Dissertation/Thesis Abstract

Design and synthesis of folic acid conjugates as cancer diagnostic and treatment agents
by Liu, Jidong, Ph.D., The University of Toledo, 2007, 228; 3348339
Abstract (Summary)

Folate receptors (FRs) are over-expressed on many tumor cell surfaces compared to most normal tissues. Uptake of folic acid (FA) or FA conjugates into cells can occur by the FR-mediated endocytic pathway. We are attempting to use this pathway to achieve two goals: (1) Deliver FA conjugates selectively to tumor cell surfaces in preference to normal cells; and, (2) Enhance the entry of FA conjugates into tumor cells to a greater extent than by their non-transport-mediated pelmeation for which physicochemical barriers can sometimes limit the entry of drugs.

Two methods have been developed to prepare pteroic acid, which is a key starting material for the syntheses of various types of FA conjugates. The first method represents the optimization of an enzymatic approach reported in the literature. The second method involves a new chemical treatment that we have shown to be generally useful for syntheses of several FA conjugates such as folate-paclitaxel (FA-PAC), folate-rhodamine dye (FA-RD), and folate-perfluorocarbon (FA-PFC) compounds. A FA-PAC conjugate was prepared to potentially increase PAC's selectivity for cancer cells versus healthy cells, and also to decrease PAC's multi-drug resistance (MDR) liability. Due to the strong fluorescence properties of rhodamine, a series of FA-RD conjugates was made to study the FA uptake transporter and the latter's release of ligands, as well as to clarify any observed selectivity demonstrated by the PAC series. A series of FA-F conjugates was prepared to determine their interactions with FRs and make them available for subsequent examination as potential ultrasound contrast agents using ultrasound imaging technology.

Three kinds of human cancer cell lines are being used for assessment of these probe's preliminary biological properties: KB; HeLa; and CEM-7A cell lines. The KB cell line has highly over-expressed FRs and the HeLa cell line has moderately over-expressed FRs. Alternatively, the CEM-7A cell line has highly over-expressed reduced folic acid carriers (RFCs) instead of FRs. A control human cell line was additionally chosen for each type of FR and RFC cell line during these tests. The reason for including the CEM-7A cell line is to examine whether the FA conjugates will be recognized as FA only by FRs or also by RFCs which tend to be more ubiquitously expressed on normal cells. Anticancer activity of the FA-PAC analog is also being examined using these kinds of cell lines wherein growth inhibition (GI50's) will indicate which compounds are the most active. For the MDR study of PAC, the pair of MCF7 and NCI/ADR-RES human breast cancer cell lines will be used for the biological testing. MCF7 is a tumor cell line without MDR while the NCI/ADR-RES cell line has over-expressed Pgp which is directly related to the degree of MDR. MCF12A will be used as a control cell line for these latter studies.

Indexing (document details)
Advisor: Erhardt, Paul W.
School: The University of Toledo
School Location: United States -- Ohio
Source: DAI-B 70/02, Dissertation Abstracts International
Subjects: Pharmacology, Pharmacy sciences
Keywords: Cancer treatment, Folate, Folic acid, Paclitaxel, Ultrasound contrast agents
Publication Number: 3348339
ISBN: 978-1-109-03806-4
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