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Using nanoparticles tagged with both a fluorescent label and a radioactive isotope of the element copper, a team of investigators at the California Institute of Technology (Caltech) has shown that targeting siRNA-containing nanoparticles to tumors increases tumor uptake rather than tumor localization. The methods that these investigators developed should be broadly applicable to studying nanoparticle biodistribution as part of the preclinical development process.
Reporting its work in the Proceedings of the National Academy of Sciences of the United States of America, a team led by Mark E. Davis, Ph.D., an investigator in the Nanosystems Biology Cancer Center at Caltech, described the multimodal imaging methods it used to measure biodistribution parameters for siRNA-loaded cyclodextrin-based nanoparticles. Davis' collaborators at Calando Pharmaceuticals, Inc., are preparing to begin a Phase I clinical trial with this siRNA-loaded nanoparticle. Small interfering RNA (siRNA) triggers a naturally occurring mechanism within cells that can silence and regulate targeted genes.
In this study, the investigators used positron emission tomography (PET) to quantify biodistribution of the nanoparticles and imaging to measure siRNA function in a mouse model of human cancer. Some of the nanoparticles were targeted with transferrin, an iron-ferrying protein that binds to a receptor overexpressed by many types of tumors. Although PET data showed that both targeted and untargeted nanoparticles accumulated to a similar extent in tumors, targeted particles reduced the bioluminescent imaging signal by 50 percent compared with nontargeted particles. These nanoparticles were designed so that bioluminescent signal reduction would occur only if the siRNA agent was successfully delivered into cells and reduced expression of its targeted gene. These results show, therefore, that the advantages of targeted nanoparticles appear to be associated with uptake into tumor cells and not with overall tumor localization.
"This work reveals that the primary advantage of targeted nanoparticles for tumor-specific delivery of siRNA is the enhanced uptake in tumor cells rather than altered biodistribution," said Davis. "The conclusions should be applicable to nanoparticle delivery systems in general, and they emphasize why targeted particles should show greater efficacy than nontargeted particles."
This work, which was funded by the NCI's Alliance for Nanotechnology in Cancer, is detailed in the paper "Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging." Investigators from the University of California, Los Angeles, and the University of Freiburg in Germany also participated in this study. This paper is available online at no cost through PubMed Central.
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To help meet the goal of reducing the burden of cancer, the National Cancer Institute (NCI), part of the National Institutes of Health, is engaged in efforts to harness the power of nanotechnology to radically change the way we diagnose, treat and prevent cancer.
The NCI Alliance for Nanotechnology in Cancer is a comprehensive, systematized initiative encompassing the public and private sectors, designed to accelerate the application of the best capabilities of nanotechnology to cancer.
Currently, scientists are limited in their ability to turn promising molecular discoveries into benefits for cancer patients. Nanotechnology can provide the technical power and tools that will enable those developing new diagnostics, therapeutics, and preventives to keep pace with today’s explosion in knowledge.
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