WF Purple Peeps
Using the techniques described by Shu, et.al., we plan to create an RNA aptamer ensemble that will target αVβ3 integrin in vivo . Inhibition of this receptor will inhibit endothelial cell proliferation, therefore inhibiting angiogenesis. We will utilize a known RNA aptamer of αvβ3 integrin (see Mi, et.al.) to create a pRNA-siRNA construct in order to better deliver the aptamer to the αvβ3 integrin receptor.
Aptamers as Therapeutics Mia, et.al., 2010
This is a review article of many aptamers that have the potential be used as therapeutic antibodies for various diseases/targets. While aptamers have positive qualities and benefits, their cost and unknown pharmacokinetics prevent them from being popular. It also discusses different roles aptamers can take as well as their advantages and limitations.
One of the aptamers listed will be investigated further in our research proposal: αvβ3 integrin-- Prevents tumor development.
Assembly of Therapeutic pRNA-siRNA Nanoparticles Using Bipartite Approach Shu, et.al., 2011
Pharmacological Characterization of Chemically Synthesized Monomeric phi29 pRNA Nanoparticles for Systemic Delivery Abdelmawla, et. al., 2011
In the first paper, "Assembly of Therapeutic pRNA-siRNA Nanoparticles Using Bipartite Approach,” two manufactured RNA sequences were combined to form a pRNA fragment, that was then able to interact/combine with other pRNA molecules to form functional large RNA nanoparticles that could successfully deliver therapeutics to their cells. These nanoparticles can be modified for a certain therapeutic or target.
The second paper, "Pharmacological Characterization of Chemically Synthesized Monomeric phi29 pRNA Nanoparticles for Systemic Delivery," continues the work from the paper above. This one shows that chemically modified pRNA nanoparticles were stable and able to be immune to certain enzymes that otherwise would have degraded unmodified RNA. These pRNA were non-toxic, and did not cause an immune response. It mentions the possibility of binding to cancer cells in vivo.
We plan to explore this possibility and target the αvβ3 integrin using an aptamer.
Targeted inhibition of αvβ3 integrin with an RNA aptamer impairs endothelial cell growth and survival Mi, et.al., 2005
This article looks at αvβ3 integrin and its necessity in cell growth, but most importantly to us, tumor invasions and metastasis and angiogenesis, by controlling endothelial cell movement, growth, and survival. By blocking αvβ3 integrin’s function with an aptamer, Apt- αvβ3, EC growth and survival was repressed. The authors believe it has potential for tumor imaging and treatment. αvβ3 integrin expression increases when angiogenesis occurs (due to decreased EC apoptosis) and is required for tumor growth. The Apt- αvβ3 was able to block angiogenesis and increase EC apoptosis. We will use the pRNA technology to deliver this aptamer to the integrin in vivo.
Integrin αvβ3-Targeted Cancer Therapy Liu, et.al., 2008
αvβ3 integrin is the “most important during tumor angiogenesis,” again this article says that inhibiting αvβ3 integrin would have the potential of treatment in cancer. This article looks at current αvβ3 integrin inhibitors and their possibility of being cancer therapeutics. This paper explains the general function of αvβ3 integrin. It goes on to explain different forms of current αvβ3 integrin inhibitors including antibodies, disintegrins, peptides, gene therapies, and integrin αvβ3 –targeted drug delivery. To progress in this area of science, “researchers must redouble their efforts to create more tailored agents with improved pharmacokinetics and pharmacodynamics, as well as establishing suitable routes of administration (e.g.,.”oral available) for clinical applications.”