Clinical application of potentially useful therapeutic/imaging agents for the treatment/detection of neurodegenerative diseases is profoundly hampered by the limited access of probes from the vasculature to the central nervous system (CNS) across the tight microvascular network of brain capillaries, associated with pericytes, and astrocyte foot processes, the blood brain barrier (BBB). As neurological research continues to reveal new targets for therapy, it is necessary to develop new delivery methods in concert, to facilitate the screening of new drug/probes for treatment and detection of diseases, respectively. We have recently designed a library of amphiphilic peptides as delivery modules, and evaluated their ability to cross the cellular membrane in vitro using fluorescence technique. This approach has been demonstrated to cross the cellular membrane of live cells efficiently and home to the cytoplasm with no registered toxicity. In this application, we propose to use amphiphilic polyarginines as a new strategy for drug delivery across the BBB for in vivo application. The underlying hypothesis focuses on a short amphiphilic myristoylated polyarginine peptide;the lipophilicity of myristic acid is designed as a steering force for the luminal membrane of brain capillaries. While, the polarity of polyarginine backbone is expected to enhance solubility of the delivery module in serum for systemic administration. In addition, the physiological expression of polycation moieties on arginines promotes electrostatic interaction with the surface of negatively charged brain capillary endothelial cells. In support of our hypothesis, we further label the delivery module with a near infrared dye as a cargo so that systemic biodistribution and accumulation of the complex in the mouse brain will be monitored using optical imaging. Overall, the proposed studies could reveal a new approach for noninvasive delivery and monitor the distribution of drug/probes a cross the BBB in an intact environment. Given the time and cost efficient of optical imaging technique, this approach will potentially facilitate the delivery of drugs/probes for treatment/detection of brain cancer, and other CNS disorders as well as for screening of new drug development, and staging of therapeutic effects on mouse models.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG026366-04
Application #
7658138
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Petanceska, Suzana
Project Start
2006-09-15
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$120,420
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Nolting, Donald D; Nickels, Michael; Price, Ronald et al. (2009) Synthesis of bicyclo[5.3.0]azulene derivatives. Nat Protoc 4:1113-7

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