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Perfluorocarbons, a class of inert, oily polymers, have a proven track record in a variety of clinical uses, including in contrast-enhanced ultrasound imaging and in eye surgery to correct a detached retina. Researchers at the Siteman Center of Cancer Nanotechnology Excellence (Siteman CCNE), led by longtime Washington University School of Medicine collaborators Samuel Wickline, M.D., and Gregory Lanza, M.D., are well on the way to developing a new use for perfluorocarbons: as the building blocks for nanoparticles capable of delivering a wide range of imaging agents and drugs to tumors. Three recently published papers highlight their progress.
In one of the new papers, published in The FASEB Journal, the Siteman CCNE team reports on its work using targeted perfluorocarbon nanoparticles to deliver both a potent fungal toxin known as fumagillin and a magnetic resonance (MR) contrast agent to the rapidly growing blood vessels that permeate a tumor. Fumagillin has shown promise in human clinical trials as an anticancer agent for a wide variety of cancers, but therapeutic doses of the drug produce sudden, severe side effects.
To overcome this limitation, the investigators encapsulated fumagillin in perfluorocarbon nanoparticles targeted to b3 integrin, a molecule found on the surface of newly developed blood vessels in tumors. The researchers found that this formulation was active in both stopping angiogenesis in tumors and reducing tumor size at fumagillin doses more than a thousandfold lower than those used in earlier animal studies and some sixtyfold lower than the doses used in human clinical trials. At this markedly lower dose, nanoparticle-delivered fumagillin not only was equally effective as the much higher dose of unencapsulated fumagillin but also produced measurable side effects in the animals receiving the nanoparticle formulation.
MR images, in which the signal from tumors was enhanced as a result of nanoparticle binding, confirmed that this formulation was having the desired therapeutic effect. This nanoparticle, then, has the potential to both treat a tumor and report on the efficacy of treatment in real time. These nanoparticles will be tested this year in preliminary human clinical trials to determine the optimal method for using them as imaging agents. These studies will lay essential groundwork for using the nanoparticles as therapeutic agents.
In a second paper, Drs. Wickline and Lanza and their colleagues demonstrated that perfluorocarbon nanoparticles could also serve as stable delivery vehicles for a class of molecules known as cytolytic peptides, which are capable of inserting themselves into a tumor cell's membrane, causing it to rupture and thus killing the cell. However, these peptides are notoriously unstable in blood, but as the investigators report in the journal Nano Letters, perfluorocarbon nanoparticles are able to incorporate these peptides into their outer coating. More importantly, these peptide-coated nanoparticles will release the peptides when they come in physical contact with cells, an effect that could be mediated using a targeting agent such as the antibody used to target avb3 integrin. Additional work, prompted by these positive results, is ongoing.
Another approach to deliver cargo from perfluorocarbon nanoparticles into cells, described in a third paper from the Siteman CCNE team, used ultrasound stimulation to trigger uptake of the nanoparticles by the irradiated cells. This work, published in the journal Nanotechnology, demonstrated that ultrasound-mediated cargo delivery does not involve disrupting the cell's membrane, although the exact transfer mechanism is not yet known.
This work, which was supported in part by the National Cancer Institute's (NCI) Alliance for Nanotechnology in Cancer, is detailed in three papers. The work on angiogenesis inhibition appears in the paper "Minute dosages of avb3-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits." Investigators from Philips Medical Systems and Kereos, Inc., also participated in this study. An abstract of this paper is available at the journal's Web site.
About National Cancer Institute
To help meet the goal of reducing the burden of cancer, the National Cancer Institute (NCI), part of the National Institutes of Health, is engaged in efforts to harness the power of nanotechnology to radically change the way we diagnose, treat and prevent cancer.
The NCI Alliance for Nanotechnology in Cancer is a comprehensive, systematized initiative encompassing the public and private sectors, designed to accelerate the application of the best capabilities of nanotechnology to cancer.
Currently, scientists are limited in their ability to turn promising molecular discoveries into benefits for cancer patients. Nanotechnology can provide the technical power and tools that will enable those developing new diagnostics, therapeutics, and preventives to keep pace with today’s explosion in knowledge.
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