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Drug delivery

SSM nanocarrier. Different regions (core, ionic interface, PEG corona, and aqueous ionic solution) are visualized on the left side of the figure. Red and orange lines separate the different regions. On the right side is the nanocarrier as it looks from the outside.

Like a marksman hitting the bull's eye, targeted drug delivery puts medicine right where it is needed. For cancer patients, this could reduce the side effects associated with treatment by not having drugs circulating throughout the entire body.

Computational chemists at the University of Illinois at Chicago, in conjunction with their experimental colleagues in the Department of Biopharmaceutical Sciences, are studying nanocarriers to further develop this potential magic bullet in the fight against cancer. Nanocarriers are like a shell casing, a delivery method for the drugs needed to kill the cancerous cells.

"To reduce the toxicity of drugs, they can first be solubilized within the biocompatible nanocarriers and then injected in this form into patients. Nanocarriers loaded with drugs can be specifically delivered to the cancer site, either through passive or active targeting, and attack only the cancer cells. In this way, the patients don't get as sick with side effects since drugs are delivered primarily to the disease site, rather than in a systemic way like in traditional chemotherapy," explained Lela Vukovic, a doctoral student at UIC.

Working under the guidance of principal investigator Petr Kral, and in collaborations with Hayat Onyuksel and Seungpyo Hong, Vukovic is studying polyethylene glycol (PEG)-ylated phospholipid and dendron-based micelles for use as drug nanocarriers. Using both traditional and GPU-based clusters (which have since been retired) at the National Center for Supercomputing Application, she performed extensive atomistic molecular dynamics simulations in which the micelles are characterized in pure water and ionic solutions.

The micelles

Amphiphilic molecules—those containing both electrically neutral (hydrophobic) groups and electrically polarized (hydrophilic) groups—dissolved in water may assemble into micelles. Their hydrophobic blocks aggregate into micelle cores in order to reduce their exposure to water, from which they are additionally protected by the outer hydrophilic blocks. Micelles assembled in aqueous solutions can remain stable when injected into the blood stream.

Micelles studied by the Kral team are made from molecules that have PEG blocks grafted onto phospholipids, which spontaneously assemble in water in a spherical arrangement. Phospholipids usually function as a structural component of membranes, while PEG is a biocompatible polymer that solvates in aqueous solutions.

While pharmacy collaborators prepare micelles with these biocompatible and regulated phospholipids for use in experiments and are testing them in vitro and in vivo, the research Kral's team is doing could be classified as fundamental.

"The experimental scientists are often interested in preparing functional constructs which can be used in different medical applications. We are more on the level of trying to understand in detail, from the perspective of a physical chemist, what the micelle looks like and how it behaves, where the drug would go, and clarifying under what conditions the drugs could be released," Kral said. "We try and provide the insight to the experimentalists to understand how their system behaves in certain conditions and how they can use the gained microscopic information to modify and improve these delivery systems in the future."

Vukovic said the nanocarrier "has very nice properties," but they still had much to learn about it microscopically. For instance, what is the influence of the solvent on the nanocarrier properties? Where do the drugs solubilize in the nanocarrier and what type of environment do they prefer? Is it possible to dissolve certain types of drugs in the nanocarrier? With the assistance of supercomputers, they are finding answers to these questions.

The phospholipid micelles Vukovic and her colleagues are studying can be prepared with targeting ligands on their surface, such as peptides, which can eventually find and attach to the cancer cell, so that the drugs are released where they should be and not anywhere else, explained Kral.

The region in the micelle in which the drug is isolated, said Vukovic, can affect its transport and release. They have performed many simulations that investigate how likely it is that drugs can be solubilized in the micelle center, at the interface between hydrophobic and hydrophilic regions, or in regions such as the outer PEG corona, where the drugs can be released prematurely into the body during delivery. They have also investigated the nanocarrier's stability in different types of solvents. This part of the study is of importance for improving nanocarrier preparation protocols, since initial solubilization of molecular cargo within the nanocarrier may be more effective when performed in pure water or other solvents.

And she and Kral have had success. Their modeling has shown that the empty nanocarrier is sensitive to its solvent environment, as its size and morphology are observed to change from small and spherical in pure water to larger and non-spherical in saline solution. In their studies of drugs within the nanocarrier, they have found that some hydrophobic drugs can have a local energy minimum in the center of the nanocarrier. When micelle cores are filled with drugs, the micelle cores change their shape and become more spherical. However, for most of the hydrophobic drugs they have studied, which usually have at least one polar chemical group, they find that drugs prefer to reside at the interface of the core and the corona, where both hydrophobic parts of the drugs and polar groups can be solubilized in their preferential environments. The simulations also indicate that the thickness of the PEG coating on the nanocarrier fluctuates, which can lead to the exposure of the core to the outer solvent. In this way, PEG likely plays a role in the stabilization of various drug and peptide molecular cargo.

The team has presented their results at many conferences, including the American Chemical Society, Pacifichem, the Computational Biophysics to Systems Biology Workshop, and at Ruhr-Universität Bochum in Bochum, Germany.

Hundreds of runs

To learn what they need to know requires patience.

They have tested micelles in pure water and in ionic solution and micelles containing four drugs so far. And as the parameters of some of the micelles made by the pharmacy group changed, they had to recalculate and do the simulations again.

"We've been working on this problem for two years," said Vukovic. "To find what we need to know, we run simulation after simulation for a couple of weeks. Then we analyze the results. We make adjustments, and then do another two weeks of simulations. Since the systems are very large, our test runs to determine which approaches to take are usually performed for several weeks."

"Our simulations are massive," said Kral. "They have up to 750,000 atoms and they need to be calculated for a relatively long time, up to 30 nanoseconds. That is why the supercomputer was very useful to us and very necessary."

Vukovic and Kral say this work would not be possible without the supercomputer resources of NCSA. While they have developed their own GPU-based computer system in their lab, it lacks the power for many of the simulations they run. They believe that future GPU-based supercomputers will significantly accelerate their calculations. Their results were recently published in the Journal of the American Chemical Society and Chemical Communications.

This summer, said Kral, they have added an undergraduate student to the team: Alan Tang, who won the Barry M. Goldwater Scholarship in 2011. This will allow them to expand the project in the next academic year to simulate micelles interacting and protecting some of the therapeutic or targeting peptides that can recognize cancer cells.

A version of this story first appeared on the NCSA's website. For more information, go to:

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