It's Not Easy Being Green

Follow the Green Team from the T/R lab section through their arduous planning leading up to their final research proposal presentation!

Contributing authors: Daniel Kim, Mimi Yen

Background Information
11/11 Research ideas  ~ MY ~

1.	 Drugs by Air

Although feared by many, the needle is the most common method of drug administration. A new technique developed by a team at MIT uses a stream of gas containing the drug that would be absorbed through the skin. The procedure, known as microscission, uses small inert aluminum oxide crystals to remove the skin’s outer layer and create microconduits through which the medicine can move. Anesthetics are then applied to the region, which offers a less painful alternative to the needle.

Reference: Scientific American http://www.sciam.com/article.cfm?id=new-drug-delivery-techniq

2.	Targeted radiation therapy

A team led by the Sloan-Kettering Cancer Center in New York has developed a molecule-sized delivery system that could make radiation therapy for a variety of cancers much safer for patients. Researchers turned to actinium-225, which has a half-life of 10 days, because of its longer half-life than the most often used radioactive element and its capability to generate alpha particles that would kill off nearby tumor cells. Actinium atoms were caged inside rings of carbon and attached to antibodies that specifically recognize cancer cells. This allows the radioactive isotopes to target the cell directly and destroy it from within.

Reference: Scientific American http://www.sciam.com/article.cfm?id=drug-delivers-longer-last

3.	Gold Nanoparticles block HIV

TAK-779 was first proposed in 1996 as an effective compound in blocking HIV from hijacking the body’s immune system. The idea was rejected, however, because of the side effects of the drug’s injection and the ineffectiveness of its oral doses. It has long been known that the ammonium salt molecules in TAK-779 triggered the side effects, but no replacement had been found that would be able to bind the drug to the T cells as effectively. Researchers found that attaching 12 modified molecules of TAK-779 to one gold nanoparticle restored the drug’s ability to prevent infection. Since the size of the gold particles are similar to the HIV proteins, it makes the material well suited to block the proteins from coming in contact with key receptors on the T cells.

Reference: Scientific American http://www.sciam.com/article.cfm?id=gold-nanoparticles-hiv

4.	A novel insulin delivery system

Chemical engineers at Purdue University reported the successful synthesis of a glucose-sensitive hydrogel that could be used to deliver insulin to diabetic patients. The hydrogel membrane immobilizes glucose oxidase and forms an insulin “reservoir”. In contrast to other hydrogel system that release trapped drugs by swelling, this method works by shrinking the membrane. The trigger for this mechanism is controlled by pH and is accomplished when the body produces high sugar levels. Glucose interacts with the glucose oxidase in the membrane, which yields gluconic acid. This in turns lowers the body’s pH and trigger the gate to open.

Reference: Modern Drug Discovery http://pubs.acs.org/subscribe/journals/mdd/v04/i04/html/MDD04FeatureVogelson.html Dorski, C. M.; Doyle, F. J.; Peppas, N. A. Polym. Mater. Sci. Eng. Proc. 1997, 76, 281.

5.	Flu Vaccine Patch

3M Drug Delivery systems has developed a new technology that would deliver its M2e universal flu vaccine using a skin patch instead of the traditional needle injection. Instead, they use microneedle technology that penetrates the skin with minimal discomfort but still allows for the intradermal delivery of therapeutics usually only available through the needle. This also increases the delivery time of the vaccination in the case of the seasonal flu or a pandemic when rapid vaccination of the population is critical to stop the disease from spreading.

Reference: Drug Delivery Technology http://www.drugdeliverytech.com/ME2/dirmod.asp?sid=7326F9BFDFF54B32B7DFFEB6C52F8056&nm=&type=news&mod=News&mid=9A02E3B96F2A415ABC72CB5F516B4C10&tier=3&nid=E78B173082AA4C11AD0BE9D6BE4EEB05

~ DK ~

1.	Artificial scaffold helps engineered heart cells better mimic real ones (Technology Review, November 3, 2008). Researchers at MIT have discovered a new material for use in heart tissue engineering. A major problem for repairing heart damage is that a scaffold for heart damage repair needs to be elastic enough to expand and contract as the heart does, but strong enough to withstand the powerful contractions. This bio-material fulfills both requirements and even aids the alignment of heart cells for proper regeneration.

