Cancer Therapy and Nanotechnology

1. Cancer Therapy and Nanotechnology Presented by Mattia M. Migliore December 5, 2006

2. Introduction: • Neoplasms: are defined as a new formation of cell clusters, which have lost their ability to control cell division. • Neoplasms can either be benign or malignant. • Benign tumors: 1. Differentiated. 2. Slow rate of proliferation. 3. Encapsulated. 4. Do not infiltrate surrounding tissue. 5. Usually do not result in patient death. http://www.scienceclarified.com/images/uesc_10_img0586.jpg

3. Introduction (cont.): • Malignant tumors: 1. High rate of cell proliferation. 2. Loss of contact inhibition. 3. Lack of differentiation. 4. Grow by invading and infiltrating. 5. Loss of cohesiveness. 6. Resistance to apoptosis. http://www.news-medical.net/images/breast%20cancer%20cell.jpg http://www.gcarlson.com/images/metastasis.jpg

4. Estimated Number of Persons Alive in the U.S.Diagnosed With Cancer by Site (N = 10.5 M) Prevalence of Cancer type in the US. Data source: 2005 Submission. U.S. estimated cancer prevalence counts were estimated by applying U.S. populations to SEER 9 and historical Connecticut Limited Duration Prevalence proportions and adjusted to represent complete prevalence. Populations from January 2003 were based on the average of 2002 and 2003 population estimates from the U.S. Bureau of the Census. www.cancer.gov.

5. The Cell Cycle and Cancer: • Cell proliferation is a tightly controlled process that ensures the accurate replication and transcription of genetic information. • Genetic mutations can either be repaired, or result in the induction of apoptosis. • Mutations in certain genes, called oncogenes, can result in dysregulation of the cell cycle, resistance to apoptosis, and in the development of cancer. • A large number of today’s most effective cancer treatments are cytotoxic agents that target the cell cycle. http://nobelprize.org/nobel_prizes/medicine/laureates/2001/press.html

6. HISTORY OF CANCER THERAPY : (Chabner and Roberts, 2005)

7. Current Cancer Treatment Strategies: • Surgery: The first line of treatment for solid tumors, and may be curative if the tumor has not metastasized. • Radiation Treatments: Uses ionizing radiation. • Chemotherapeutic Agents: Three main classes of cytotoxic drugs used to treat neoplastic disease. The alkylating agents, the antimetabolites, and the natural products. http://www2.slac.stanford.edu/vvc/art/schematic.gif

8. Current Cancer Treatment Strategies (cont.): • Alkylating agents: Form covalent bonds on double stranded DNA, and prevent transcription. Activation of DNA repair mechanisms result in DNA strand breaks, and in apoptosis. • Antimetabolites: Most effective during the S phase of the cell cycle. Include the folic acid analogs (ex. methotrexate), pyrimidine analogs (ex. fluorouracil), and purine analogs (ex. mercaptopurine). Their mechanisms of action are to inhibit DNA synthesis, and/or to inhibit transcription and translation. http://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-409/ Cancer/Cancer_images/Nitrog_must.gif http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/methotrexate.gif

9. Current Cancer Treatment Strategies (cont.): • Natural Products: include the vinca alkaloids (ex. vincristine), taxanes (ex. paclitaxel), and epipodophyllotoxins (ex. etoposide). Mechanisms of action include DNA intercalation, inhibition of DNA and RNA synthesis, inhibition of topoisomerase, free radical production, and inhibition of microtubule formation. http://en.wikipedia.org/wiki/DNA_intercalation

10. Current Cancer Treatment Strategies (cont.): • Photodynamic Therapy: Uses a photosensitizing drug (porfimer sodium). • Hormonal treatments: For certain types of tumors. • Angiogenesis Inhibitors: Inhibit tumor vascularization. The first FDA approved angiogenesis inhibitor was bevacizumab, which is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF). http://www.orienttumor.com/english/MT/PDT/002_s.jpg http://www.gene.com/gene/research/images/angiogenesis.jpg

