Targeted drug delivery: DNA robocontainers
DNA robots have learned how to fight cancer cells
Dmitry Malianov, "Newspaper.Ru»
With the help of DNA robots folded in the manner of origami, bioengineers from Harvard University managed to deliver "black marks" to cancer cells - a command to self–destruct.
A research group at the Wiss Institute of Bioengineering at Harvard University has designed a DNA robot capable of finding the right targets in a mixed cell culture and transmitting the right molecular instructions, for example, to command a cancer cell to self-destruct.
This technology, which simulates the work of the immune system, will in the future allow programming immune responses at the cellular level in the treatment of various diseases. An article describing it (A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads) was published on Friday in Science.
Using the DNA origami method, which allows you to create complex three-dimensional objects from individual DNA chains, Dr. Shawn Douglas and a former employee of the Wiss Institute Ido Bahelet from Israel's Bar-Ilan University designed a DNA robot in the form of a nanoscale cylinder open at both ends. The DNA fragment, which plays the role of a container, is rolled into a cylinder held by special DNA latches, which open after recognizing certain combinations of proteins marking pathology on the cell membrane. Having found the target, the latches change their configuration, and the cylinder opens, releasing the working fragment of an antibody – an instruction protein enclosed inside, interacting with certain signal receptors on the outer surface of the cell membrane.
Special nucleotide sequences (aptamers) play the role of a latch,
holding the DNA cylinder in the closed state.
Aptamers are able to selectively bind to certain proteins
(for example, proteins on the surfaces of cell membranes),
opening the cylinder and releasing the antibody. // Science
DNA origami robots in folded and disassembled state
Using DNA robots, Douglas and Bahelet transmitted certain "messages" hidden inside the cylinders to the cells of two types of cancer – leukemia and lymphoma.
The "messages" contained instructions that included a mechanism for self-destruction of cells by analogy with the standard immune procedure for removing aging or atypical cells from the body. And since tumor leukocytes and lymphocytes understand different molecular instructions, the "messages" inside the DNA cylinders were differently combined fragments of antibodies.
The proposed technology of nanotherapeutic programming simulates a natural immune algorithm in which white blood cells, constantly patrolling the bloodstream, react to foreign particles, including pathogenic cells. Leukocytes find diseased cells, attach to them and transmit instructions through special proteins ordering the cell to self-destruct. By endowing the DNA cylinder with various "latches" and instructor proteins, it is thus possible to create nanoscale transformer robots programmed to search for and instruct various pathogenic cells.
"Eventually, we will be able to combine various sensory and logical functions in such DNA devices, combining structural fragments of DNA, antibodies, aptamers and metalloproteins in different ways in order to properly affect cancer cells and T-lymphocytes (a type of lymphocytes that play an important role in the acquired immune response. – Newspaper.Ru)," Dr. George Church, professor of genetics at Harvard Medical School and lead researcher in the project to create DNA robots, comments on the article in Science.
By tuning DNA cylinders and antibodies loaded into them in different ways, the authors of the study forced DNA robots to find the right targets in mixed cultures of healthy and cancerous leukocytes and lymphocytes, clinging to pathogen cell receptors and transmitting the necessary instructions to cells.
The result of the work of DNA robots was controlled by luminescent labeling of antibodies, metalloproteins, as well as by means of an electron microscope, which allows direct observation of the configuration of DNA cylinders.
Due to the good biocompatibility of DNA containers, which, having done their job, are destroyed without having a toxic effect on the body, DNA robots have long been considered as one of the most promising technologies in the treatment of oncological and other diseases requiring targeted cellular drug delivery or cell reprogramming. The main problem remains the choice of the most effective method of delivery and unloading of the medicine, as well as the launch of a particular instruction.
A robot in the form of an open DNA cylinder, which can be loaded by closing a DNA fragment with just one "click", and also easily unloaded by programming a DNA latch for a combination of pathogenic proteins, leaves behind one of the main obstacles that stood in the way of nanotherapy. The novelty of the technology also lies in the fact that, unlike the previously proposed solutions, such a DNA device is able to respond not only to the basic nucleic sequences of DNA and RNA inside pathogenic cells, but also to act at a higher signaling level, selectively reacting to marker proteins located on the outer cell membrane.
So far, robots are successfully finding their targets in vitro – in a specially prepared cell culture. It is clear that test tube experiments are very different from the real conditions in which DNA devices will have to work. The immune system will perceive foreign DNA objects as foreign bodies, so robots will have to be taught to bypass immune defenses or mask them, for example, by covering DNA cylinders with proteins native to the body. Anyway, the first step on the way to nanotherapy has been taken – the task of creating logical nanodevices based on DNA can be considered solved.
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17.02.2012