contrast ultrasound imaging is a compelling imaging technique, as it is widely-used, inexpensive, portable, and permits real-time anatomical and molecular imaging. Within the past five years, we have created new imaging methods, evaluated the physics and bioeffects of microbubble contrast agents and developed new synthesis strategies. We developed a spectral approach to quantify bound agents and here will determine the sensitivity and accuracy of this strategy. This new method is insensitive to system gain and does not require the use of high mechanical index pulses. We apply these methods to evaluate the avidity of ligands for a set of receptors that are up-regulated in angiogenesis, focusing on breast, prostate and bladder cancer. (back to top)
We have developed liposomal particles that can be activated by exogenous energy sources, thus locally delivering drugs. For particles that can be activated by ultrasound, we have found that a 60-fold increase in delivery of hydrophilic molecules (as compared to free drug administration) can be achieved. In order to activate particles with ultrasound using mild heating, a short acyl chain must be incorporated—as a result, the particles are not fully stable during circulation. In order to improve stability, we have designed particles with a longer acyl chain that can deliver a greater dose but require a new method of activation. By incorporating gold nanoparticles within the lipid bilayer of liposomes, these particles can be heated using electromagnetic waves, releasing the drug in any region deep within the body and achieving a 200-fold increase in drug accumulation. Although the gold particles can also be used to directly ablate a region, their use to locally deliver a drug in a safe and efficacious manner could be important in cancer therapeutics, and we are therefore developing the system and particles to deliver hydrophilic molecules using electromagnetic energy. As a proof of concept, we will load the particles with a hydrophilic drug and demonstrate delivery and efficacy in a murine tumor model. Our goals are to quantify, refine and enhance the RF-EM heating device for heating gold nanoparticles, test and improve release of cargo from temperature-sensitive liposomes using gold nanoparticles, compare delivered dose of hydrophilic drug using RF-EM method vs. ultrasound heating as a function of treatment duration, and demonstrate efficacy of drug release in implanted tumor models. (back to top)
Engineering Approaches to Molecular Imaging
Dr. Ferrara is the principal investigator for an NIH T32 training grant from the National Institute of Biomedical Imaging and Bioengineering in the area of Molecular Imaging (TPMI). Molecular imaging is a highly interdisciplinary research field, involving scientists from the biological, engineering, physical and medical sciences. The heart of this Program is the Biomedical Engineering Graduate Group, a cross-disciplinary program spanning 25 departments that administers the Ph.D. degree. Two graduate tracks, biomedical imaging and cell & molecular systems engineering, are combined to create this training program. The didactic program includes core courses spanning biology, mathematics and instrumentation, and many elective courses covering each molecular imaging modality, as well as cellular biology and receptor-ligand interactions. A unique hands-on molecular imaging laboratory, using the Center for Molecular and Genomic Imaging, facilitates exploration of the resolution, contrast and sensitivity of each imaging modality.(back to top)