D. Gomika Udugamasooriya, Ph.D.
D. Gomika Udugamasooriya, Ph.D., is developing methods to construct targeting molecules that can preferentially bind to cancer cells over normal cells, to diagnose and treat cancers. His approach promises a pathway to cancer diagnosis, treatment, and monitoring that is far more effective and less costly than current chemotherapeutics.
As basic targeting molecules, Dr. Udugamasooriya uses peptoids, which are molecular rearrangements of peptides, short amino acid chains that are fundamental components of cells. Although peptoids also resemble chains of amino acids, they differ in that the structurally important side-chain moieties attach to nitrogens of the amide bonds of the peptide-like backbone rather than to carbons. This subtle structural difference gives peptoids an enormous advantage as highly biologically amenable synthetic molecules, as well as carriers of molecular cargo into the cell. Unlike peptides, they are ignored by the body's protective immune system and can circulate in the bloodstream without being degraded, perhaps allowing them to be taken orally. However, they are like peptides in that they readily bind to and are absorbed by the cells that they target.
In his research, Dr. Udugamasooriya synthesizes peptoids by attaching individual building blocks called organic amines, highly diverse structural moieties, to microscopic plastic beads, and building the molecules step-by-step by adding to the chain. Each reaction is facilitated by a conventional home-type microwave oven, completing each step in less than one minute. He uses a combinatorial technique to synthesize in only days huge collections of hundreds of thousands of peptoid molecules that differ only slightly in their structure. In this combinatorial technique, building blocks are added each time to growing chains by a "split and pool" approach that yields separate arrays of differing compounds. Thus, the number of different molecules grows exponentially at each step, producing millions of different compounds on separate beads, with each single bead displaying multiple copies of a unique sequence.
Dr. Udugamasooriya screens these peptoid libraries to identify those that will target a particular surface receptor unique to a cancer cell by first genetically engineering two lines of cells with and without the receptor. He then tags the two types of cells with two colors of quantum dots, tiny fluorescent crystals. He then mixes the tagged cells with the peptoids carrying library beads and uses a microscope to isolate directly those peptoids that selectively bind to the receptor of interest in the cells, avoiding other non-specific targeting peptoids.
Dr. Udugamasooriya has used the screening technique to identify peptoids that selectively target receptors found on cancer cells. For example, he has demonstrated that he can isolate peptoids that selectively bind to and inhibit the VEGF receptor-2, which when activated in cancer cells and tumor vasculature is a major trigger of formation of blood vessels that enable tumor growth.
Importantly, this screening technique can be applied to identify cancer-targeting peptoids without even knowing a distinguishing receptor on the cells. For example, it can be used to identify peptoids that target cancer stem cells, those cells that are the driving force behind tumor proliferation and complexity. By isolating cancer stem cells from peripheral cancer cells, and tagging each with a different colored quantum dot, the screening technique can be applied to isolate peptoids that target only the cancer stem cells.
In experiments, he has used the same screening approach to directly identify peptoids that target an individual patient's cancer cells, but not normal cells. In this approach, normal and cancer cells from the same patient are tagged differently and mixed with a peptoid library. Dr. Udugamasooriya then uses the tags to identify those peptoids that bind selectively to the cancer cells. Such a technique offers the promise of personalized approaches to cancer treatment, in which a cancer patient's own cells are used to generate a targeting molecule tailored to attack the cancer, bypassing the costly, time-consuming, and less effective conventional drug development process practiced today.
While peptoids by themselves may have therapeutic value, they can also be attached to cancer-killing molecules and existing drugs, immensely improving the potency. The same peptoid can also be used to image cancers using PET, MRI, and other techniques, by attaching an imaging agent such as an MRI contrast agent, as already demonstrated with VEGFR2 binding peptoid as the carrier molecule. Thus, they can be used not only to treat cancers but also to determine the efficacy of that treatment in shrinking a tumor.
For publication information please view Dr. Udugamasooriya's faculty profile.