Folate receptor-targeted imaging agents for cancer and inflammatory diseases
Abstract
Folate receptor-targeted imaging agents have previously been utilized to image and diagnose both cancer and inflammatory diseases in animals and humans. These imaging agents are now being further developed for novel applications. Fluorescence guided surgery is one such application that allows for the real time removal of FR+ tumors by surgeons. In Chapter 5, we explore the use of tumor-specific targeting ligands to deliver near-infrared (NIR) fluorescent dyes specifically to FR expressing cancers, thereby rendering only the malignant cells highly fluorescent. We report here upon intravenous injection into tumor-bearing mice with metastatic disease, these ligand−NIR dye conjugates render receptor-expressing tumor tissues fluorescent, enabling their facile resection with minimal contamination from healthy tissues. A major objective of personalized medicine for inflammatory and autoimmune diseases lies in developing methods for identifying patients who will eventually benefit from a therapy. The ability to select patients who will respond to therapies for these diseases is especially acute, because of the cost and damage associated with failed therapies. We describe in Chapters 2 and 3 a clinical test that will rapidly predict the response of a patient with an autoimmune/inflammatory disease to any of the most commonly employed therapies. This test involves quantitative assessment of uptake of folate receptor-targeted imaging agents by FR+ macrophages that accumulate at sites of inflammation. Murine models of a variety of inflammatory diseases show markedly decreased uptake of folate receptor-targeted radioimaging agents in inflamed lesions upon initiation of a successful therapy, but no decrease in uptake upon administration of an ineffective therapy, both long before any change in clinical symptoms can be detected. Once FR-targeted imaging agents have been employed to identify patients with inflammatory diseases, the next logical step is to treat those patients with FR-targeted therapies. In Chapter 4 we use a folate-targeted imaging agent to assess disease in rats induced to develop osteoarthritis. These rats were also treated with a FR-targeted anti-inflammatory drug. Treated rats were found to have significant attenuation of joint damage in the knees of MIA rats when compared to saline treated controls. With the rapid emergence of targeted nanoparticples in recent years, we found it important to study the effect of size on nanoparticle accumulation in solid tumors. As discussed in Chapter 6, we demonstrate that the low molecular weight folate-fluorescein conjugate accumulated in the tumor mass by the two hour time point ∼40-fold more readily on a molar basis than the high molecular weight folate-BSA-fluorescein conjugate. Because the effects of nanocarrier size, shape, chemistry, and targeting ligand are interconnected and complex, we suggest that these parameters must be carefully optimized for each nanocarrier to ensure optimal drug delivery in vivo.
Degree
Ph.D.
Advisors
Low, Purdue University.
Subject Area
Biochemistry|Physical chemistry|Medicine|Oncology
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