A) Nanoscale drug delivery to pancreatic cancer cells
Background: Pancreatic cancer ranks as the fourth leading cause of death by cancer in the United States. Approximately, 30,000 people are diagnosed with pancreatic cancer and a similar number die of the disease each year.1, 2 Typically, 19% of patients with patients with cancer of the exocrine pancreas survive 1 year after diagnosis, and only 4% survive 5 years after diagnosis.2 The problem is particularly acute in the African American population, since they are 2 times more likely to die than patients from other minority groups.3 The incidence of pancreatic cancer in African-American population exceeds those in the white population by about 50% to 90%.4 Pancreatic cancer offers a clear example of a tumor that, despite the advances in science and medicine, remains an almost insurmountable challenge for curative treatment.5
Nano-scale science includes the study of objects and systems in which at least one dimension is 1-100 nm. Within the last decade, there have been a plethora of publications that have demonstrated potential applications of nanotechnology, which include catalysts, components of systems for drug delivery, magnetic storage media, and electronic and optical devices 6, 7. Polymeric drug delivery systems are an important tool in the treatment of cancer and genetic diseases. Indeed, drug delivery systems have impacted nanotechnology, resulting in the use of nano-particles for drug delivery and gene delivery. The efficacy of anticancer drugs, however, may be inhibited by the extracellular matrix (ECM) proteins including collagen I, collagen IV, fibronectin, and laminin that surround the cancer cell. The advantages of nano-particles are that they are submicrometer colloidal particles capable of tumor penetration through the ECM. These polymeric nano-particles can be made ferric magnetic, which has the advantage that an external localized magnetic field gradient can be applied to the chosen site to attract drug-loaded magnetic nanoparticles from blood circulation. A recent study by Jain et al. 8 demonstrated the feasibility of using oleic acid (OA)-Pluronic-coated iron oxide magnetic nanoparticles for drug loading. We want to extend this study using the pancreatic anti-cancer drugs 5-Fluorouracil and gemcitabine that inhibit DNA replication and repair, and Flavopiridol, which is an inhibitor of several cyclin-dependent kinases (CDKs).9, 10 The specific goals of this research proposal include the following:
1. Synthesize and characterize Fe surface modified colloidal nanoparticles.
2. Test in-vitro activity using pancreatic cell cultures of solution phase drug vs drug-loaded OA-Pluronic stabilized iron oxide nanoparticles.
1. Jaffee EM, Hruban RH, Canto M, Kern SE. Focus on pancreas cancer. Cancer Cell 2004;2:25-28.
2. Hansel DE, Kern SE, Hruban RH. Molecular pathogenesis of pancreatic cancer. Ann. Rev. Genom. Hum. Genet. 2003;4:237-56.
3. Shavers VL, Brown LB. Racial and ethnic disparities in the receipt of cancer treatment. J. Natl. Cancer Inst. 2002;5:334-57.
4. Silverman DT, Hoover RN, Brown LM., et al. Why do black Americans have a higher risk of pancreatic cancer than white Americans? Epidemiology 2003;4:45-45.
5. Randriamahefa A, Fernandez-Zapico ME, Mladek, et al. The First Initiative Targeted to Increase the Training of African-American Scientists in Pancreatic Cancer Research. Pancreas 2005;30(3):288-91.
6. Szacilowski K, Macyk W, Drzewiecka-Matuszek A, Brindell M, Stochel G. Bioinorganic Photochemistry: Frontiers and Mechanisms. Chemical Reviews 2005;105:2647-94.
7. Daniel M-C, Astruc D. Gold Nanoparticles: Assembly, Supramolecular Chemistry, Quantum-Size-Related Properties, and Applications toward Biology, Catalysis, and Nanotechnology. Chemical Reviews 2004;104:293-346.
8. Jain TK, Morales MA, Sahoo SK, Leslie-Pelecky DL, Labhasetwar V. Iron Oxide Nanoparticles for Sustained Delivery of Anticancer Agents. molecular pharmaceutics 2005;3(2):194-205.
9. Zhai S, Senderowicz AM, Sausville EA, Figg WD. Flavopiridol, a novel cyclin-dependent kinase inhibitor, in clinical development. Ann. Pharmacother. 2002;36(5).
10. Pasetto LM, Jirillo A, Stefani M, Monfardini S. Old and new drugs in systematic therapy of pancreatic cancer. Critical Reviews in Oncology/Hematology 2004;49:135-51.
