Texas A+M University is one of five collaborating institutions in an $18 million National Institutes of Health-funded research program to develop nanotechnology-based therapies and diagnostics tools for treating heart and lung diseases.
The award, “Integrated Nanosystems for Diagnosis and Therapy,” is one of four Programs of Excellence in Nanotechnology (PEN) funded nationwide through the National Heart, Lung, and Blood Institute. It will support five years of nanoparticle-focused research led by co-principal investigators Karen L. Wooley of Texas A&M and Michael J. Welch of Washington University School of Medicine in St. Louis in conjunction with colleagues at the University of Texas Southwestern Medical Center and the University of California, Santa Barbara and Berkeley.
Nanoparticles — tiny particles no more than 1 to 100 billionths of a meter in size — can be custom-engineered by scientists to deliver imaging agents or therapies, such as drugs, chemotherapies or genetic material, to specific targets, including tumors, particular cell types or sites of inflammation.
“Nanoparticles have several advantages over the small molecules typically used in imaging and therapeutics,” says Welch, professor of radiology and developmental biology at Washington University. “Not only can we load them with agents that deliver therapies to specific targets, we can include imaging agents that help us track both the nanoparticles and the therapeutic agent, and change the surface of the particles to customize the amount of time they spend in the body.”
The new initiative includes four primary research projects. Wooley, who holds the W.T. Doherty-Welch Chair in Chemistry at Texas A&M and is considered one of the top chemists worldwide in the field of materials and polymer chemistry, will lead one that focuses on the design of advanced nanomaterials. In addition, she will be involved in two others that will develop nanomaterials to address lung-related infectious diseases and acute lung injury — one of which also involves internationally renowned Texas A&M biochemist James C. Sacchettini, holder of the Wolfe-Welch Chair in Science.
“The work that will be conducted through this Program of Excellence in Nanotechnology is expected to lead to remarkable advances in well-defined, multi-functional systems that will dramatically alter the future of medical practice by providing non-invasive detection, diagnosis and treatment of lung and cardiovascular diseases with greater degrees of sensitivity and selectivity,” Wooley says. “We have established a diverse team of physical scientists, biologists, radiologists and medical practitioners to address the various hurdles that will be encountered in the design of integrated nanosystems and their translation to effective devices. The state of Texas is playing a key role through its investigators at Texas A&M University and the University of Texas Southwestern Medical Center.”
Wooley, who relocated to Texas A&M from Washington University in July 2009, serves as head of a synthetic chemistry group that will investigate the fundamental aspects of nanostructured materials which will lead to the design and creation of novel systems capable of impacting the detection, diagnosis and treatment of heart and lung diseases. Scientists target nanoparticles to different objectives in the body by customizing the particles’ physical and chemical properties. For instance, she says, they can adjust the materials from which the nanoparticles are made to alter their size, shape and flexibility or their internal and external chemical compositions. Control over each parameter will allow for modification of the nanomaterials’ trafficking in the human body as well as their interactions with bacteria or diseased cells and enable researchers to identify sites of infection or injury and to deliver therapeutics.
“It is not a case that nanoparticles are able to actually ‘target’ a certain place in the body,” Wooley explains. “However, if they have particular chemistries, they can be made to migrate or diffuse differently from small molecules or microscopic materials and selectively bind to receptors to be retained within those regions. Effectively, their cargo is carried along so that it then takes on their unique biodistribution, thereby providing for enhanced delivery of imaging agents and therapies.”
Sacchettini, a member of the structural biology group housed in Texas A&M’s new Interdisciplinary Life Sciences Building, is critical to another project led by Carolyn L. Cannon, MD, of the University of Texas Southwestern Medical Center that emphasizes the application of nanoparticles as a means of treating patients with cystic fibrosis, an inherited condition that subjects patients to repeated, life-shortening lung infections. Cannon’s previous research has shown that silver-based therapeutic agents act as antimicrobials and can treat lung infections in mouse models. In addition, she has found that delivering those treatments with nanoparticles increases their effectiveness and reduces the required dosage. Cannon, Sacchettini and their colleagues will use the new NHLBI funding to complete the preclinical research necessary to begin testing this approach in humans with cystic fibrosis and other infectious diseases, such as tuberculosis and malaria.
“Nanoparticles armed with a powerful drug payload aimed at infectious agents in the body are the equivalent of medical star wars,” Sacchettini explains. “If this approach works, it will significantly reduce or eliminate drug side effects, even for the most powerful and toxic drugs.”
A third team of researchers, led by Steven L. Brody, MD, associate professor of medicine at Washington University, will use nanoparticles to diagnose and treat various forms of acute lung inflammation.
“Trauma and infectious diseases are the most common causes of this inflammation, but there are others, including exposure to hazardous chemicals and additional genetic factors, that we don’t fully understand yet,” Brody says. “We have some simple therapies, such as antibiotics, but to make real progress, we need the flexibility and power that nanotechnology can provide, both in diagnosis and therapy.”
As proof of principle, Brody and his colleagues will be working to develop ways to use nanoparticles to image and suppress the activity of nitric oxide synthase, an enzyme commonly produced at high levels in inflammatory reactions in the lungs and airway.
The fourth group, led by Pamela K. Woodard, MD, professor of radiology at Washington University, will work to develop nanoparticles to help physicians detect early atherosclerosis. Researchers have already created and tested nanoparticles that target a biological indicator which appears very early in the plaque formation process. The indicator is a receptor that blood cell vessels begin producing at higher levels even before plaques start to stabilize.
Preclinical studies have shown such nanoparticle-based agents offer major advantages over the small-molecule agents more typically used to look for plaques. Scientists plan to test the nanoparticle-based imaging agents in phase I clinical trials in the final years of the award.
“We want to find ways to stratify patients based on risk of heart disease, which could potentially allow us to begin preventive treatments earlier in the disease process,” Woodard says.
The award also will fund two developmental projects evaluating receptors that can be targeted with nanoparticles to image atherosclerosis and investigating unique ways to use optical imaging techniques to track the behavior of nanoparticles.
A nanomaterials production core, led by Craig J. Hawker, professor of chemistry, biochemistry and materials at the University of California, Santa Barbara, and director of the UCSB Materials Research Laboratory, will provide facilities for the scaled-up production of promising nanoparticle systems for preclinical studies. The National Center for Therapeutics Manufacturing — a newly developed, state-of-the-art biomanufacturing facility that is a result of a partnership between The Texas A&M University System, the Texas Engineering Experiment Station, Texas A&M University and the state of Texas — and other facilities at Washington University each will provide resources for additional nanoparticle production to provide materials for use in preclinical and clinical trials.
A portion of the funds will support educational programs designed for students from elementary to postgraduate levels to stimulate interest in careers in medical nanotechnology development.
“The success of this Program of Excellence in Nanotechnology will be measured not only by technological advances, but also by the education and training of creative, intelligent and hard-working students and postdoctoral associates who will perform the research activities that will determine the future of the nanotechnologies under development,” Wooley adds.