Stroke is the third leading cause of death in the United States and, for many survivors, often results in functional impairment and long-term disability. Treatment of acute stroke in the United States is primarily with intravenous (IV) tissue-type plasminogen activator (tPA) and nearly 50% of patients treated achieve almost full recovery. However, few patients with stroke arrive within three hours of symptom presentation and receive IV tPA. Moreover, the potential for significant bleeding, particularly intracerebral hemorrhage, induced by traditional thrombolytics diminishes their clinical use. In this project, we will develop and evaluate fibrin-targeted thrombolytic nanoparticles for treatment of acute stroke. We hypothesize that fibrin-targeted thrombolytic nanoparticles will allow site-directed dissolution of acute thrombus using lower dosages of thrombolytic agent which are constrained by particle size to the circulation, even in the presence of """"""""leaky"""""""" endothelium. Our intent is to develop an agent that would be safe and effective for immediate administration by emergency technicians or physicians. Rapid initiation of revascularization is the cornerstone to neurologic rescue.. The major goals of this program will be: To organically synthesize, characterize and demonstrate in vitro, a prototype fibrin-targeted thrombolytic perfluorocarbon nanoparticle (Fibrin-Lytic-NP) based surface coupling of urokinase. These agents will evaluate, characterized, and optimized in vitro for biological activities (homing, plasminogen activation, and fibrin degradation), stability until use, and rapid preparation for on-site administration. To demonstrate pharmacokinetics and pharmacodynamics of the homing and thrombolytic bioactivity of Fibrin-Lytic-NPs for intra-arterial thrombosis in dog studied in situ and in circulation. To evaluate the dose dependent safety of Fibrin-Lytic-NP with particular regard to hemorrhagic complications in vivo rodent surgical wound models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059302-04
Application #
7849491
Study Section
Special Emphasis Panel (ZRG1-BCMB-S (51))
Program Officer
Jacobs, Tom P
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$329,176
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Pan, Dipanjan; Kim, Benjamin; Hu, Grace et al. (2015) A strategy for combating melanoma with oncogenic c-Myc inhibitors and targeted nanotherapy. Nanomedicine (Lond) 10:241-51
Pan, Dipanjan; Schirra, Carsten O; Wickline, Samuel A et al. (2014) Multicolor computed tomographic molecular imaging with noncrystalline high-metal-density nanobeacons. Contrast Media Mol Imaging 9:13-25
Schmieder, Anne H; Winter, Patrick M; Williams, Todd A et al. (2013) Molecular MR imaging of neovascular progression in the Vx2 tumor with ?v?3-targeted paramagnetic nanoparticles. Radiology 268:470-80
Wu, Lina; Luderer, Micah; Yang, Xiaoxia et al. (2013) Surface passivation of carbon nanoparticles with branched macromolecules influences near infrared bioimaging. Theranostics 3:677-86
Wu, Lina; Cai, Xin; Nelson, Kate et al. (2013) A Green Synthesis of Carbon Nanoparticle from Honey for Real-Time Photoacoustic Imaging. Nano Res 6:312-325
Pan, Dipanjan; Cai, Xin; Kim, Benjamin et al. (2012) Rapid synthesis of near infrared polymeric micelles for real-time sentinel lymph node imaging. Adv Healthc Mater 1:582-9
Kim, Benjamin; Schmieder, Anne H; Stacy, Allen J et al. (2012) Sensitive biological detection with a soluble and stable polymeric paramagnetic nanocluster. J Am Chem Soc 134:10377-80
Lanza, Gregory M (2012) ICAM-1 and nanomedicine: nature's doorway to the extravascular tissue realm. Arterioscler Thromb Vasc Biol 32:1070-1
Pan, Dipanjan; Sanyal, Nibedita; Schmieder, Anne H et al. (2012) Antiangiogenic nanotherapy with lipase-labile Sn-2 fumagillin prodrug. Nanomedicine (Lond) 7:1507-19
Pan, Dipanjan; Schirra, Carsten O; Senpan, Angana et al. (2012) An early investigation of ytterbium nanocolloids for selective and quantitative ""multicolor"" spectral CT imaging. ACS Nano 6:3364-70

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