Shapes Could Matter Big Time in DNA Nanoparticle Therapy
Researchers from Johns Hopkins and Northwestern universities have discovered that the shape of nanoparticles that move DNA through the body could make a big difference in how well such therapies work to treat cancer and other diseases. The scientists also have figured how to control these shapes.
"These nanoparticles could become a safer and more effective delivery vehicle for gene therapy, targeting genetic diseases, cancer and other illnesses that can be treated with gene medicine," said Hai-Quan Mao, an associate professor of materials science and engineering in Johns Hopkins' Whiting School of Engineering.
Mao, who has been developing nonviral nanoparticles for gene therapy for a decade, uses an approach that involves compressing healthy snippets of DNA within protective polymer coatings. The particles are designed to deliver their genetic payload only after they have moved through the bloodstream and entered the target cells. Then, once within the cells, the polymer degrades and ultimately releases the DNA. Using this DNA as a template, the cells can produce functional proteins that combat disease.
Another advantage to this technique, Mao said, is that he and his team can "tune" nanoparticles in three shapes that resemble rods, worms and spheres. These shapes mimic the shapes and sizes of viral particles.
The particle shapes used in this research are formed by packaging the DNA with polymers and exposing them to various dilutions of an organic solvent. DNA's aversion to the solvent, with the help of the team's designed polymer, causes the nanoparticles to contract into a certain shape with a "shield" around the genetic material to protect it from being cleared by immune cells.
This illustration (at right) depicts DNA molecules (light green), packaged into nanoparticles by using a polymer with two different segments. One segment (teal) carries a positive charge that binds it to the DNA, and the other (brown) forms a protective coating on the particle surface. The image is provided by Wei Qu, Northwestern (simulation cartoons) and Xuan Jiang, Johns Hopkins (microscopic images)
By adjusting the solvent surrounding these molecules, the Johns Hopkins and Northwestern researchers were able to control the shape of the nanoparticles. The team’s animal tests showed that a nanoparticle’s shape could dramatically affect how effectively it delivers gene therapy to the cells. The cartoon images in the foreground, obtained though computational modeling, matched closely with the gray background images, which were collected through transmission electron microscopy. To investigate why nanoparticles assumed these three shapes Mao enlisted assistance from colleagues at Northwestern, who are experts in conducting similar experiments with powerful computer models.
Erik Luijten, an associate professor of materials science and engineering and of applied mathematics at Northwestern's McCormick School of Engineering and Applied Science, led the computational analysis of the findings to determine why the nanoparticles formed into different shapes.
"Our computer simulations and theoretical model have provided a mechanistic understanding, identifying what is responsible for this shape change," Luijten said. "We now can predict precisely how to choose the nanoparticle components if one wants to obtain a certain shape."
His computer models allowed Luijten and his team to mimic traditional lab experiments at a far faster pace. The molecular dynamic simulations were performed on Northwestern's high-performance computing system (called Quest).
The computations were so complex that some of them required 96 computer processors working simultaneously for one month.
The result was that the computer noted dramatic jumps in corolation between certain shapes and impact in the body. "The worm-shaped particles resulted in 1,600 times more gene expression in the liver cells than the other shapes," Mao said. "This means that producing nanoparticles in this particular shape could be the more efficient way to deliver gene therapy to these cells."
The work appears in a paper published in the Oct. 12 online edition of the journal Advanced Materials. Lead authors are Wei Qu, a graduate student in Luijten's research group at Northwestern, and Xuan Jian, who was a doctoral student in Mao's lab. Along with Mao and Luijten other co-authors are Deng Pan, Yong Ren, John-Michael Williford and Honggang Cui.