The National Institute for Computational Sciences

Improving Cancer Treatment

Simulations Can Aid the Design of More-efficient Drug Delivery Mechanisms

[Image credit: Cancer Cells—© Sheelamohanachandran2010 |]

According to this year’s American Cancer Society (ACS) estimations, in the time it takes you to read this paragraph (about 20 seconds) one American will be newly diagnosed with cancer. That equates to 190 people per hour and more than 4.5 thousand per day. The ACS notes that in all of 2014, we will likely see 1,665,540 new cases of cancer across the United States.

When we reach beyond America’s borders and take into account the global rates of occurrence published by the World Health Organization (WHO), the figures quickly become even more startling. In 2012 for instance, we saw nearly 14.1 million new cancer cases across the planet.

With these numbers in mind, it quickly becomes apparent that the advancement of cancer treatment is an essential duty for modern medicine.

Fortunately, several forms of cancer treatment currently exist. Among these treatments, surgery, radiation therapy, immunotherapy, and chemotherapy are perhaps the most well known.

This last form of treatment, often abbreviated as chemo, involves the use of different types drugs to kill cancerous cells by impairing their rapid cell division. One of these drugs, called paclitaxel, was discovered in 1962 when it was isolated from the bark of the Pacific Yew.

Paclitaxel works by increasing microtubule stability in the cell and keeping the cell from dividing. In other words, it prevents the completion of the cell cycle, which allows it to be used as a form of cancer treatment for solid tumors caused by breast, lung, and ovarian cancer, among others.

Paclitaxel is, by nature, a hydrophobic drug. This means that it has no inherent attraction to water, making it difficult to introduce the drug into a water-filled environment such as a cell.

Hydrophobic Drug Interactions with a Cell Membrane

Sharon Loverde and Myungshim Kang at the College of Staten Island, City University of New York (CUNY), have recently been investigating this relationship between hydrophobic drugs and their interaction with a cell membrane.

Last month, Loverde and Kang published their most recent paper: "Molecular Simulation of the Concentration-Dependent Interactions of Hydrophobic Drugs with Model Cellular Membranes." The paper was published in The Journal Of Physical Chemistry B.

Loverde and Kang’s investigation dealt with molecular dynamics simulations of the transport of hydrophobic drugs through the cell membrane. The simulations were run using the Kraken supercomputer (decommissioned earlier this year), which was managed by the National Institute for Computational Sciences (NICS).

In their paper, Loverde and Kang indicate that it is not well known how most hydrophobic drugs penetrate cell membranes. But, as Loverde stated in an email interview, “[These molecular dynamics investigations] can help pharmaceutical research design new drugs and predict how these drugs will be transported across the cell membrane.”

One of the key findings from their study was that the behavior of a hydrophobic drug in a biomembrane might be dependent on the concentration of drugs involved.

By calculating the free energy (the energy that is available for a reaction to take place) Loverde and Kang revealed that the “distribution and transportability of the drug in the membrane are affected by the concentration, resulting in a more favorable insertion of the following incoming drug molecules.”

The simulations for this investigation produced models with time scales of about 350 nanoseconds and length scales measured in nanometers. (To give you an idea of the actual size and time scale of these models, they are about 1/1000th of the thickness of a sheet of paper and only last long enough for light to travel about 3.5 feet.)

By characterizing this concentration-dependent behavior, Loverde and Kang illustrate not only the traits of paclitaxel but also other hydrophobic drugs as they interact with cell membranes. “Additionally,” Loverde said, “our simulations can guide the design of new drug delivery vehicles.”

Future Endeavors

“The next steps for research,” she said, “include the development of more accurate multi-scale or coarse-grained models to describe the interaction at longer time scales (microseconds or more) and length scales (approaching micrometers).”

Jacob Pieper, science writer, NICS, JICS

Article posting date: 5 November 2014

About JICS and NICS: The Joint Institute for Computational Sciences (JICS) was established by the University of Tennessee and Oak Ridge National Laboratory (ORNL) to advance scientific discovery and state-of-the-art engineering, and to further knowledge of computational modeling and simulation. JICS realizes its vision by taking full advantage of petascale-and-beyond computers housed at ORNL and by educating a new generation of scientists and engineers well versed in the application of computational modeling and simulation for solving the most challenging scientific and engineering problems. JICS runs the National Institute for Computational Sciences (NICS), which had the distinction of deploying and managing the Kraken supercomputer. NICS is a leading academic supercomputing center and a major partner in the National Science Foundation's eXtreme Science and Engineering Discovery Environment, known as XSEDE. In November 2012, JICS sited the Beacon system, which set a record for power efficiency and captured the number one position on the Green500 list of the most energy-efficient computers.