Targeting the Folate Receptor, a Novel Cancer Treatment

1. Targeting the Folate Receptor, a Novel Cancer Treatment Kenneth S Brandenburg Graduate Student, Bioengineering Department Faculty Advisor: Dr. G. Ali Mansoori, Bioengineering Department Abstract What is Folate? Tissue Distribution Folate Receptor Kinetics In this research the author presents studies in the molecular mechanism of Folic Acid – Folate receptor interactions, intermolecular mechanisms of Folic Acid-nanoparticle conjugation and nano-optimization modeling of the most effective conjugation for a targeting strategy. Folate, a salt derivative of Folic Acid, is rapidly gaining acceptance as a targeting ligand for cancer treatments utilizing nanotechnology. In order to optimize a nanoparticle based treatment for cancer, an intense literature review was completed. The review considered: Folate Receptor populations within the human body and abundance, Folate Receptor cycles in endocytosis, Folic Acid — Folate Receptor chemical kinetics, Folate conjugated Nano-carriers, and several proposed nanotechnology based techniques for cancer treatments. Based on the literature review, several areas of Folate – Nanotechnology were identified for future investigation such as Folate Receptor structure imagining, Folate – Conjugate intracellular trafficking, and refinement of nanotechnology based cancer treatments. These future investigations can be accomplished through the use of X-ray crystallography and complex protein folding simulations, Quantum Dots in imaging the intracellular trafficking and delivery of Folate molecules, and further chemical kinetics studies of Folate conjugated Nano-carriers in vivo. Due to its promising characteristics of non-immunogenicity, specificity for cancer, and easy Nano-carrier conjugation, Folate is a front runner as a targeting system for many cancer treatments and needs to be further explored to validate its use in nanotechnology based cancer therapies. • Vitamin B-9 • Cofactor for One Carbon Synthesis • Purines and thymidine • Blood Concentration ~ 20nM Folate • Concentration regulated by the Kidneys Folate Endocytosis • Folate Receptor • 38,000 Dalton Protein • Linked in the Hydrophobic region of the phospholipid bi-layer • 3 Isoforms: Alpha (α), Beta (β), and Gamma (γ) • Does not enter clathrin coated pit pathway • Linear Increase of Association with the number of Folic Acid Molecules Attached • Exponential decrease of Dissociation with the number of Folic Acid Molecules Attached • Units/ml/mg Protein • Very Strong Positive: 1000+ • Strong Positive: 100 – 1000 • Positive: 10 – 100 • Weak Positive: 0.1 – 10 • Negative: 0 Materials Delivered via Folate BioE 396/397 2005-2006 • Healthy tissue: Restricted to the luminal surface [12] • Luminal Surface faces away from the blood stream • Prevents the binding of Folate to its receptor in healthy tissues • Cancerous Tissue: The Folate Receptor faces the blood stream Future Work Folate Receptor Population • Folate Receptor structure • X-Ray diffraction or Protein Folding Simulations • Folate-conjugate intracellular trafficking and kinetics • Folate-Conjugate Design • Cleavable bonds for improved drug release and delivery • Other Applications for other diseases References • Doucette MM and Stevens VL. “Folate Receptor Function Is Regulated in Response to Different Cellular Growth Rates in Cultured Mammalian Cells”. Journal of Nutrition. 131 (2001): 2819-2825 • Leamon CP and Reddy JA. “Folate-targeted Chemotherapy.” Advanced Drug Delivery Reviews. 56 (2004): 1127-1141 • Rothberg KG, Ying Y, Kolhouse JF, Kamen BA, and Anderson RGW. “The Glycophospholipid-linked Folate Receptor Internalizes Folate Without Entering the Clathrin-coated Pit Endocytic Pathway.” Journal of Cell Biology. 110 (1990): 637-649 • Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, Zurawski VR, and Kamen BA. “Distribution of the Folate Receptor GP38 in Normal and Malignant Cell Lines and Tissues.” Cancer Research. 52 (1992): 3396-3401 • Hong S, Leroueil PR, Majoros IJ, Orr BG, Baker JR, Banaszak Holl MM. “The Binding Avidity of a Nanoparticle-Based Multivalent Targeted Drug Delivery Platform.” Chemistry and Biology. 14 (2007): 107-115 • Nagayasu A, Uchiyama K, and Kiwada H. “The size of liposomes: A Factor which Affects their Targeting Efficiency to Tumors and Therapeutic Activity of Liposomal Antitumor Drugs.” Advanced Drug Delivery Reviews. 40 (1999): 75-87 • Brandenburg KS, Kent M, Swan D, and Mansoori GA. “Cancer Treatment through Nanotechnology” Senior Design 2005-2006, Bioengineering 396/397, UIC 1) Iron Oxide (10 nm in diameter) Super paramagnetic particle used to generate the heat necessary to induce hyperthermia. Does not retain magnetism when removed from a magnetic field. 2) Gold (5nm in diameter) Used to prevent aggregation of iron oxide particles. Biomolecules (Folate) can be easily bonded to gold nanoparticles. 3) Folate (Method of Delivery) Cancer cells over express Folate receptors. High solubility in water. High affinity for its receptor 4) Polyethylene Glycol (PEG) SC: Sub Confluence C: Confluence PC: Post Confluence