Associate Professor of Chemical and Biomolecular Engineering Hyunjoon Kong, graduate student and member of the Regenerative Biology and Tissue Engineering research theme at the Institute for Genomic Biology, Cartney Smith, and colleagues made it a goal to improve MR imaging (MRI), and turned current contrast agent technology on its head. The new compound they designed in cooperation with Roger Adams Professor of Chemistry Steven C. Zimmerman is not only more efficient, but also self-assembling.
When physicians conduct an MRI, they administer a contrast agent: a chemical that, when injected into the bloodstream or ingested by the patient prior to the MRI, improves the overall clarity of structures or organs in the resulting image. One frequent class of contrast agent, often employed for imaging of blood vessels and internal bleeding, contains gadolinium, a rare-earth metal.
Presently, biomedical researchers have discovered ways to increase the efficiency of specific contrast agents by linking them with nanoparticles. The contrast agent being used is packaged inside or bonded to the surface of microscopic particles, which can be orchestrated to target certain regions of the body or extend the agent's activity.
Researchers are now investigating the multipurpose use of nanoparticles. If particles could be filled with several types of contrast agents or dyes instead of just one, or a contrast agent along with another type of diagnostic aid or a medication, doctors could more proficiently test for and treat conditions, and limit the number of injections administered on patients.
However, compounds squeezed in together into a nanoparticle do not always fair well together. For instance, contrast agents may attach to other chemicals, diminishing their efficacy. Moreover, when contrast agents are enclosed inside a nanoparticle, they may not work as well. Attempts to bind agents to the outer surface of nanoparticles through covalent formation is also riddled with problems, as they can negatively affect the activity of the nanoparticles or the compounds that they carry.
Kong, Smith and colleagues addressed these issues by using interactions between naturally occurring biomolecules as a blueprint. Many kinds of proteins are strongly connected to cell membranes not by covalent bonds, but by the total of several weaker forces, the attraction of positive and negative charges, and the tendency of non-polar (oil-like) substances to seek each other and avoid water.
The group theorized that the same kinds of forces could be used to bind a contrast agent to the surface of a type of nanoparticle called a liposome, which resembles a small piece of cell membrane in the shape of a tiny bubble. The researchers designed a "fastener" molecule, DTPA-chitosan-g-C18, that is charged, attracting it to the liposome and attaching it to the contrast agent gadolinium. A nonpolar region centers it to the liposome membrane.
In a chain of experiments reported in a recent ACS Nano article, Kong and others showed that their fastener molecule readily inserted itself into the membrane of pre-made liposomes. Gadolinium stably linked with the adjusted nanoparticles in solution, and experiments in animal models revealed that these nanoparticles produced clear diagnostic images.
"The strategy works like Velcro on a molecular level to adhere functional units to the outer leaflet of a liposome. This work represents a new material design strategy that is scalable and easily implemented. The development of improved contrast agents has the potential to directly impact patients' lives by detecting damaged blood vessels," said Smith, who was also first author on the study.