The blood-brain barrier (BBB) is the major obstacle to delivery of drugs to the brain for treating brain disorders (i.e., brain tumor, Alzheimer's, Parkinson's). The development of small and large molecules (i.e., peptides, proteins, and oligonucleotides) as anticancer agents has been hampered by the low permeation of these molecules through the BBB due to the presence of tight junctions and efflux pumps. Therefore, our long-term goal is to improve the in vivo delivery of anticancer drugs to the brain. Our central hypothesis is that modulating the adherens junction of the BBB using E-cadherin peptides can enhance the porosity of the intercellular junctions and, thus, enhance the paracellular permeation of small and large anticancer drugs. We found that an HAV peptide can improve the permeation of mannitol and an anticancer agent (daunomycin) into the brain using the in-situ brain perfusion rat model. In addition, a combination of HAV peptide and verapamil has a synergistic effect to improve the delivery of daunomycin to the brain. Therefore, the first aim of this project is to optimize the effect of HAV peptide in enhancing the delivery of paracellular markers into the brain. Second, the mechanism of transport of daunomycin upon modulation of the BBB with a combination of HAV peptide and verapamil will be investigated. Third, the BBB modulatory activity of HAV peptides will be improved by forming cyclic peptides. Fourth, the mechanism of action of HAV peptide in modulating cadherin-cadherin interactions in the intercellular junctions will be elucidated. Finally, the effects of HAV peptides on brain tumor responsiveness in vivo will be determined.

Public Health Relevance

One of the problems in developing drugs for brain disease is the difficulty in delivering them to the brain;this is due to the presence of the blood-brain barrier (BBB), which prevents the drug from entering the brain. Thus, if a way is found to improve the permeation of drugs through the blood-brain barrier, it will very beneficial to patients with brain disorders including brain tumors. Recent development of small and large molecules (i.e., peptides, proteins, and oligonucleotides) as therapeutic agents for brain diseases has been hampered by the low permeation of these molecules through the BBB. Therefore, our long-term goal is to improve the in vivo delivery of small and large drugs through the BBB. Using an animal model, we have found an HAV peptide that improves the delivery of anticancer drug (daunomycin) to the brain. Thus, this project is designed to optimize the delivery of anticancer agents to treat brain tumor in the brain tumor animal model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075374-02
Application #
8320154
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Bosetti, Francesca
Project Start
2011-08-15
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$305,551
Indirect Cost
$69,799
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Prasasty, Vivitri D; Krause, Mary E; Tambunan, Usman S F et al. (2015) (1)H, (13)C and (15)N backbone assignment of the EC-1 domain of human E-cadherin. Biomol NMR Assign 9:31-5
On, Ngoc H; Kiptoo, Paul; Siahaan, Teruna J et al. (2014) Modulation of blood-brain barrier permeability in mice using synthetic E-cadherin peptide. Mol Pharm 11:974-81
Trivedi, Maulik; Laurence, Jennifer S; Williams, Todd D et al. (2012) Improving the stability of the EC1 domain of E-cadherin by thiol alkylation of the cysteine residue. Int J Pharm 431:16-25