Protein and Metabolic Engineering
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Cell Penetrating Peptides for Targeted Drug Delivery
The plasma membrane protects cells by regulating the access of molecules to the cellular cytoplasm. Only compounds within a narrow range of size, charge, and polarity are able to passively diffuse across the membrane. Recent advances in the developmental, molecular, and cellular biology of many devastating human diseases has led to the discovery of “mechanism-based” therapies, such as gene therapy and monoclonal antibodies, which show great promise in vitro. However, these successes have been difficult to translate in vivo due to difficulties in targeting and delivering large exogenous therapeutics specifically to the appropriate cells.
Cell penetrating peptides (CPPs) are short, mostly basic peptides can traverse biological membranes and enter cells. Since their original discovery, CPPs have been used to deliver a wide variety of cargos to different cell types, including fluorochromes, enzymes, antibodies, DNA, phage particles, and nanoparticles. It has been suggested that CPPs, such as the TAT CPP, could be valuable vectors for the delivery of therapeutic agents to different cell and tissue types in vivo. Unfortunately, the use of CPPs in the therapeutic arena has been problematic due to their general lack of cellular specificity.
An alternative approach used to ensure cell type specificity is the development of peptides that interact with specific cell surface receptors. It has been proposed that all tissue types have specific “zip code” molecules on their vasculature. Phage display has been used to map this system leading to the identification of homing peptides (HPs) that localize to different cell subtypes. This represents a valuable new approach to targeting material to different cell and tissue types, but applications using HPs are limited by the fact that the HPs generally do not enter the targeted cells.
We are using Directed Evolution to create Specific Cell Penetrating Peptides (SCPPs). The SCPPs will exhibit combined CPP and HP behavior. These peptides will target specific cell and tissue types in vivo, and they will enable the delivery of therapeutic cargos, such as DNA, proteins, or other exogenous materials, to targeted cellular cytoplasms. We are collaborating with Prof. Barclay Morrison's laboratory in the Department of Biomedical Engineering in order to create SCPPs that are specific for different brain cell types. We are especially interested in engineering SCPPs that can target cells that are damaged following traumatic brain injury. There is a narrow window of time following a brain injury where the targeted delivery of neurotrophic agents to injured cells could provide a significant benefit to the head injured patient.
- Gao S, Simon MJ, Hue CD, Morrison B 3rd, and Banta S. An unusual cell penetrating peptide identified using a plasmid display-based functional selection platform. ACS Chem Biol. 2011 May 20;6(5):484-91. DOI:10.1021/cb100423u |
- Kang WH, Simon MJ, Gao S, Banta S, and Morrison B 3rd. Attenuation of astrocyte activation by TAT-mediated delivery of a peptide JNK inhibitor. J Neurotrauma. 2011 Jul;28(7):1219-28. DOI:10.1089/neu.2011.1879 |
- Gao S, Simon MJ, Morrison B 3rd, and Banta S. A plasmid display platform for the selection of peptides exhibiting a functional cell-penetrating phenotype. Biotechnol Prog. 2010 Nov-Dec;26(6):1796-800. DOI:10.1002/btpr.490 |
- Simon MJ, Kang WH, Gao S, Banta S, and Morrison B 3rd. Increased delivery of TAT across an endothelial monolayer following ischemic injury. Neurosci Lett. 2010 Dec 3;486(1):1-4. DOI:10.1016/j.neulet.2010.09.029 |
- Simon MJ, Kang WH, Gao S, Banta S, and Morrison B 3rd. TAT is not capable of transcellular delivery across an intact endothelial monolayer in vitro. Ann Biomed Eng. 2011 Jan;39(1):394-401. DOI:10.1007/s10439-010-0144-x |
- Simon MJ, Gao S, Kang WH, Banta S, and Morrison B 3rd. TAT-mediated intracellular protein delivery to primary brain cells is dependent on glycosaminoglycan expression. Biotechnol Bioeng. 2009 Sep 1;104(1):10-9. DOI:10.1002/bit.22377 |
- Gao S, Simon MJ, Morrison B 3rd, and Banta S. Bifunctional chimeric fusion proteins engineered for DNA delivery: optimization of the protein to DNA ratio. Biochim Biophys Acta. 2009 Mar;1790(3):198-207. DOI:10.1016/j.bbagen.2009.01.001 |