“Targeted imaging and therapeutic agents for cancer.” We have been developing methods to target drugs specifically to diseased cells, thereby avoiding the usual collateral toxicity to healthy cells. In the case of cancer, we initially exploited up-regulation of the folate receptor on cancers of the ovary, lung, kidney, endometrium and breast to target imaging and therapeutic agents to these cancers. Considerable preclinical data as well as the results from the clinical trials of six folate-linked drugs demonstrate that the ligand-targeting strategy holds promise for increasing drug potency while reducing unwanted toxicity.
We have also developed a targeting ligand that selectively delivers attached drugs to prostate specific membrane antigen (PSMA) on prostate cancer cells. Imaging and therapeutic studies in both animals and humans demonstrate that this new targeting ligand can not only improve the diagnosis of prostate cancer, but also enhance treatment of the disease (see images). Moreover, because PSMA is also expressed on the neovasculature of almost all solid tumors, we are now exploring the use of our PSMA targeting ligand to image and destroy the vasculature in other solid tumors.
More recently, novel targeting ligands have been designed for tumor-specific drug delivery to other cancers, including malignancies of the bladder, pancreas, stomach, brain, liver, colon, skin, endometrium and esophagus. Development of relevant applications of these new ligands for the imaging and therapy of these other human cancers is also currently underway (see image).
"Fluorescence-guided surgery of cancer.” One of the more exciting applications to arise from the above tumor specific ligands has been their use in the highly specific delivery of near infrared dyes to cancer cells. When such tissue-transparent fluorescent dyes are injected intravenously immediately prior to surgery, the fluorescent conjugates are observed to “light up” cancer tissues without illuminating adjacent normal tissues. These highly visible tumor markers enable the surgeon to locate and resect considerably more malignant lesions than has been here-to-fore possible with any other surgical technique (see videos of human surgeries).
“Targeted imaging and therapeutic agents for inflammatory and autoimmune diseases.” Targeted drugs of all sorts are also being developed for the diagnosis and treatment of autoimmune, inflammatory, cardiovascular, infectious, and central nervous system (CNS) diseases, including rheumatoid arthritis, atherosclerosis, Alzheimer’s disease, Crohn’s disease, psoriasis, influenza virus infections and Parkinson’s disease. In all cases, targeting ligands are designed, synthesized, and tested both in vitro and in vivo for their abilities to deliver attached drugs selectively to the cells responsible for the above diseases. Both preclinical and clinical data on these drugs demonstrate that the ligand targeting strategy can also be applied to improve drug performance outside of the oncology space.
“Structure and Function of the Human Erythrocyte Membrane.” We are also studying the structure and function of the human red blood cell membrane and its role in health and disease. Included in this research are projects aimed at characterizing: i) the organization of membrane-spanning proteins into multi-protein complexes in the membrane, ii) the interactions between these membrane complexes and the underlying cytoskeleton, iii) the effects of mutations and deficiencies in specific membrane proteins on membrane properties, iv) the signal transduction pathways that control cell shape, flexibility, metabolism, ion transport, and senescence, and v) the crystallographic structures of important membrane proteins. Because the membrane-spanning protein, band 3, catalyzes anion transport, links the cytoskeleton to the membrane, organizes a glycolytic enzyme complex on the membrane, binds/regulates at least 8 other proteins, and serves as the senescent cell antigen, we are exploring its structure and function in detail.
“Development of new therapies for malaria and sickle cell disease.” During the course of the above research, we have discovered a novel signaling pathway mediated by non-receptor tyrosine kinases and the membrane-spanning protein, band 3. In this pathway, phosphorylation of specific tyrosines in band 3 promotes an intramolecular interaction with an atypical SH2-like domain in band 3, thereby causing: i) inhibition of anion transport, ii) dissociation of the spectrin-actin cortical cytoskeleton from the membrane, and iii) release of a glycolytic enzyme complex from the membrane, along with other major membrane rearrangements. Because activation of this pathway appears to contribute to several major symptoms of malaria, sickle cell disease and other erythrocyte pathologies, we are developing inhibitors of various steps in the pathway to treat the aforementioned diseases. Indeed, early results from clinical trials on a new therapy for malaria, conducted in collaboration with Professors Franco Turrini (University of Torino) and Dinh Huynh Chien (University of Hue), appear to be very promising.