B) Nanoscale science: Biomaterials a surface science approach (C. C. Perry)
Introduction: Surfaces play a vital role in catalysis, biology and medicine with most biological cellular detection/response occurring at the cell interface. Numerous examples show that the surface properties of a material are directly related to in-vitro biological performance such as protein adsorption and cell growth (Prime and Whitesides 1993; Li, Li et al. 2004; Rosi and Mirkin 2005). In certain research areas, e.g. catalysis and microelectronics, the combination of well defined surfaces have resulted in a detailed understanding of the role that surface structure and chemistry play (Burda, Chen et al. 2005). Specific research objectives include the following.
3. characterize Au and Fe surface modified colloidal Nanoparticles.
4. Characterize protein adsorption on self-assembled monolayers (SAMs) to model non-specific protein adsorption.
5. Evaluate and optimize the protein adsorption resistance of surface-modified SAMs
Poly(ethylene) glycol (PEG)
Nano-particle synthesis and characterization: Short term projects involve the synthesis of SAMs on Au, and Au and Fe nanoparticles using published techniques (Prime and Whitesides 1993; Daniel and Astruc 2004; Burda, Chen et al. 2005; Love, Estroff et al. 2005). The Au nanoparticles will be surface modified with alkyl thiols, and (polyethylene glycol) PEG thiolates along with laser ablation experiments to control particle size (Burda, Chen et al. 2005). In addition to Fe nanoparticle synthesis, we will attempt to synthesize bimetallic particles of Fe/Cu and Fe/Ni. The magnetic nanoparticles will be further modified by addition of starch and oleic acid (OA)-Pluronic coated iron nanoparticles (Jain, Morales et al. 2005). Material characterization will be performed using surface analytical techniques including transmission electron microscopy (TEM), infrared (IR) and UV-VIS. Mass spectroscopy will be used for molecular weight determination.
Non-specific protein adsorption: Many strategies have been developed to inhibit non-specific protein adsorption. This is relevant for a wide array of medical devices including catheters, heat valves, and stents, etc. Protein adsorption on an implant surface is the first stage leading to a deleterious inflammatory response in tissue (Castner and Ratner 2002). We will perform uptake experiments of various SAMs on Au with fluorescent labeled proteins Fibrinogen and Lysozyme and bovine serum albumin. This will be compared with model, Polyethylene oxide (PEO) (CH2CH2O)n surfaces, which were found to give good anti-fouling characteristics (Prime and Whitesides 1993; Love, Estroff et al. 2005).
Environmental Remediation: Nanoscale iron particle environmental remediation technologies can potentially provide cost-effective solutions to some of the most challenging environmental cleanup problems. Nanoscale iron particles have large surface areas and high surface reactivity making them potentially very effective for the transformation and detoxification of a wide variety of common environmental contaminants, such as chlorinated organic solvents, organochlorine pesticides, and PCBs (Zhang 2003). However, these iron nanoparticles generally agglomerate and adhere to soil particles. The goal is to use surface modification by polymers (e.g. poly(acrylic acid)) (PAA) to optimize adsorption of hydrophobic organic contaminants. We will use CCl4 as a model contaminant and compare its remediation using 1) zero-valent Fe and Fe/Pd nanoparticles; 2) magnetite (Fe3O4) encompassed in starch, (OA)-Pluronic coated, and PEGylated iron nanoparticles.
Burda, C., X. Chen, et al. (2005). "Chemistry and Properties of Nanocrystals of Different Shapes." Chemical Reviews 105: 1025-1102.
Castner, D. G. and B. D. Ratner (2002). "Biomedical surface science: Foundations to frontiers." Surface Science 500: 28-60.
Daniel, M.-C. and D. Astruc (2004). "Gold Nanoparticles: Assembly, Supramolecular Chemistry, Quantum-Size-Related Properties, and Applications toward Biology, Catalysis, and Nanotechnology." Chemical Reviews 104: 293-346.
Jain, T. K., M. A. Morales, et al. (2005). "Iron Oxide Nanoparticles for Sustained Delivery of
Anticancer Agents." MOLECULAR PHARMACEUTICS 3(2): 194-205.
Li, X., Y. Li, et al. (2004). "Liposome Induced Self-Assembly of Gold Nanoparticles
into Hollow Spheres." Langmuir 20: 3734-3739.
Love, J. C., L. A. Estroff, et al. (2005). "Self-Assembled Monolayers of Thiolates on Metals as a Form of
Nanotechnology." Chemical Reviews 105: 1103-1169.