Low Research Lab
Research
Our work is at the interface of biochemistry, biotechnology, biophysics and medicinal chemistry. Work in progress includes:
Targeted Therapeutics
We have developed methods to target drugs selectively to pathologic cells, thereby avoiding the usual collateral toxicity to healthy cells. In initial studies of tumor cell targeting, we have exploited the up-regulation of the folate receptor on malignant cells to target a variety of pharmaceuticals to cancers of the ovary, lung, kidney, colon, endometrium, breast and myelogenous cells of the bone marrow. However, because many cancers of the prostate, skin, liver, brain, pancreas, and head and neck do not over-express a folate receptor, we have had to design novel targeting ligands that can deliver attached imaging and therapeutic agents specifically to these cancers also. Eight drugs based on the technology that we have developed are currently in human clinical trials.
Novel ligand-targeted imaging agents are also being developed for a variety of inflammatory and autoimmune diseases, including rheumatoid arthritis, Crohn’s disease, atherosclerosis, lupus, osteoarthritis, diabetes, sarcoidosis, Sjogren's disease, organ transplant rejection, tissue trauma, and psoriasis. Moreover, we are also designing, synthesizing and testing in vivo novel targeting ligands for drug delivery to infectious pathogens, including HIV, influenza virus, Staphylococcus, Streptococcus, malaria, Bacillus anthracis, Salmonella, Mycobacterium tuberculosis, and many others.
Fluorescence-Guided Surgery for Cancer
One of the more important applications of the novel targeting ligands described above lies in aiding the surgeon to locate, identify and remove all malignant nodules during cancer surgery. For this purpose, we are developing tumor-targeted fluorescent dyes that can highlight the tumor when exposed to a fluorescent light. Clinical trials of our targeted dyes indicate that up to 5X more malignant loci are resected with the aid of the dyes than without them. We believe that these novel surgery tools can save lives and reduce morbidity among cancer patients. Results of the first clinic trial with our initial tumor-targeted fluorescent dye may be found in Nature Medicine: "Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor -a targeting: first in-human results" van Dam et al. Nature Medicine 17: 1315-19 (2011).
Rapid Identification and Detection of Human Pathogens
We are developing novel methods for the rapid detection and identification of human pathogens. Because rapid identification and treatment of an infectious virus or bacterium often constitutes the best method for preventing its spread, significant interest now exists in methods that can yield an accurate diagnosis within minutes of pathogen encounter. We are designing these methods, while placing special emphasis on detection of those pathogens with the potential to trigger a pandemic (e.g. avian influenza virus, Vibrio cholera, Bacillus anthracis, Mycobacterium tuberculosis, Pseudomonas, Listeria, Yersinia, and E. coli, etc.). Our method involves capture of the pathogenic microbe on a patterned surface that has been derivatized with a diversity of low molecular weight ligands that recognize and bind each individual pathogen. Analysis of the pathogen-coated surface by interferometry then allows rapid identification and quantitation of each microbe in a complex biological sample.
Human red blood cell membrane
We are studying the structure and function of the human red blood cell membrane and its role in health and disease. 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 studying its structure and function at the molecular level. We are also investigating the roles of other membrane proteins in controlling cell shape, regulating erythrocyte metabolism, modulating cell flexibility, and mediating oxygen delivery. Recently, we have been placing special emphasis on developing a cure for drug-resistant malaria.