Novel Agent for Lymph Node Imaging and Targeted Gene Therapy

Institution: University of California, Davis
Investigator(s): Erik Wisner, D.V.M. -
Award Cycle: 1996 (Cycle II) Grant #: 2IB-0042 Award: $40,912
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Imaging, Biomarkers, and Molecular Pathology: improving detection and diagnosis



Initial Award Abstract (1996(
The primary purpose of this study is to develop a contrast agent that improves detection of cancerous lymph nodes in women with breast cancer. An additional goal is to determine if the same agent can simultaneously be used to transport genetic material to cancer cells as an innovative method of cancer therapy. Depending on the size of the primary lesion at the time of the initial cancer staging (that is, the determination of the size, nature, and extent of the tumor), up to 65% of women with breast cancer have a cancer that has spread (metastasized) to the lymph nodes in the nearby area of the original cancer. Physical examination and diagnostic imaging procedures (such as X rays) are currently unreliable for determining whether or not the cancer has metastasized to the lymph nodes, and therefore surgical removal of regional lymph nodes is often required for accurate cancer staging. For those patients with cancerous lymph nodes, systemic chemotherapy, radiation therapy and/or surgery is currently necessary for control of regional disease. Although not yet routinely used, many recent studies have shown that incorporating pieces of DNA into cancer cells (gene transfection) can halt tumor growth and sometimes result in shrinkage of the tumor. Developing strategies to improve the efficiency of gene transfection could result in revolutionary changes in the way cancer is treated.

Magnetic resonance imaging (MRI) is one of a number of diagnostic imaging tests currently used to evaluate lymph nodes for cancer staging. However, because lymph nodes appear similar to surrounding tissues on MR images, lymph node detection can be difficult and telling the difference between normal and cancerous nodes is often impossible. Therefore, the development of an easily administered "contrast" agent—a substance that increases the visibility of node tissue—could significantly improve lymph node detection and cancer staging accuracy.

We intend to develop a new and novel contrast agent by combining a currently used MR contrast agent called Gd-DTPA with microscopic particles known as liposomes. When injected under the skin, this new contrast agent should accumulate in the small lymphatic vessels and be carried to regional lymph nodes. In the targeted node, the agent will collect and concentrate, producing a defined area of contrast enhancement. MR imaging studies will then be performed to determine the extent of enhancement of the lymph node image. Imaging properties of the agent will be evaluated both with and without genetic material (DNA) incorporated into the liposome core. We will then determine the extent of DNA uptake and expression in cells within targeted lymph nodes. Successful transport and incorporation of DNA into lymph node cells using Gd-bound liposomes would demonstrate the potential of this material to serve both as a therapeutic and as a diagnostic imaging agent.

Development of an easily administered contrast medium that enhances regional lymph node appearance on MR images could lead to earlier detection of breast cancer metastasis and more accurate cancer staging. This could also have a significant clinical impact in reducing the need for diagnostic surgical lymph node removal and its attendant complications. Directed gene therapy targeted to regional lymph nodes could also provide an ancillary or alternative approach to current regional breast cancer treatment strategies.


Final Report (1997)
The primary purpose of this study was to develop a magnetic resonance contrast agent to improve early detection of cancerous lymph nodes in women with breast cancer. A second goal was to determine whether this agent could also be used for DNA transport to metastatic cancer cells as an innovative method of cancer therapy.

Physical examination and diagnostic imaging procedures are currently unreliable for diagnosing lymph node metastasis and therefore surgical removal of regional lymph nodes is often required for accurate cancer staging. For those patients with cancerous lymph nodes, systemic chemotherapy, radiation therapy and/or surgery is necessary for control of regional disease. Magnetic resonance imaging (MRI) is one of a number of diagnostic imaging tests used to evaluate lymph nodes for cancer staging. However, because lymph nodes appear similar to surrounding tissues on MR images, lymph node detection can be difficult and differentiation of normal and cancerous nodes is often impossible. Therefore, the development of an easily administered contrast agent that increases the visibility of node tissue could significantly improve lymph node detection and cancer staging accuracy. Although not yet routinely used, many recent studies have shown that incorporating DNA fragments into cancer or normal cells (gene transfection) can halt tumor growth and sometimes result in tumor regression. Developing strategies to improve the efficiency of gene transfection could result in revolutionary changes in the way cancer is treated. This investigation has demonstrated a proof-of-principle in the development of a combined diagnostic imaging and therapeutic agent for breast cancer diagnosis and therapy.

We have successfully developed a prototype diagnostic and therapeutic agent by binding conventional MR contrast materials to lipid microspheres, or liposomes (i.e., microscopically small membrane-enclosed sacs made in the laboratory). In preliminary imaging studies, this agent significantly improves the visibility of regional lymph nodes on MR images after subcutaneous injection. In addition, we have demonstrated significant uptake and expression of marker DNA material in cells cultures exposed to the agent after incorporating the marker into the core of the liposome component.

An easily administered contrast medium that enhances regional lymph node appearance on MR images could lead to earlier detection of breast cancer metastasis and more accurate cancer staging. This could also have a significant clinical impact in reducing the need for diagnostic surgical lymph node removal and its attendant complications. Directed gene therapy targeted to regional lymph nodes could also provide an ancillary or alternative approach to current regional breast cancer treatment strategies.

A novel agent for indirect MR lymphography and gene transfection
Periodical:Veterinary Radiology and Ultrasound
Index Medicus: Vet Radiol Ultrasound
Authors: Wisner ER, Nanz MH, and Bennett MJ
Yr: 1996 Vol: 37 Nbr: 6 Abs: 2-9 Pg:466

A modular lymphographic magnetic resonance imaging contrast agent: contrast enhancement with DNA transfection potential
Periodical:Journal of Medicinal Chemistry
Index Medicus: J Med Chem
Authors: Wisner ER, Aho-Sharon KL, Bennett MJ, Penn SG, Lebrilla CB, Nantz MH
Yr: 1997 Vol: 40 Nbr: 25 Abs: Pg:3992-6