This dissertation explores the use of the folate receptor (FR) for targeted drug delivery to tumors. The FR is a highly selective tumor marker overexpressed in more than 90% of ovarian carcinomas. Two main strategies for targeted drug delivery to FR-positive cells are: 1) coupling to a monoclonal antibody against the receptor, and 2) coupling to a high-affinity ligand, folic acid. Folic acid retains its receptor-binding properties when derivatized via its γ-carboxyl group. Folate conjugation has been successfully applied in vitro for the targeted delivery of various agents, including protein toxins, anti-T-cell receptor antibodies, interleukin-2, chemotherapy agents, γ-emitting radiopharmaceuticals, magnetic resonance imaging contrast agents, liposomal drug carriers, and gene transfer vectors. The dissertation presents novel approaches to using FR-mediated delivery. First, FR-targeted liposomes were evaluated as carriers for a lipophilic boron compound for neutron capture therapy. These carriers showed specific receptor binding and FR-mediated endocytosis in vitro. Second, novel pH-sensitive liposome formulations incorporating oleyl alcohol were evaluated. FR-targeting was combined with these pH-sensitive liposomes for drug delivery, and these FR-targeted, pH-sensitive liposomes showed ~17 times greater FR-dependent cytotoxicity in a FR(+) cell line compared with non-pH-sensitive liposomes. Third, a novel lipophilic conjugate of folate, folate-polyethylene glycol (PEG)-cholesterol, was synthesized and evaluated for FR-mediated delivery of liposomes to tumor cells. All three approaches demonstrated that folic acid's small size, convenient availability, simple conjugation chemistry, and lack of immunogenicity make it an ideal ligand for targeted drug delivery. The research was supported by grants from the National Cancer Institute (NIH), the Department of Energy, and the American Cancer Society. The dissertation committee included Dr. Robert J. Lee, Dr. William L. Hayton, Dr. Alfred E. Staubus, and Dr. Susan R. Mallery. The work was conducted at The Ohio State University, and the dissertation was submitted in partial fulfillment of the requirements for the Doctor of Philosophy degree in the Graduate School of The Ohio State University.This dissertation explores the use of the folate receptor (FR) for targeted drug delivery to tumors. The FR is a highly selective tumor marker overexpressed in more than 90% of ovarian carcinomas. Two main strategies for targeted drug delivery to FR-positive cells are: 1) coupling to a monoclonal antibody against the receptor, and 2) coupling to a high-affinity ligand, folic acid. Folic acid retains its receptor-binding properties when derivatized via its γ-carboxyl group. Folate conjugation has been successfully applied in vitro for the targeted delivery of various agents, including protein toxins, anti-T-cell receptor antibodies, interleukin-2, chemotherapy agents, γ-emitting radiopharmaceuticals, magnetic resonance imaging contrast agents, liposomal drug carriers, and gene transfer vectors. The dissertation presents novel approaches to using FR-mediated delivery. First, FR-targeted liposomes were evaluated as carriers for a lipophilic boron compound for neutron capture therapy. These carriers showed specific receptor binding and FR-mediated endocytosis in vitro. Second, novel pH-sensitive liposome formulations incorporating oleyl alcohol were evaluated. FR-targeting was combined with these pH-sensitive liposomes for drug delivery, and these FR-targeted, pH-sensitive liposomes showed ~17 times greater FR-dependent cytotoxicity in a FR(+) cell line compared with non-pH-sensitive liposomes. Third, a novel lipophilic conjugate of folate, folate-polyethylene glycol (PEG)-cholesterol, was synthesized and evaluated for FR-mediated delivery of liposomes to tumor cells. All three approaches demonstrated that folic acid's small size, convenient availability, simple conjugation chemistry, and lack of immunogenicity make it an ideal ligand for targeted drug delivery. The research was supported by grants from the National Cancer Institute (NIH), the Department of Energy, and the American Cancer Society. The dissertation committee included Dr. Robert J. Lee, Dr. William L. Hayton, Dr. Alfred E. Staubus, and Dr. Susan R. Mallery. The work was conducted at The Ohio State University, and the dissertation was submitted in partial fulfillment of the requirements for the Doctor of Philosophy degree in the Graduate School of The Ohio State University.