Publication Date

Fall 2010

Document Type

Project Summary

Degree Name

Master of Science

Department

Analytical Chemistry

First Advisor

Walter Henne, Jr., Ph.D.

Second Advisor

Stephen Kent, M.B.A.

Third Advisor

Patty Fu-Giles, Ph.D.

Abstract

Recent clinical studies have shown the importance of folate receptor in drug delivery system as they increase the potency and reduce toxicity of many cancer therapies. The folate receptor alpha ( FR-a) binds with high affinity for folic acid and serves for receptor mediated transport of folate into cells. Folate is necessary for DNA metabolism and thus it is speculated that rapidly dividing cancer cells have an increased requirement for folic acid. It is known that FR-a levels are elevated in specific malignant diseases (solid tumors, leukemia) and thus the FR receptor serves as useful targeting moiety for the diagnosis and detection of FR+ cancers. Drugs that have been attached to the folate include protein toxins, chemotherapeutic DNA, radioimaging agents, magnetic resonance imaging agents and liposomes with entrapped drugs.

In liposomal systems, the overall conjugation between the liposome and folic acid is very important for therapeutic activity due to

1) The need to present folate to the cancer cell surface unencumbered from bulky liposome( in order to bind to the folate surface)

2) The need to have adequate folate ligands for efficient binding to cell but not too many spacers/folate molecules that could result in non-specific binding.

In traditional liposomal systems, folate is attached to a PEG (poly ethylene glycol), which is incorporated into the lipid membrane via a hydrophobic tail. Although widely established, liposomes require a fair degree of technical ability to synthesize and analyse.

Recently, it has been discovered that apoferritin (iron transport protein), a 440kD polymeric protein, is capable of being dissociated into its respective subunits at low pH (pH ~ 2) and re-associated at pH ~ 7 to reform the apoferritin cage for the therapeutic purposes. Based on these results, our project aim is to synthesize a folate based apoferritin probe. The type of folate conjugation to the protein (i.e. synthesis of the folate spacer arm), the degree of folate labeling to the protein, the amount of dye incorporation into the protein cage and the types of dyes, drugs or other agents will also be assessed which would be eventually be tested for cell uptake. These type of these cages may be useful for the production of radio-imaging agents, MRI contrast agents, and other drug delivery platforms similar to liposomes.