Ultrasound offers a unique approach to image-guided therapy. First, tumor vasculature is detected using echo contrast imaging. Next, focused, higher-intensity ultrasound pulse sequence is applied to activate contrast/drug carrier material and release the therapeutic agent in the insonated area. In this application we propose the design and evaluation of a new generation of ultrasound-triggered drug carrier materials. Drug carrier microbubbles and liposome constructs will be applied to release antitumor agents or thrombus-generating enzyme into tumor vasculature. Selective drug deposition in the tumor mass will be achieved. Targeted cytotoxic effect on the tumor and targeted thrombosis will result in restriction of tumor growth and apoptosis.
Specific aims (R21 Phase): 1. Prepare targetable microbubble drug delivery constructs and perform ultrasound-mediated release of model dye markers from liposomes, liposomes attached to microbubbles, and microbubble carriers. Evaluate release efficacy as a function of liposome/particle membrane composition, structure, phase transition temperature and ultrasound intensity, frequency and pulse characteristics to achieve optimal release. 2. Evaluate targetability of microbubble/liposome/drug constructs to activated endothelium in cell culture, assess drug release, gel and endothelial cell culture deposition. 3. Study ultrasound-mediated """"""""triggering"""""""" activation of microbubble/liposome/enzyme constructs in vitro; evaluate release and therapeutic enzyme availability to convert the substrate. 4. Assess the ability of ultrasound energy to destroy microbubble drug carrier systems in an in vivo subcutaneous tumor on demand with image-guided targeting of ultrasound application focus.
Specific aims (R33 Phase): 1. Study acute toxicity, biodistribution, vascular behavior and targeting of microbubbles and microbubble-liposomes constructs in a mouse model after intravenous administration comparing echo imaging, fluorescence and radioactive labeling of shells and contents of drug carrier particles. 2. Investigate in vivo accumulation of microbubbles, liposomes/complexes, and encapsulated cytotoxic agents in the areas of insonation, by ultrasound imaging, biodistribution of radiolabeled and fluorescent markers, fluorescence in vivo optical imaging, and tissue histology, as well as longer-term survival animals studies. 3. Perform ultrasound activation of thrombin drug carrier constructs; release thrombin selectively in the areas of model vasculature during intravital microscopy. Monitor blood and microbubble flow through target tissue. 4. Demonstrate arrest of tumor growth by ultrasound-triggered release of thrombin from microbubble constructs selectively in the areas of tumor vasculature during insonation of a solid tumor, per se and in combination with cytotoxic drug-loaded particles. Monitor blood flow within the tumor after treatment. Perform final optimization of the drug carrier formulation and ultrasound activation parameters. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA102880-01A2
Application #
7315436
Study Section
Special Emphasis Panel (ZRG1-SBIB-S (51))
Program Officer
Farahani, Keyvan
Project Start
2007-08-01
Project End
2008-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$205,154
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Klibanov, Alexander L; Hossack, John A (2015) Ultrasound in Radiology: From Anatomic, Functional, Molecular Imaging to Drug Delivery and Image-Guided Therapy. Invest Radiol 50:657-70
Rychak, Joshua J; Klibanov, Alexander L (2014) Nucleic acid delivery with microbubbles and ultrasound. Adv Drug Deliv Rev 72:82-93
Schlesinger, David; Benedict, Stanley; Diederich, Chris et al. (2013) MR-guided focused ultrasound surgery, present and future. Med Phys 40:080901
Wang, Shiying; Mauldin, F William; Klibanov, Alexander L et al. (2013) Shear forces from flow are responsible for a distinct statistical signature of adherent microbubbles in large vessels. Mol Imaging 12:396-408
Klibanov, Alexander L (2013) Ultrasound contrast materials in cardiovascular medicine: from perfusion assessment to molecular imaging. J Cardiovasc Transl Res 6:729-39
Unnikrishnan, Sunil; Klibanov, Alexander L (2012) Microbubbles as ultrasound contrast agents for molecular imaging: preparation and application. AJR Am J Roentgenol 199:292-9
Hernot, Sophie; Unnikrishnan, Sunil; Du, Zhongmin et al. (2012) Nanobody-coupled microbubbles as novel molecular tracer. J Control Release 158:346-53
Guenther, Felix; von zur Muhlen, Constantin; Ferrante, Elisa A et al. (2010) An ultrasound contrast agent targeted to P-selectin detects activated platelets at supra-arterial shear flow conditions. Invest Radiol 45:586-91
Klibanov, Alexander L (2009) Preparation of targeted microbubbles: ultrasound contrast agents for molecular imaging. Med Biol Eng Comput 47:875-82
Hernot, Sophie; Klibanov, Alexander L (2008) Microbubbles in ultrasound-triggered drug and gene delivery. Adv Drug Deliv Rev 60:1153-66

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