Interdisciplinary Life Science - PULSe Great research is a matter of choice

Philip S. Low

Philip S.  Low Profile Picture

Ralph C. Corley Distinguished Professor
Ph.D. UC, San Diego, 1975

Contact Info:

Training Group(s):
Molecular Signaling and Cancer Biology
Immunology and Infectious Diseases
Biomolecular Structure and Biophysics
Membrane Biology

Current Research Interests:

Our laboratory is working in two areas that stem from a basic interest in membrane structure and function. First, we are investigating the function and molecular organization of the human red blood cell membrane (see cartoon below). Included in this research are projects aimed at characterizing: i) the interactions between the membrane and its underlying cytoskeleton (see sketch), ii) the signal transduction pathways that control cell shape and flexibility, iii) the crystallographic structure of important membrane proteins, and iv) the changes in membrane architecture that trigger unwanted red cell adhesion.

A second research thrust focuses on the use of targeting ligands to deliver covalently attached therapeutic and imaging agents specifically to pathologic tissues for medical purposes. Because the receptor for the ligand, folic acid, is measurably overexpressed by activated macrophages (but no other hematopoietic cells) and many types of human cancers, we are attaching folic acid to drugs in order to facilitate their binding and uptake by both activated macrophages and cancer cells. Molecules targeted to tumors with folate to date include: i) radioimaging agents, ii) chemotherapeutic drugs, iii) gene therapy constructs, iv) liposomes with encapsulated drugs, v) protein toxins, vi) immunotherapeutic agents, vii) radiotherapeutic complexes, viii) MRI contrast agents, ix) nanoparticles, x) optical imaging agents, xi) oligonucleotides, and xii) various therapeutic proteins. In general, the folate conjugates have proven to be highly potent and nontoxic to normal tissues. Two folate targeted drugs are currently in human clinical trials for various types of cancer.

As mentioned above, folate-drug conjugates are also targeted with high specificity to activated macrophages. Because activated (but not resting) macrophages either cause or worsen a variety of serious human diseases, including rheumatoid arthritis, atherosclerosis, ulcerative colitis, Crohn's disease, psoriasis, osteomyelitis, multiple sclerosis, graft versus host disease, glomerulonephritis, systemic lupus erythematosis, and osteoporosis, we have undertaken to develop targeted therapies that selectively eliminate or inactivate the responsible activated macrophages. Preclinical data from our lab that have resulted in soon-to-be initiated clinical trials in rheumatoid arthritis have demonstrated that the strategy is highly effective and is accompanied by little or no toxicity.

Selected Publications:

Kodippili G. C.; Spector, J.; Sullivan, C.; Kuypers, F. A.; Labotka, R.; Gallagher, P. G.; Ritchie, K.; Low, P. S., Imaging of the diffusion of single band 3 molecules on normal and mutant erythrocytes. Blood 2009, 113, 6237-6245.

Kularatne S. A.; Wang, K.; Santhapuram, H. K. R.; Low, P. S., Prostate-Specific Membrane Antigen Targeted Imaging and Therapy of Prostate Cancer Using a PSMA Inhibitor as a Homing Ligand. Molecular Pharmaceutics 2009, 6, 780-789.

Kularatne S. A.; Zhou, Z. G.; Yang, J.; Post, C. B.; Low, P. S., Design, Synthesis, and Preclinical Evaluation of Prostate-Specific Membrane Antigen Targeted Tc-99m-Radioimaging Agents . Molecular Pharmaceutics 2009, 6, 790-800.

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