Reference: Technology Review http://www.technologyreview.com/biomedicine/21625/

2.	Self-propelled microbots navigate through blood vessels (Technology Review, October 31, 2008). Researchers at the Ecole Polytechnique de Montreal have created a ‘microbot’ made of a self-propelling bacterium and microscopic beads. The natural bacteria contains magnetic beads that aid in navigation toward better environmental conditions; the researchers used this natural quality to ‘steer’ the microbot by changing the magnetic fields around the ‘microbot’. The intended goal of the microbots is drug delivery to tumors.

Reference: Technology Review http://www.technologyreview.com/computing/21619/?a=f

3.	Electricity generation from model organic wastewater in a cassette-electrode microbial fuel cell (Applied Microbiology and Biotechnology, August 2008, 80(2):325-30). Researchers have designed a new microbial fuel cell that derives electrical energy from organic matter in wastewater. These fuel cells are designed as ‘cassettes’ and can be combined to form larger fuel cells. This new cell is extremely potent due to its dual roles of electricity generation and waste treatment.

4.	Single celled organisms could be “trained” to deliver drugs (Technology Review). A researcher at the National Institute for Medical Research (United Kingdom) has suggested that bacteria can “learn” to respond a certain way when given the appropriate stimulus. Similar to the Pavlovian model of associating the bell with food and causing salivation through strengthening neural connectivity, the model presented here suggests that the pairing of environmental inputs (one natural, the other desired by the researcher) can lead the bacteria to respond appropriately when only one of the inputs (desired by the researcher) is present.

Reference: Technology Review http://www.technologyreview.com/biomedicine/21447/

5.	Metabolic engineering to enhance bacterial hydrogen production (Microbial Biotechnology, August 2007). These researchers have modified E. coli to produce hydrogen at 141 times the normal level. Using a E. coli library, the researchers constructed multiple deletions in the cell’s genome to direct the cell’s metabolism toward hydrogen production. This engineering feat is important as hydrogen fuel may be an important source of energy in the future.

Conclusion: Both members are particularly interested in the topic of cancer therapy. Continue literature search and decide on Tuesday in class what would be the best direction to take this project.

Literature Search
~ MY ~

Cancer therapies

ANGIOGENESIS INHIBITORS (anti-VEGF agents such as bevacizumab)

Tumor angiogenesis plays a huge role in the progression of cancer. The normal process of angiogensis in the body is controlled by a very tightly regulated system of promoting factors and inhibitors. The "angiogenic switch" may occur during tumor expansion, which may cause some cells to be outside the oxygen diffusion limit and become hypoxic. Tumor cells respond to hypoxia by activing a transcription factor that directly transactivates genes involved in the process of angiogenesis, including the vascular endothelial growht factor (VEGF).

VEGF has been suggested to play a key role in the angiogenesis regulation, as it acts as both an endothelial cell survival factor and as a recruiter of circulating precursors. VEGF overexpression has been significantly correlated with decreased survival in several tumor types. Bevacizumab is a recombinant monoclonal antibody that is humanised by the incorporation of murine BVEGF-binding residues into a human IgG framework. It prevents the interaction between VEGF and its receptors by binding to soluble VEGF.

~ Longo et al., 2008 (pancreatic cancer --> targeting cancer)

~ Aita et al., 2008 (Targeting the VEGF pathway in the treatment of non-small lung cancer cells)

~ Raskopf et al., 2008 (siRNA targeting VEGF inhibits tumor angiogenesis in vivo) ~ Norden et al., 2008 (Novel anti-angiogenic therapies for malignant gliomas)

CHEMOTHERAPY INNOVATIONS

Side effects of chemotherapy are due the drugs taking effect on all of the body's cells. Thus, the main research behind chemotherapy is the search for a method to target cancer cells. By targeting only cancerous cells, patients undergoing chemotherapy would not their health and their lives as significantly affected.

~ Luo et al., 2008 (short hairpin RNA targeting c-FLIP sensitizes cells to chemotherapy)

~ Wheate, 2008 (Improving platinum(II)-based anticancer drug delivery using cucurbit[n]urils)

~ Munnier et al., 2008 (Novel method of doxorubicin–SPION reversible association for magnetic drug targeting)

 ~ DK ~

NANOPARTICLES AS CANCER THERAPIES

Nanoparticles of all kinds hold great potential as drug delivery agents and cancer therapies. Specifically, nanoparticles are known to have strong localization abilities as well as active intracellular delivery; thus, nanoparticles are an ideal substrate for drugs and other peptides for cancer diagnosis and treatment. The nanoparticles can effectively localize to the tumor through antigen-antibody interactions and enter the cell through receptor-mediated endocytosis. Furthermore, nanoparticles can carry large amounts of drug (due to large surface-to-volume ratios) and can carry multiple drugs and ligands on its surface. These properties make nanoparticles a strong candidate for optimized and varied cancer therapies.

