Journal of the National Cancer Institute Advance Access published online on July 10, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm043
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Multifunctional Nanoparticles for Combining Ultrasonic Tumor Imaging and Targeted Chemotherapy
Affiliations of authors: Department of Bioengineering, University of Utah, Salt Lake City, UT (NR, ZG); Department of Radiology, School of Medicine, University of Utah, Salt Lake City, UT (AK)
Correspondence to: Natalya Rapoport, PhD, DSc, Department of Bioengineering, University of Utah, 20 S. 2030 E. Rm 108, Salt Lake City, UT 84112 (e-mail: natasha.rapoport{at}m.cc.utah.edu).
Background: Drug delivery in polymeric micelles combined with tumor irradiation by ultrasound results in effective drug targeting, but this technique requires prior tumor imaging. A technology that combined ultrasound imaging with ultrasound-mediated nanoparticle-based targeted chemotherapy could therefore have important applications in cancer treatment.
Methods: Mixtures of drug-loaded polymeric micelles and perfluoropentane (PFP) nano/microbubbles stabilized by the same biodegradable block copolymer were prepared. Size distribution of nanoparticles was measured by dynamic light scattering. Cavitation activity (oscillation, growth, and collapse of microbubbles) under ultrasound was assessed based on the changes in micelle/microbubble volume ratios. The effect of the nano/microbubbles on the ultrasound-mediated cellular uptake of doxorubicin (Dox) in MDA MB231 breast tumors in vitro and in vivo (in mice bearing xenograft tumors) was determined by flow cytometry. Statistical tests were two-sided.
Results: Phase state and nanoparticle sizes were sensitive to the copolymer/perfluorocarbon volume ratio. At physiologic temperatures, nanodroplets converted into nano/microbubbles. Doxorubicin was localized in the microbubble walls formed by the block copolymer. Upon intravenous injection into mice, Dox-loaded micelles and nanobubbles extravasated selectively into the tumor interstitium, where the nanobubbles coalesced to produce microbubbles with a strong, durable ultrasound contrast. Doxorubicin was strongly retained in the microbubbles but released in response to therapeutic ultrasound. Microbubbles cavitated under the action of tumor-directed ultrasound, which enhanced intracellular Dox uptake by tumor cells in vitro to a statistically significant extent relative to that observed with unsonicated microbubbles (drug uptake ratio = 4.60; 95% confidence interval [CI] = 1.70 to 12.47; P = .017) and unsonicated micelles (drug uptake ratio = 7.97; 95% CI = 3.72 to 17.08; P = .0032) and resulted in tumor regression in the mouse model.
Conclusions: Multifunctional nanoparticles that are tumor-targeted drug carriers, long-lasting ultrasound contrast agents, and enhancers of ultrasound-mediated drug delivery have been developed and deserve further exploration as cancer therapeutics.
| CONTEXT AND CAVEATS Prior knowledge Ultrasound irradiation of drug-encapsulated micelles has shown promise as a means of achieving targeted treatment of tumors in animal models. However, the possibilities of using drug and carrier fomulations that produce (in vivo) both micelles and echogenic microbubbles to encapsulate drug, thus improving drug release and uptake and at the same time providing the imaging modality needed for focused ultrasound treatment of tumors, had not been explored. Study design Formulations for producing drug-encapsulated micelles and microbubbles and their response to ultrasound were characterized physically. Then, in vivo experiments were conducted in animal models to measure the extent to which they improved ultrasound-mediated drug uptake in tumors (relative to micellar formulations) and permitted tumor imaging. Contribution A novel approach for treatment of tumors that makes use of the echogenic properties of drug carriers to both improve drug uptake and simplify imaging is described. Implications The possibilities for targeted drug delivery to tumors based on focused ultrasound of drug-containing echogenic microbubbles deserves further exploration. Limitations Additional development and characterization of this experimental approach is required before its possible therapeutic advantages can be determined.
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Manuscript received September 28, 2006; revised April 30, 2007; accepted June 7, 2007.
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J Natl Cancer Inst 2007 99: 1057.