In a first-of-its-kind study that furthers the applications of nanomedicine, the technique of “DNA origami” through programmed nanorobots has proven successful against breast cancer, melanoma, ovarian and lung cancer tumors.
Nanomedicine is a nascent field opening nanotechnologies to a wide range of applications in preventive and palliative care. Currently, nanomedicine includes the use of molecule-sized structures, called nanoparticles, to identify and treat diseases. Within nanomedicine, oncological uses and cancer treatment is an exponentially developing area.
A team of scientists from Arizona State University (ASU), in conjunction with cooperation partners from the National Center for Nanoscience and Technology (NCNST) at the Chinese Academy of Sciences, has reached an important benchmark for nanomedicine by creating and programming nanorobots tasked with cutting off the blood supply of tumors to trigger their shrinkage, an action they have successfully completed.
Professor Hao Yan, director of the ASU’s Center for Molecular Design and Biomimetics confirmed that his team has developed a fully autonomous DNA robotic system programmed with a highly precise drug design and targeted therapy for the first time.
The application of nanorobots in oncological therapies was hindered by the need to design, build and control prototypes that, while successfully destroying cancerous tumors, would also leave healthy cells unharmed. But since 2013 NCNST researchers embarked on an attempt to build nanorobots tasked with a clear mission: use high precision to find and starve a tumor by cutting off its blood supply. With this approach, DNA-based nanocarriers were used to induce blood coagulation with great efficacy, gradually isolating the tumor’s blood source.
The nanorobots are structures at a scale of one-thousandth the width of a human hair. Their key component is a DNA origami sheet, a 90 nanometers by 60 nanometers DNA flat rectangle. This sheet can self-fold into different shapes and sizes. For this particular study, a blood-clotting enzyme called thrombin was attached to the DNA origami sheet’s surface. This enzyme is able to stop the blood flowing into the tumor by creating a blood clot that eventually triggers a tumor “mini heart attack” and causes its demise. On average, some four thrombin molecules were attached to the DNA origami sheet. The nanorobots in question have been programmed to the extent that according to NCNST professor Baoquan Ding, they can “transport molecular payloads and cause on-site tumor blood supply blockages”.
Scientists injected human cancer cells into a mouse to induce aggressive tumor growth. As the tumor began to grow, the nanorobots were deployed through an intravenous injection into the mouse’s bloodstream, where they find their way towards the tumor’s feeding blood vessel. At this point, the DNA sheet is folded on itself like a small tube. Once the sheet lands and secures position on the blood vessel surface, the sheet unfolds and exposes the thrombin molecules right at the entry of the tumor’s feeding channel and triggering the gradual process of creating the blood clot. In the experiments, the nanorobots were observed to congregate in large numbers and surround the tumor just hours after the deploying injection.
The research team guided by Prof. Hao Yan has managed to reach a milestone by creating a fully programmable nanorobot capable of autonomy to perform its mission. But the team went further and ensured that the nanorobots only attack cancer cells to avoid damage to non-cancerous tissues and cells. This was achieved by adding a payload on the nanorobot’s surface, named a DNA aptamer. This payload specifically targets the nucleolin protein, which is produced in high amounts on a cancerous tumor’s endothelial cell surfaces and is absent from healthy cell surfaces. Of particular importance for the success of this method was to trigger the thrombin enzyme only when the DNA sheet was already inside the tumor blood vessels.
Within 24 hours of deploying the nanorobots, blood supply to the tumor was disrupted and tumors suffered damage. Once the anti-tumoral attack was finished, most of the nanorobots degraded from the body within a day. By 48 hours scientists detected advanced thrombosis in the tumors and by 72 hours all tumor vessels showed the presence of thrombi.
Encouraging results also came out of the nanorobotic application in melanoma mouses, where 3 out of 8 mice displayed complete tumor regression, a doubling of survival time, and prevented metastasis, hinting at a potential for therapeutic applications of nanorobots. For lung cancer mouse tests tumor tissue shrinkage was observed after two weeks of treatment.
The nanorobots were found to not exert any changes in normal blood coagulation, cell morphology or spread to the brain which could raise the risk of strokes. Therefore so far as their application in mice and large animals is concerned, the nanorobots were safe, effective and immunologically inert in their mission to attack tumors.
Professor Yan is optimistic that the approach developed for this study can be applied to many types of cancer since blood vessels feeding cancerous tumors are the same. Now, the design of nanorobots carrying different enzymes and agents to target more specifically other types of cancer would bring nanotechnology much closer to a practical medical application and more so, to eradicate tumors and metastases. But beyond oncology, the scientists may have developed an approach that could allow the creation of many effective and safe drug delivery platforms at the molecular scale for a wide range of other diseases.
Suping Li, Qiao Jiang, Shaoli Liu, Yinlong Zhang, Yanhua Tian, Chen Song, Jing Wang, Yiguo Zou, Gregory J Anderson, Jing-Yan Han, Yung Chang, Yan Liu, Chen Zhang, Liang Chen, Guangbiao Zhou, Guangjun Nie, Hao Yan, Baoquan Ding, Yuliang Zhao. A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo. Nature Biotechnology, 2018; DOI: 10.1038/nbt.4071