Davis, M., Chen, Z., Shin, D. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature Reviews Drug Discovery 7, 771-782 (September 2008). http://www.nature.com/nrd/journal/v7/n9/full/nrd2614.html

Byrne, J., Betancourt, T., Brannon-Peppas, L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Available online 20 September 2008. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3R-4TGS78D-1&_user=501045&_coverDate=09%2F20%2F2008&_alid=825326425&_rdoc=1&_fmt=high&_orig=search&_cdi=4953&_sort=r&_docanchor=&view=c&_ct=320&_acct=C000022659&_version=1&_urlVersion=0&_userid=501045&md5=159f162f8af7892e2289efab28d80cd9

CONSIDERATION OF INTEGRIN

Integrins are cell surface receptors that interact with the extracellular matrix and control growth and movement of the cell. In current literature, certain integrins have been shown to play a role in cancer metastasis and growth. In addition, suppressing those integrins can lead to apoptosis. Thus, targeting integrins can be a potential cancer therapy.

Zhao-yang, Z., Ke-sen, X., Qing-si, H., Wei-bo, N., Jia-yong, W., Yue-tang, M., Jin-shen, W., Guo-qiang, W., Guang-yun, Y., Jun, N. Signaling and regulatory mechanisms of integrin ανβ6 on the apoptosis of colon cancer cells. Cancer Letters Volume 266, Issue 2, 8 August 2008, Pages 209-215. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T54-4S62Y6K-3&_user=501045&_coverDate=08%2F08%2F2008&_alid=825284582&_rdoc=8&_fmt=high&_orig=search&_cdi=4992&_sort=r&_docanchor=&view=c&_ct=1256&_acct=C000022659&_version=1&_urlVersion=0&_userid=501045&md5=6f972989ac38439af2fa8069f34ee4b7

Huang, Y., Sook-Kim, M., Ratovitski, E. Midkine promotes tetraspanin–integrin interaction and induces FAK-Stat1α pathway contributing to migration/invasiveness of human head and neck squamous cell carcinoma cells. Biochemical and Biophysical Research Communications Volume 377, Issue 2, 12 December 2008, Pages 474-478 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WBK-4TN5GCK-F&_user=501045&_coverDate=12%2F12%2F2008&_alid=825286842&_rdoc=15&_fmt=high&_orig=search&_cdi=6713&_sort=d&_docanchor=&view=c&_ct=19788&_acct=C000022659&_version=1&_urlVersion=0&_userid=501045&md5=e916756fa1282579dccd57a3d9bc0d75

Pec, M., Artwohl, M., Fernández, J., c, Souto, M., de la Rosa, D., Giraldeza, T., Valenzuela-Fernándeze, A., Díaz-González, F. Chemical modulation of VLA integrin affinity in human breast previous cancer cells. Experimental Cell Research Volume 313, Issue 6, 1 April 2007, Pages 1121-1134 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WFC-4MYVGB4-2&_user=501045&_coverDate=04%2F01%2F2007&_alid=825318902&_rdoc=1&_fmt=high&_orig=search&_cdi=6791&_sort=r&_docanchor=&view=c&_ct=14904&_acct=C000022659&_version=1&_urlVersion=0&_userid=501045&md5=0cf79ff7f362805e68c2422f67d2f19d

OTHER CRAZY THOUGHTS

What if we could 'quench' radioactivity of actinium or some other highly potent atom in a crown ether, and somehow (through ligand interactions with cancer cells) cause the crown ether to break open only when it's attached to a cancer cell?

What if we could send a nanoparticle into a cancer cell through receptor-mediated endocytosis and have the nanoparticle 'release' solute particles into the cytoplasm? This would cause the cell to lyse, allowing the nanoparticle to travel free again to another cancer cell. Thus the treatment is reusable.

Or what if we could design a virus that is specific to cancer alone and have it deliver siRNA to the cells? Maybe use the virus structure as the interface?

11/18 Conclusion: Research idea - create a nanoparticle that recognizes a cancer-specific antigen. Upon attachment, the nanoparticle undergoes a conformational change to expose the anti-VEGF ligand. This will then attach to VEGF (a surface receptor protein) on the cell, thus blocking angiogenesis and further tumor progression. The cells will, hopefully, die of natural causes due to the lack of nutrients.

For next time: gather information on the VEGF pathway (Background) and find details on the development of the nanoparticle (Methods).