Molecular automata can help researchers build more targeted therapeutics

July 30, 2013

Molecular automata assess the presence of two cell-surface markers (credit: Maria Rudchenko et al./Nature Nanotechnology)

A new technique for developing more targeted drugs with reduced side effects by using “molecular automata” — a mixture of antibodies and short strands of DNA — has been demonstrated by Hospital for Special Surgery (HSS) and Columbia University researchers.

These short DNA strands, aka oligonucleotides, can be manufactured by researchers in a laboratory for any user-specified sequence.

How it works

All cells have many receptors on their cell surface. When antibodies or drugs bind to a receptor, a cell is triggered to perform a certain function or behave in a certain manner. Drugs can target disease-causing cells by binding to a receptor, but in some cases, disease-causing cells do not have unique receptors and therefore drugs also bind to healthy cells and cause “off-target” side effects.

The researchers conducted their experiments using white blood cells. All white blood cells have CD45 receptors, but only subsets have other receptors such as CD20, CD3, and CD8. In one experiment, HSS researchers created three different molecular robots. Each one had an antibody component of either CD45, CD3 or CD8 and a DNA component.

The DNA components of the robots were created to have a high affinity to the DNA components of another robot. DNA can be thought of as a double stranded helix that contains two strands of coded letters, and certain strands have a higher affinity to particular strands than others.

The researchers mixed human blood from healthy donors with their molecular robots. When a molecular robot carrying a CD45 antibody latched on to a CD45 receptor of a cell and a molecular robot carrying a CD3 antibody latched on to a different welcoming receptor of the same cell, the close proximity of the DNA strands from the two robots triggered a cascade reaction.

Certain strands were ripped apart and more complementary strands joined together. The result was a unique, single strand of DNA that was displayed only on a cell that had these two receptors. The addition of a molecular robot carrying a CD8 antibody docking on a cell that expressed CD45, CD3 and CD8 caused this strand to grow.

The researchers also showed that the strand could be programmed to fluoresce when exposed to a solution. The robots can essentially label a subpopulation of cells allowing for more targeted therapy. The researchers say the use of increasing numbers of molecular robots will allow researchers to zero in on more and more specific subsets of cell populations.

“The automata trigger the growth of more strongly complementary oligonucleotides. The reactions occur fast. In about 15 minutes, we can label cells,” said Maria Rudchenko, M.S., the first author of the paper and a research associate at Hospital for Special Surgery. In terms of clinical applications, researchers could either label cells that they want to target or cells they want to avoid.

“This is a proof of concept study that it works in human whole blood,” said Dr. Rudchenko. “The next step is to test it in animals.”

If molecular robots work in studies with mice and eventually human clinical trials, the researches say there are a wide range of possible clinical applications. For example, cancer patients could benefit from more targeted chemotherapeutics. Drugs for autoimmune diseases could be more specifically tailored to impact disease-causing autoimmune cells and not the immune cells that people need to fight infection.

The study was funded, in part, by the National Institutes of Health, National Science Foundation, and the Lymphoma and Leukemia Foundation.