Molecular Robots Help Build More Customized Drugs for Cancer, Arthritis Therapy

Many pharmaceutical agents designed to fight for cancer or autoimmune diseases have unpleasant side effects because while they kill disease-causing cells, they also affect the healthy ones. Now, a new study has demonstrated an approach for developing more targeted drugs, by using molecular “robots” to target more specific populations of cells.

“This is a proof of concept study using human cells,” said Sergei Rudchenko, PhD, director of flow cytometry at Hospital for Special Surgery (HSS; New York, NY, USA), and a senior author of the study. “The next step is to conduct tests in a mouse model of leukemia.” The study’s findings, a collaboration between researchers from HSS and Columbia University (New York, NY, USA) was published online July 2013 on the website of the journal Nature Nanotechnology.

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

For instance, Rituximab (Rituxan, developed by Genentech, South San Francisco, CA, USA) is used to treat rheumatoid non-Hodgkin’s lymphoma, arthritis, and chronic lymphocytic leukemia by binding to CD20 receptors of abnormal cells that are causing the diseases. However, specific immune cells also have CD20 receptors and then the agent can disrupt an individual’s ability to initiate a fight against infection.

In the new study, scientists have designed molecular robots that can detect numerous receptors on cell surfaces, thereby effectively labeling more specific subpopulations of cells. Called molecular automata, the molecular robots, are made up of an amalgam of antibodies and short strands of DNA. These short DNA strands, called oligonucleotides, can be generated by researchers in a laboratory with any user-specified sequence.

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 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 attached to a different welcoming receptor of the same cell, the close proximity of the DNA strands from the two robots triggered a cascade reaction, where 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 demonstrated that the strand could be programmed to fluoresce when exposed to a solution. In essence, the robots can label a subpopulation of cells allowing for more targeted therapy. The researchers reported that the use of increasing numbers of molecular robots will allow researchers to narrow in on more specific subsets of cell populations. In computer programming language, the molecular robots are performing what is known as an “if yes, then proceed to X function.”

“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, MS, the first author of the paper and a research associate at Hospital for Special Surgery. In terms of clinical applications, researchers could label either 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 are successful in experiments with mice and ultimately human clinical trials, the researchers noted that there is a wide range of potential clinical applications. For example, cancer patients could benefit from more targeted chemotherapeutics. Drugs for autoimmune diseases could be more specifically personalized to impact disease-causing autoimmune cells and not the immune cells that are needed to fight infection, according to the scientists.

Related Links:
Hospital for Special Surgery
Columbia University