Image: Dr. Kong and others demonstrated that their fastener molecule readily inserted itself into the membrane of pre-made liposomes. Gadolinium stably associated with the modified nanoparticles in solution, and experiments in animal models showed that these nanoparticles produced clear diagnostic images (Photo courtesy of Janet Sinn-Hanlon, DesignGroup@VetMed, University of Illinois).
Biomedical scientists have increased the effectiveness of specific contrast agents that are frequently used for imaging blood vessels and internal bleeding by linking them with nanoparticles. The contrast agent being used is packaged inside or bonded to the surface of microscopic particles, which can be designed to target specific parts of the body or prolong the agent’s activity.
When associate professor of chemical and biomolecular engineering Dr. Hyunjoon Kong, graduate student Cartney Smith, and colleagues from the Institute for Genomic Biology, University of Illinois at Urbana-Champaign (USA) set out to improve magnetic resonance imaging (MRI) technology, they turned to current contrast agent technology inside out.
When clinicians perform an MRI scan, they administer a contrast agent: a compound that, when injected into the bloodstream or ingested by the patient just before the MRI, improves structure or organ clarity in the resulting image. One typical class of contrast agent, frequently used for imaging of blood vessels and internal bleeding, contains gadolinium, a rare-earth metal.
Recently, biomedical researchers have discovered ways to increase the effectiveness of certain contrast agents by associating them with nanoparticles. The contrast agent being used is packaged inside or bonded to the surface of microscopic particles, which can be designed to target certain regions of the body or prolong the agent’s activity. They are now examining the multipurpose use of nanoparticles. If particles could be loaded with several types of contrast agents or dyes instead of one, or a contrast agent along with another type of diagnostic aid or a medication, clinicians could more effectively test for and treat disorders, and limit the number of injections received by patients.
Similar to children sharing a new plaything, although, compounds packed together into a nanoparticle cannot always play well together. For instance, contrast agents may bind to other chemicals, reducing their effectiveness. Furthermore, when contrast agents are enclosed inside a nanoparticle, they may not work as well. Efforts to attach agents to the outer surface of nanoparticles by covalent formation are also challenging, as they can negatively affect the nanoparticle activity or the compounds that they carry.
Drs. Kong, Smith and colleagues attacked these challenges by using interactions between naturally occurring biomolecules as a guide. Many types of proteins are strongly attached to cell membranes not by covalent bonds, but by the sum of multiple weaker forces—the attraction of positive and negative charges, and the tendency of nonpolar (oil-like) compounds to seek each other and avoid water.
The group theorized that the same types of forces could be used to attach a contrast agent to the surface of a type of nanoparticle called a liposome, which resembles a little 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 binding it to the contrast agent gadolinium. A nonpolar region anchors it to the liposome membrane.
In a series of experiments reported October 2014 American Cancer Society’s journal ACS Nano article, Dr. Kong and coworkers demonstrated that their fastener molecule easily inserted itself into the membrane of pre-made liposomes. Gadolinium stably associated with the engineered nanoparticles in solution, and research in animal models revealed that these nanoparticles generated well-defined diagnostic images.
“The strategy works like Velcro on a molecular level to adhere functional units to the outer leaflet of a liposome,” said Dr. Smith, who was first author on the study. “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.”
One of the difficulties of working with liposomes is their tendency to degrade inside the body. When the fastener-loaded liposomes degraded, some of the efficacy of the gadolinium was lost. In a second study published April 8, 2014, in the journal Langmuir,
Drs. Kong and Smith developed a process for chemically cross-linking the components of the nanoparticle that prolonged the life of the nanoparticles in biologic environments.
Institute for Genomic Biology, University of Illinois at Urbana-Champaign