Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

DNA 'Trojan horse' smuggles drugs into resistant cancer cells

24.02.2016

Cells mistake DNA casing for food, consume drugs and die

Researchers at The Ohio State University are working on a new way to treat drug-resistant cancer that the ancient Greeks would approve of--only it's not a Trojan horse, but DNA that hides the invading force.


This is a rotating view of a single drug-resistant leukemia cell, after it's absorbed DNA nanostructures. Fluorescent markers show that the nanostructures have been taken deep into the cell, into the organelles that will digest them.

Image by Matthew Webber, courtesy of The Ohio State University

In this case, the invading force is a common cancer drug.

In laboratory tests, leukemia cells that had become resistant to the drug absorbed it and died when the drug was hidden in a capsule made of folded up DNA.

Previously, other research groups have used the same packaging technique, known as "DNA origami," to foil drug resistance in solid tumors. This is the first time researchers have shown that the same technique works on drug-resistant leukemia cells.

The researchers have since begun testing the capsule in mice, and hope to move on to human cancer trials within a few years. Their early results appear in the journal Small.

The study involved a pre-clinical model of acute myeloid leukemia (AML) that has developed resistance against the drug daunorubicin. Specifically, when molecules of daunorubicin enter an AML cell, the cell recognizes them and pumps them back out through openings in the cell wall. It's a mechanism of resistance that study co-author John Byrd of The Ohio State University Wexner Medical Center compared to sump pumps that draw water from a basement.

He and Carlos Castro, assistant professor of mechanical engineering, lead a collaboration focused on hiding daunorubicin inside a kind of molecular Trojan horse that can bypass the pumps so they can't eject the drug from the cell.

"Cancer cells have novel ways of resisting drugs, like these pumps, and the exciting part of packaging the drug this way is that we can circumvent those defenses so that the drug accumulates in the cancer cell and causes it to die," said Byrd, a professor of internal medicine and director of the Division of Hematology. "Potentially, we can also tailor these structures to make them deliver drugs selectively to cancer cells and not to other parts of the body where they can cause side effects."

"DNA origami nanostructures have a lot of potential for drug delivery, not just for making effective drug delivery vehicles, but enabling new ways to study drug delivery. For instance, we can vary the shape or mechanical stiffness of a structure very precisely and see how that affects entry into cells," said Castro, director of the Laboratory for Nanoengineering and Biodesign.

In tests, the researchers found that AML cells, which had previously shown resistance to daunorubicin, effectively absorbed drug molecules when they were hidden inside tiny rod-shaped capsules made of DNA. Under the microscope, the researchers tracked the capsules inside the cells with fluorescent tags.

Each capsule measures about 15 nanometers wide and 100 nanometers long--about 100 times smaller than the cancer cells it's designed to infiltrate. With four hollow, open-ended interior compartments, it looks less like a pill a human would swallow and more like an elongated cinder block.

Postdoctoral researcher Christopher Lucas said that the design maximizes the surface area available to carry the drug. "The way daunorubicin works is it tucks into the cancer cell's DNA and prevents it from replicating. So we designed a capsule structure that would have lots of accessible DNA base-pairs for it to tuck into. When the capsule breaks down, the drug molecules are freed to flood the cell."

Castro's team designed the capsules to be strong and stable, so that they wouldn't fully disintegrate and release the bulk of the drugs until it was too late for the cell to spit them back out.

And that's what they saw with a fluorescence microscope--the cells drew the capsules into the organelles that would normally digest them, if they were food. When the capsules broke down, the drugs flooded the cells and caused them to disintegrate. Most cells died within the first 15 hours after consuming the capsules.

This work is the first effort for the engineers in Castro's lab to develop a medical application for the DNA origami structures they have been building.

Though DNA is stereotypically called the "building blocks of life," engineers today use natural and synthetic DNA as literal building blocks for mechanical devices. Previously, the Ohio State engineers created tiny hinges and pistons of DNA.

As Castro pointed out, DNA is a polymer--albeit a naturally occurring one--and he and his colleagues shape it into tiny devices, tools or containers by exploiting the physical interactions of the bases that make up the polymer chain. They build chains from DNA sequences that will naturally attract and bind with one another in certain ways, so that long the long polymers automatically fold up, or "self-assemble," into useful shapes.

In the case of this DNA Trojan horse, the researchers used the genome of a common bacteriophage, a virus that infects bacteria, and synthetic strands that were designed to fold up the bacteriophage DNA. Although the folded-up shape performs a function, the DNA itself does not, explained Patrick Halley, an engineering graduate student who is doing this work to earn his master's degree.

"One of the hardest things to get across when you're introducing this technology to people is that the DNA capsule doesn't do anything except hold a shape. It's just a static, rigid structure that carries things. It doesn't encode any proteins or do anything else that we normally think of DNA as doing," Halley said.

In keeping with the idea of DNA origami manufacturing, Castro said he hopes to create a streamlined and economically viable process for building the capsules--and other shapes as well--as part of a modular drug delivery system.

Byrd said the technique should potentially work on most any form of drug-resistant cancer if further work shows it can be effectively translated to animal models, though he stopped short of suggesting that it would work against pathogens such as bacteria, where the mechanisms for drug resistance may be different.

###

Other co-authors on the paper included Emily McWilliams, Matthew Webber, Randy Patton, Comert Kural and David Lucas. Funding for the research came from start-up funds provided to Castro by the Department of Mechanical and Aerospace Engineering, the Leukemia and Lymphoma Society, the National Cancer Institute, the D. Warren Brown Foundation, Four Winds Foundation and the Harry T. Mangurian Jr. Foundation.

Contact: Carlos Castro, 614-292-2662; Castro.39@osu.edu

John Byrd, 614-293-8330; Byrd.96@osu.edu

Written by Pam Frost Gorder, 614-292-9475; Gorder.1@osu.edu

Pam Frost Gorder | EurekAlert!

Further reports about: DNA DNA origami Trojan horse cancer cells capsule drug-resistant drugs leukemia

More articles from Life Sciences:

nachricht New method to rapidly map the 'social networks' of proteins
27.06.2017 | Salk Institute

nachricht X-ray experiments reveal two different types of water
27.06.2017 | Deutsches Elektronen-Synchrotron DESY

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Collapse of the European ice sheet caused chaos

27.06.2017 | Earth Sciences

NASA sees quick development of Hurricane Dora

27.06.2017 | Earth Sciences

New method to rapidly map the 'social networks' of proteins

27.06.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>