Folate -targeted liposomal drug delivery: Applications from cancer to arthritis

Mary Jo Turk, Purdue University

Abstract

Folate-targeted drug delivery is a means by which therapeutic and imaging agents may be selectively transported to folate receptor-expressing cancers, while leaving normal tissues unaffected. Recently, folate receptor (FR) over-expression has also been identified on activated macrophages, which are largely responsible for rheumatoid arthritis. There currently exists a need for the development of novel folate-targeted therapeutic and imaging agents for the treatment and diagnosis of both cancer and arthritis. The goals of this thesis research were to (1) devise an assay for rapid and accurate quantitation of FR, (2) investigate and optimize folate-targeted liposomes for delivery to tumors, and (3) determine if folate-conjugates target macrophages associated with arthritis. In achieving the first goal, a radioligand-binding assay was designed which enabled rapid and accurate determination of FR levels in human and murine tissue samples. Second, to optimize the unloading of folate-targeted liposomes in cells, a peptide was designed to form pores in bilayers at endosomal pH's. Characterization of this peptide established its ability to unload liposomes with high efficiency and to enhance delivery of drugs and genes into folate-receptor bearing cells. Next, folate receptor-mediated targeting of liposomes to tumors was demonstrated in-vivo using an tumor model. Interestingly, tumor-associated macrophages were also targeted by folate-liposomes, which lead us to further investigate folate targeting of activated macrophages. Subsequent analysis of rat and dog arthritis models demonstrated folate-targeted imaging of activated macrophages in arthritic extremities and joints. These experiments collectively demonstrate the wide ranging utility of folic acid for targeted disease diagnosis and therapy.

Degree

Ph.D.

Advisors

Low, Purdue University.

Subject Area

Biochemistry|Pharmacology

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