Nanochains Mark Micrometastases for Early Diagnosis, Treatment
Malignant cells that leave a primary tumor, travel the bloodstream, and grow out of control in new locations cause the vast majority of cancer deaths. A new type of nanoparticle construct, developed at Case Western Reserve University, detects these metastases in mouse models of breast cancer far earlier than current methods, which is a step toward earlier detection and treatment. This approach relies on targeted chain-shaped nanoparticles that can be detected using magnetic resonance imaging (MRI).
Images of the precise location and extent of metastases could be used to guide surgery or thermal ablation, or the same technology used to find cancer could be used to deliver cancer-killing drugs directly to the cells before a tumor forms, the researchers suggest. This team, which was led by Efstathios Karathanasis, published its findings in the journal ACS Nano.
Tumor detection technologies often fail to uncover cancer cells that have taken hold in new locations because young metastases are smaller in size and do not behave the same as established tumors. After a breast cancer cell enters the bloodstream, it most often stops in the liver, spleen, or lungs and begins overexpressing surface molecules called integrins, which play an important role in metastasis. Integrins act as a glue between the cancer cell and the lining of a blood vessel that feeds the organ, and it is these molecules that the new nanochains target.
To home in on the cancer marker, the researchers first needed to build a nanoparticle that would drift out of the central flow of the blood stream and reach the blood vessel walls. Spherical nanoparticles tend to go with the flow, so Dr. Karathanasis’ team tailored iron oxide nanoparticles to chemically connect to one another in a linear fashion. Due to its size and shape, the resulting chain tumbles out of the main current and skirts along vessel walls, where attached integrin-binding molecules can latch on to sites bordering tumors. Compared to individual nanospheres, the chain’s attachment rate in flow tests was nearly 10-fold higher.
Each chain comprises four iron oxide nanoparticles that are also coated with a fluorescent molecule. The resulting chains are visible in an MRI scan and using fluorescence microscopy.
Next, the team tested the chains in a mouse model of an aggressive form of breast cancer that metastasizes to sites and organs much the same way as it does in humans. From published research, the investigators knew that metastases would be present five weeks into the modeling. They injected nanochains into the bloodstream and, within an hour, two imaging techniques, fluorescence molecular tomography and MRI, showed where traveling cancer cells had established footholds, primarily in the liver and lungs. The metastases located using the nanochains ranged from 0.2 to 2 millimeters in diameter.
Subsequent imaging at high magnification showed that these metastatic cancer cells were found mostly in the blood vessel walls, before they had time to grow into organ tissue. “Once metastatic cells move into the tissue, develop their own microenvironment, and grow into a 1-centimeter lesion, it typically indicates a late stage of metastatic disease which has an unfavorable outcome,” Dr. Karathanasis said. Now that they have proved the concept works, the team is bringing clinical radiologists on board to conduct a new study that will estimate how much new cancer the technology finds and misses.
This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, “Imaging metastasis using an integrin-targeting chain-shaped nanoparticle.” An abstract of this paper is available at the journal's website.