Transcript 06.Folate_poster

Targeting the Folate Receptor, a Novel Cancer Treatment
Kenneth S Brandenburg Graduate Student, Bioengineering Department
Faculty Advisor: Dr. G. Ali Mansoori, Bioengineering Department
Abstract
In this research the author presents studies in the
molecular mechanism of Folic Acid – Folate receptor
interactions, intermolecular mechanisms of Folic Acidnanoparticle 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 Xray 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 Nanocarriers 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.
BioE 396/397 2005-2006
What is Folate?
•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 bilayer
•3 Isoforms: Alpha (α), Beta (β), and Gamma (γ)
•Does not enter clathrin coated pit pathway
Tissue Distribution
Adult Males (18-24
years)
Choroid Plexus Very Strong Positive
Kidney
Positive
Positive – Strong
Lung
Positive
Thyroid
Positive
Liver
Negative
Spleen
Negative
Skin
Positive
Pancreas
Weak Positive
Heart
Weak Positive
Ovary
Not Done
•Units/ml/mg Protein
•Very Strong Positive: 1000+
•Strong Positive: 100 – 1000
•Positive: 10 – 100
•Weak Positive: 0.1 – 10
•Negative: 0
Cell Lines
Tissue
Folate Receptor Kinetics
Infant Females (1-17
months)
Very Strong Positive
Strong Positive
Positive
Positive
Negative
Negative
Not Done
Positive
Weak Positive
Strong Positive
•Linear Increase of Association with the number of Folic
Acid Molecules Attached
•Exponential decrease of Dissociation with the number of
Folic Acid Molecules Attached
Materials Delivered via Folate
Bound Folate
(pmol/106 cells)
Less than 0.1
Fibroblast
Chinese Hamster Ovary
Less than 0.1
Monkey Kidney Epithelial cell line (MA104)
1
Ovarian Carcinoma (IGROV1)
20
Colon Carcinoma (Caco-2)
20
Nasopharyngeal epidermoid carcinoma (KB)
50 - 200
•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
Folate Receptor Population
Material
Size (nm)
Application
Quantum Dots
2—10
Imaging
Metallic
Nanoparticles
0.5—100
Drug Delivery, Thermal
Ablation
Liposomes/Micelles
30—400
Drug Delivery
1—15
Drug Delivery
Haptens
Less than 10
Provoke Immune Response
Chemotherapeutics
Less than 10
Direct Drug Delivery
Dendrimers
Future Work
• 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
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
1. 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
2. Leamon CP and Reddy JA. “Folate-targeted Chemotherapy.” Advanced Drug Delivery
Reviews. 56 (2004): 1127-1141
3. 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
4. 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
5. 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
6. 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
7. Brandenburg KS, Kent M, Swan D, and Mansoori GA. “Cancer Treatment through
Nanotechnology” Senior Design 2005-2006, Bioengineering 396/397, UIC