11. Current Cancer Treatment Strategies (cont.): • Tyrosine Kinase Inhibitors: Inhibit DNA synthesis and/or gene transcription. There are currently three FDA approved tyrosine kinase inhibitors: Imatinib, gefitinib, and erlotinib. • Biological Response Modifiers (BRMs): Enhance the body’s ability to effectively fight cancer, or they minimize chemo side effects. BRMs include interferons, interleukins, colony-stimulating factors, monoclonal antibodies, and vaccines for the prevention of certain types of cancer. http://www.amn107.com/images/aee788Large.jpg

12. Nanotechnology in the Treatment of Cancer: • Nanotechnology has generated a great deal of interest in the field of oncology due to its potential to selectively deliver and concentrate drugs to tumors while minimizing damage to healthy cells. • Two FDA approved nanoparticle formulations for the treatment of cancer: 1. Abraxane®: a suspension of albumin-bound paclitaxel (130 nm). FDA approved in January, 2005. 2. Doxil®: liposomal formulation of doxorubicin (100 nm). Approved in February, 2005. http://www.abraxane.com/images_charts/vhs_tape_box.gif http://www.doxil.com/images/clientChart.gif

13. Nanoparticle drug-delivery systems under development for the treatment of cancer : • Adriamycin-loaded nanoparticle formulation: In vivo studies demonstrated superior efficacy. In this study, rats were implanted with liver tumors and were later treated with either adriamycin alone, or with adriamycin-loaded nanoparticles (average diameters of 93 nm) injected directly into the hepatic artery (Chen et al., 2004). • Paclitaxel-loaded gelatin nanoparticles: These nanoparticles showed significant activity against a bladder cancer cell line in vitro (Lu et al., 2004). • Hydrolysable polymeric micelle system: Engineered with a hydrolysable segment that confers it a longer degradation half-life, and which makes it more stable when administered intravenously. A longer circulation half-life may result in greater tumor drug deposition, and in greater cytotoxic effectiveness (Zeng and Pitt, 2006).

14. Nanoparticle drug-delivery systems under development for the treatment of cancer (cont.): • Dendrimers:Under investigation for the delivery of oligonucleotides to cancer cells for gene therapy.Dendrimers, ranging in 130-280 nm in size, were demonstrated to increase oligonucleotide uptake by 14 fold in an in vitro breast cancer cell line(Santhakumaran et al., 2004). • Nanocells: A new nanoparticle drug-delivery system that makes it possible to combine drugs with different mechanisms of action in the same particle, and to design their temporal release. These nanocells have an outer pegylated-phospholipid block-copolymer containing an antiangiogenic drug (combrestastatin), and an inner nanoparticle core containing a cytotoxic drug (doxorubicin) (Sengupta et al., 2005). Nanoparticles: Scientists Work on an Anti-Cancer Smart Bomb imagine a cancer drug that can burrow into a tumour, seal the exits and detonate a lethal dose of anti-cancer toxins, all while leaving healthy cells unscathed. MIT researchers have designed a nanoparticle to do just that.MEDICA.de; Source: Massachusetts Institute of Technology

15. Nanoparticles in the Treatment of Cancer: • Nanoparticles themselves can also be used to destroy cancer cells directly. • Metal nanoparticles, together with near infrared light, have been shown to increase cell death in tumors by generating hyperthermia (Hirsch et al., 2003). • Gold nanoparticles inhibit angiogenesis by binding to vascular endothelial growth factor and basic fibroblast growth factor and preventing them from activating their receptors (Mukherjee et al., 2006).

16. Conclusions: • The search for effective cancer treatments has evolved over the years from a non-specific screening approach, to a molecular mechanism-driven targeted approach. • Nanoparticles hold great potential as drug-delivery carriers, and as selective cytotoxic agents against carcinogenic cells. • Preliminary results indicate that the future of cancer treatment will include nanoparticles. • However, more studies are still needed to demonstrate the superior effectiveness, and diminished toxicity of nanoparticles.