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.
| Nolting, Donald D; Nickels, Michael; Tantawy, Mohammed N et al. (2012) Convergent synthesis and evaluation of (18)F-labeled azulenic COX2 probes for cancer imaging. Front Oncol 2:207 |
| Nolting, Donald D; Nickels, Michael L; Guo, Ning et al. (2012) Molecular imaging probe development: a chemistry perspective. Am J Nucl Med Mol Imaging 2:273-306 |
| Nolting, Donald D; Gore, John C; Pham, Wellington (2011) NEAR-INFRARED DYES: Probe Development and Applications in Optical Molecular Imaging. Curr Org Synth 8:521-534 |
| Mackay, Patrick S; Kremers, Gert-Jan; Kobukai, Saho et al. (2011) Multimodal imaging of dendritic cells using a novel hybrid magneto-optical nanoprobe. Nanomedicine 7:489-96 |
| Sakuma, Shinji; Kataoka, Makoto; Higashino, Haruki et al. (2011) A potential of peanut agglutinin-immobilized fluorescent nanospheres as a safe candidate of diagnostic drugs for colonoscopy. Eur J Pharm Sci 42:340-7 |
| Kobukai, Saho; Kremers, Gert-Jan; Cobb, Jared G et al. (2011) Induction of antitumor immunity by dendritic cells loaded with membrane-translocating mucin 1 Peptide antigen. Transl Oncol 4:1-8 |
| Pham, W (2010) Detection and Treatment of Diseases Using Light. IFMBE Proc 27:19-22 |
| Kobukai, Saho; Baheza, Richard; Cobb, Jared G et al. (2010) Magnetic nanoparticles for imaging dendritic cells. Magn Reson Med 63:1383-90 |
| Nickels, Michael; Xie, Jingping; Cobb, Jared et al. (2010) Functionalization of iron oxide nanoparticles with a versatile epoxy amine linker. J Mater Chem 20:4776-4780 |
| 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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