From optimal dosing of folate-conjugates for the diagnosis and treatment of cancer to novel therapies in arthritis
Abstract
A variety of human cancer cells and inflammatory macrophages over-express the receptor that binds folic acid. Folic acid can be attached to virtually any molecule without compromising its affinity to the folate receptor, making folate-linked molecules an attractive method for the detection and treatment of human cancers and arthritis. The dosing regimen for folate-linked molecules previously had not been optimized. Therefore, we sought to analyze the binding properties, rate of internalization, frequency of recycling, and rate of unloading of the folate receptor in human cancer cells and animal models. From these studies, we gained greater insight both regarding folate receptor-mediated endocytosis, and the optimal dosing regimen of folate-linked molecules for detection and treatment of patients with cancer and arthritis. Activated macrophages, which are abundant in inflamed joints and organs of rodents, dogs, and humans with arthritis, were observed to over-express the folate receptor. In a recent publication, we demonstrate that these activated macrophages can be selectively targeted using folate-linked imaging agents, providing visual detection of the affected joints. Here, folate-FITC is shown to bind to this population of activated macrophages, thereby decorating the cell surfaces with highly immunogenic molecules. Under conditions where the animal has already been immunized against FITC, activated macrophages are rapidly eliminated from the body, resulting in a significant improvement of arthritis; including reduced paw swelling, bone and cartilage disintegration, and systemic inflammation. Furthermore, our folate-targeted immunotherapy is observed to reduce symptoms of arthritis as effectively as current anti-arthritis treatments, including methotrexate, Celecoxib®, Etanercept ®, and Ankinra®. Therefore, folate-targeted immunotherapy appears worthwhile for the treatment of patients with arthritis as well as for other autoimmune diseases caused or worsened by activated macrophages that over-express the folate receptor.
Degree
Ph.D.
Advisors
Low, Purdue University.
Subject Area
Biochemistry
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