Researchers Use Nanoparticles to Image a Broad Range of Tumors
Materials Research Society | Published: 02 January 2014
In the last decade, researchers have designed nanoparticles that can detect certain cancer biomarkers. While effective, the technique's applications have been limited because the biomarkers vary significantly between organ site and cancer type. Now, researchers at the University of Texas (UT) Southwestern Medical Center have created nanoparticles that can zero in on common factors of the tumor microenvironment, allowing them to quickly and reliably image a number of different cancers in mice.
"We established a novel nanomaterial strategy to amplify tumor signals and suppress the normal blood signal to achieve specific tumor detection in a broad range of tumors," said Jinming Gao, a UT professor of oncology and pharmacology and corresponding author of the study, published recently in the journal Nature Materials . "Hopefully, we can find and cure more cancers with image-guided surgery."
Recently, scientists have been able to fabricate nanoprobes that target biomarkers specific to cancer cells, including Her2/neu, EGFR and folate receptors. Such methods have yielded successful diagnostic tumor imaging, helping to steer patients towards personalized therapy. However, these approaches aren't applicable for a broad range of tumors, or even all patients with the same type of tumor, because each cancer has its own unique set of genotypes and phenotypes. Point of fact: the biomarker Her2/neu is only expressed in less than 25 percent of breast cancer patients. What's more, these probes are designed to be always on, making it difficult to achieve specificity and image contrast between cancerous cells and normal cells, Gao said.
Instead of trying to detect tumors using biomarkers, Gao and his colleagues decided to take another approach - targeting common factors in the tumor microenvironment. The pH of tumors, for example, is between 6.5 and 6.8, compared with blood's pH of 7.4. Along with this elevated acidity, tumors are also marked by rapid blood vessel growth. To create their robust nanoprobes, the researchers implemented three critical components.
The first component is an ultra pH-sensitive core, which is based on a unique hydrophobic nanoscale phenomenon induced by micellization. "We're still trying to understand the science behind it," Gao said, adding that the cores can detect changes in acidity less than 0.25 pH units. The second element they included was a series of fluorophores with emission ranges from 500 to 820 nm. To suppress fluorescent activation in the blood and increase activation in the tumors, they used fluorescence quenching induced by homo-fluorescence resonance energy transfer. The final piece of the puzzle was a targeting unit that binds to cell surface receptors.
The team first created two different types of nanoprobes, which remained off in the blood. One nanoprobe was designed to turn on when it encountered the acidic extracellular pH in the tumor microenvironment - its fluorescence activation increased by over 100-fold when it encountered the acidic mouse serum environments in ex vivo experiments. The second type of nanoprobe remained off in the acidic tumor pH, but activated 128-fold inside the lysosomes of tumor endothelial cells (pH of 5.0 to 6.0) after receptor-mediated endocytosis.
The researchers then constructed an integrated nanoprobe and performed in vivo experiments to test its efficacy in 10 mouse tumor models with diverse cancer phenotypes and organ sites. The nanoparticles were successful in all models, and able to image tumors as small as 1 mm 3 within just one hour of intravenous injection. The team also tracked changes in animal body weight, and liver and kidney functions, to determine the potential toxicity of the nanoparticles, and found little noticeable changes, showing that the nanoprobes are safe.
The unique tumor-detecting nanoprobes are still a long way from hospital use, as the team still needs to conduct clinical trials. They've already adapted the technology to use a dye that's approved by the Food and Drug Administration for imaging applications, and they've also conducted tumor surgery studies. "So far we are getting some very promising data," Gao said. "We eventually want to translate it into the OR and hopefully help people that might have tumors."
Read the abstract of the study in the journal Nature Materials here .