A drug prototype based on a barrel of DNA stuffed with antibodies potentially could lead to cancer drugs that cause fewer side effects. The drug carrier can target particular cell types very specifically, attach to their surface, and trigger signaling cascades within. Researchers at Harvard who developed the DNA nanorobot have demonstrated a variety of capabilities, including the ability to trigger apoptosis in leukemia cells in vitro (Science 2012;335:831–4).
![A DNA nanorobot springs open like a clamshell to reveal its payload, antibody drugs (purple). The DNA shell is held together by 2 DNA locks (red) that open when they meet molecular keys (green) found on the surface of a cell. Top left shows a side view of the DNA shell in its closed state. [Photo courtesy of Campbell Strong, Shawn Douglas, and Gaël McGill using Molecular Maya and Cadnano]](/view-large/figure/8406593/292photo1.jpeg)
A DNA nanorobot springs open like a clamshell to reveal its payload, antibody drugs (purple). The DNA shell is held together by 2 DNA locks (red) that open when they meet molecular keys (green) found on the surface of a cell. Top left shows a side view of the DNA shell in its closed state. [Photo courtesy of Campbell Strong, Shawn Douglas, and Gaël McGill using Molecular Maya and Cadnano]
A DNA nanorobot springs open like a clamshell to reveal its payload, antibody drugs (purple). The DNA shell is held together by 2 DNA locks (red) that open when they meet molecular keys (green) found on the surface of a cell. Top left shows a side view of the DNA shell in its closed state. [Photo courtesy of Campbell Strong, Shawn Douglas, and Gaël McGill using Molecular Maya and Cadnano]
The DNA nanorobot was designed by researchers led by George Church, PhD, professor of genetics at Harvard Medical School, using a method called DNA origami. Over the past several years, researchers have developed software programs that write sequences of DNA strands that, when synthesized and mixed together, will self-assemble to form complex 3-dimensional shapes such as boxes.
The Harvard group built on this work, designing a DNA cylinder lined with protein-binding sections on the inside that can hold onto a payload. The cylinder opens up like a clamshell, with DNA springs on one side and DNA locks on the other. The locks are based on aptamers, sequences of DNA that bind tightly and specifically to particular molecules—for instance, cell-surface proteins typical of T cells or aggressive leukemia cells. When the aptamer locks find their targets, they latch on, and the DNA box springs open, revealing the payload. The nanorobot's 2 aptamers can target different antigens.
In the experiments with leukemia cells, the researchers loaded the DNA nanorobots with an antibody drug that binds to a surface receptor on the cancer cells, initiating a signaling cascade that flips the cells' kill switch. The study suggested that the nanorobots didn't interact with other types of cells.
The researchers call the DNA drug carrier a nanorobot because it performs a logic function—adding 2 input signals (the presence of the 2 molecular keys) to generate an output (opening to reveal its payload) like an “AND” logic gate in electronics.
Shawn Douglas, PhD, a fellow at the Wyss Institute for Biologically Inspired Engineering at Harvard and co-first author on the Science paper, notes that before the researchers can test the DNA nanorobots in mice, they must scale up production a thousand-fold. He adds that they'll have to modify the DNA structures so that the structures will stay in the circulation—it's likely the current design would be cleared from the bloodstream quite rapidly.
For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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