A. Take the unmodified liposome and now incorporate what nature has taught through surface modifications HYPOTHESIS: B. Specifically, ligands that will recognize and bind specific receptors C. Molecules like oligosacc or polymers that will hydrate the interface and decrease undesirable interactions |
CLEVELAND-- Researchers at Case Western Reserve University are developing an innovative drug delivery device to help treat cardiovascular disease.
"Cardiovascular disease is the number one killer in the U.S., particularly for men who die of strokes and heart attacks brought on by blocked or closed arteries," said Roger Marchant, the lead researcher on the study and professor in the department of biomedical engineering at Case Western Reserve University. "Our research focuses on using liposomes, small spherical shaped artificial vesicles only 100 nanometers across or 1/100 the size of a single cell, as drug carriers that could be injected to directly target damaged areas of the arteries in intravascular disease," he said.
Liposomes are produced from natural nontoxic phospholipids (fat derivatives in which one fatty acid has been replaced by a phosphate group and one of several nitrogen-containing molecules) and cholesterol. They are already being used as carriers for water soluble anticancer drugs that treat cancers of the blood, lymph system, bladder, breast, stomach, lungs, ovaries, thyroid, nerves, kidneys, bones and soft tissues, including muscles and tendons and others.
"Liposomes as a drug delivery device is novel in cardiovascular disease," Marchant said. "These nanoscale devices are extremely versatile because they are easily modified, they encapsulate a large volume for carrying therapeutic drug agents and we can vary their composition."
Marchant is developing the liposomes to target injured arteries with the help of a $1.4 million grant from the National Heart, Lung and Blood Institute of the National Institutes of Health. He works with co-investigator Zhong-Wu Guo, CWRU professor of chemistry, as well as Jim Anderson, CWRU professor of pathology. Anderson handles the modeling for testing the device; Cleveland Clinic researchers Marc Penn, a cardiologist who supervises rat models with invivo targeting of the device; and Kandice Marchant, a pathologist and CWRU adjunct professor in the department of biomedical engineering who has performed in vitro blood testing.
For the liposome to succeed as a cardiovascular drug carrier, it must target and bind with damaged cells that have a unique surface receptor. The CWRU research team has used an RGD peptide, a cell adhesion sequence, to stabilize the weak outer structure of the liposome and help lead it directly to the GPIIb-IIIa receptor expressed on the platelets that form in response to vascular injury, and coagulation factor VII-derived peptides that target the receptors on damaged endothelial and vascular smooth muscle cells. The team plans to evaluate the liposomes targeting ability in rat models.
For the liposome to succeed as a cardiovascular drug carrier, its lifetime in the blood stream must also increase. "We design liposomes to target and bind unique cell surface receptors and use mimics of a cell's sugar coating to inhibit protein adsorption to the liposome and increase its longevity in the bloodstream," Marchant said. "Current liposome systems only last approximately 12 hours as opposed to a normal red blood cell, which can circulate 120 days. We plan to evaluate the circulation lifetime in mouse models."
Marchant believes that liposomes will be common carriers for drug delivery in less than 10 years. He considers liposomes a viable alternative approach to existing treatments, such as angioplasty, blood-thinning drugs and aortocoronary bypass surgery.
"Microscopic liposomes could carry drug therapy right to an injured vessel, helping patients to avoid heart attack," Marchant said. "Secondarily, clinicians and cardiologists could use these liposomes with a built-in drug agent to treat patients after a stent placement."
Note: Images available at www.cwru.edu/pubaff/univcomm/2002/7-02/liposomes.htm