Targeted nanoparticles map tumor blood supply in 3-D, assess therapy

One of the defining characteristics of solid tumors is the development of a network of new blood vessels to nourish the rapidly reproducing malignant cells. Now, using a nanoparticle targeted to those new blood vessels, a joint academic-industrial research team, led by investigators from the Siteman Center of Cancer Nanotechnology Excellence, has developed a way to construct a three-dimensional (3-D) map of tumor-induced angiogenesis and monitor the effects of drug therapies on those new blood vessels.

Reporting its work in the FASEB Journal, a research team headed by Washington University in St. Louis colleagues Gregory Lanza, M.D., and Samuel Wickline, M.D., described its development of a perfluorinated nanoparticle loaded with gadolinium ions, which boost magnetic resonance imaging (MRI) signals, and then coating this nanoparticle with a peptide that targets new blood vessels. This particular peptide binds strongly to a cell-surface protein known as a5b1 integrin. For the sake of comparison, the investigators also prepared an identical nanoparticle but coated it with a related peptide that does not bind to a5b1 integrin. They also prepared a third nanoparticle coated with a small organic molecule that binds to both a5b1 integrin and avb3 integrin.

When the investigators injected the nanoparticle targeted to a5b1 integrin into tumor-bearing mice, they were able to use MRI to produce a 3-D map of tumor-associated blood vessels. From this map, the researchers were able to show that nearly all of the new blood vessels were on the rim of the tumor. The investigators confirmed these findings through microscopic examination of the tumors after they had been removed surgically from the mice.

Next, the investigators injected the mice with nanoparticles loaded with a drug known as fumigillin, which stops new blood vessel growth. Some of these nanoparticles were coated with the a5b1 integrin targeting peptide, whereas others were coated with the small organic molecule that binds to both a5b1 integrin and avb3 integrin. They then used the MRI-enhancing nanoparticle that targeted a5b1 integrin and avb3 integrin to assess any therapeutic changes produced by the fumagillin-loaded nanoparticles. The resulting 3-D images showed that the dual-targeted, drug-loaded nanoparticle decreased tumor-associated angiogenesis to near neglible levels. The singly targeted nanoparticles were less effective, and the untargeted nanoparticle was ineffective at reducing angiogenesis.

Somewhat surprisingly, the reduction in angiogenesis did not have an effect on tumor size. The researchers attributed this observation to the fact that the tumor model they used does not produce as much angiogenesis as do other more common models of human cancer. The researchers chose this model because they wanted to determine whether their nanoparticles could image relatively sparse angiogenesis, a normally difficult proposition.

This work, which is detailed in the paper "In Vivo Tumor Cell Targeting With 'Click' Nanoparticles," was supported by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. Investigators from Philips Healthcare and the University of Missouri also contributed to this work. An abstract of this paper is available through PubMed. View Abstract.


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