The goal of this project is to develop a novel combined ultrasonography/chemotherapy modality for the image-guided targeted tumor therapy using a new class of multifunctional nanoparticles that combine properties of (i) tumor-targeted drug carriers;(ii) ultrasonic drug delivery enhancers;and (iii) ultrasound contrast agents. These formulations comprise mixtures of drug-loaded polymeric micelles and nano- or micro-emulsion droplets stabilized by the same (or different) biodegradable block copolymer. The nanodroplets convert into highly echogenic microbubbles upon systemic injection. The phase state and size of the nanodroplets is controlled by the copolymer/perfluorocarbon concentration ratio and type of the copolymer. Upon injection, the drug-loaded polymeric micelles and nanobubbles extravasate through the defective tumor microvasculature and selectively accumulate in the tumor interstitium. Extravasated nanobubbles aggregate and/or coalesce into highly echogenic microbubbles in the tumor tissue thus serving as potent, tumor-selective, and long-lasting ultrasound contrast agents. These features of the developed systems allow contrast-enhanced diagnostic tumor imaging and tumor chemotherapy being provided by the same """"""""smart"""""""" echogenic and targetable polymeric system.
Specific Aims i nclude 1. To measure and optimize ultrasound responsiveness (cavitation properties) of drug-loaded microbubbles depending on the type of the stabilizing copolymer, bubble size, and therapeutic ultrasound parameters. 2. To test and optimize ultrasound imaging properties of the designed systems using a panel of orthotopically grown internal tumor models. 3. To optimize ultrasound-modulated drug delivery properties of the micelle/microbubble systems in vitro and in vivo using breast cancer and pancreatic cancer tumor models in nu/nu mice. Relevance: The developed systems provide for combining ultrasound tumor imaging and ultrasound-mediated targeted chemotherapy, which is expected to substantially reduce side effects, enhance treatment outcome, and improve quality of life of cancer patients.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Zullo, Steven J
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University of Utah
Biomedical Engineering
Schools of Engineering
Salt Lake City
United States
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Gupta, Roohi; Shea, Jill; Scafe, Courtney et al. (2015) Polymeric micelles and nanoemulsions as drug carriers: Therapeutic efficacy, toxicity, and drug resistance. J Control Release 212:70-7
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Shea, Jill E; Nam, Kweon-Ho; Rapoport, Natalya et al. (2011) Genexol inhibits primary tumour growth and metastases in gemcitabine-resistant pancreatic ductal adenocarcinoma. HPB (Oxford) 13:153-7
Rapoport, Natalya; Christensen, Douglas A; Kennedy, Anne M et al. (2010) Cavitation properties of block copolymer stabilized phase-shift nanoemulsions used as drug carriers. Ultrasound Med Biol 36:419-29
Mohan, Praveena; Rapoport, Natalya (2010) Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking. Mol Pharm 7:1959-73
Rapoport, Natalya; Kennedy, Anne M; Shea, Jill E et al. (2010) Ultrasonic nanotherapy of pancreatic cancer: lessons from ultrasound imaging. Mol Pharm 7:22-31

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