Imaging and treatment via nanoshells
The right particles help both image and destroy tumors
Given the right design, one nanoparticle can help image a tumor and then help destroy it. That is the finding of a research group comprising members from Rice University in Houston and from Texas A&M University in College Station. Led by Rice bioengineering professor Jennifer L. West and associate bioengineering professor Rebekah A. Drezek, the team first demonstrated that nanoshells — nanoparticles with a dielectric core surrounded by a thin metal shell — could be used as a contrast agent for optical coherence tomography (OCT) imaging in the near-IR. They then showed that the shells could be used to attack tumors through near-IR heating.
According to Drezek, the ultimate goal is to use the nanoshells for image-guided photothermal cancer therapy. It will enable “a patient-specific approach to when and where to treat,” she said.
Figure 1. Samples from mice injected with gold-coated nanoshells exhibit improved silver-enhancement tissue staining (A) over those from mice injected with phosphate-buffered saline (B). Images reprinted with permission of the American Chemical Society.
Nanoshells are of particular interest in this combined role as both imaging and therapeutic agents because they are composed of multiple layers. This structure makes it possible to tune the shells to strongly backscatter an incoming signal, making them act as a contrast-enhancing agent. At the same time, they can be made to be strongly absorbent, allowing them to heat up when irradiated, thus photothermally ablating any tissue that surrounds the particles.
The researchers used OCT, in which a beam of light is split in two, with one beam sent into a reference path and bounced off a mirror at an adjustable distance while the other probes the sample. When it is recombined with the reference beam, reflectivity data is provided from which imaging information can be extracted. When the reference mirror is moved, the probe point moves to different depths, allowing a map of the tissue deep within a sample to be built up.
Scientists have been looking for ways to enhance the signals obtained with OCT and thereby to improve its usefulness. Nanoshells are a leading contender for this because they are small and they circulate easily. They are known to accumulate in tumors because of the leaky vasculature present, and they are biocompatible and have adjustable optical parameters.
Figure 2. Shown above are optical coherent tomographic images of normal skin and muscle tissue of mice that were injected either with nanoshells (A) or with phosphate-buffered saline (PBS) (B). Similarly shown are representative images from tumors of mice systemically injected with nanoshells (C) or with PBS (D).
“Contrast agents for OCT have been limited by the need to generate strong backscatter at the appropriate wavelengths, typically 800 to 1300 nm. Nanoshells are promising in that their resonance can be tuned to arbitrary wavelengths from the visible through the near-IR,” Drezek said.
In constructing the nanoshells, the investigators grew a 12-nm-thick gold shell around an ~119-nm-diameter silica core. They chose this arrangement of materials in part because calculations showed that two-thirds of the nanoshells’ light extinction at 800 nm resulted from absorption, with the rest caused by scattering. In addition, measurements with a UV-visible spectrophotometer from Varian Inc. of Walnut Creek, Calif., showed that the extinction for nanoshells of this size and composition peaked at 800 nm.
They coated the shells with polyethylene glycol to enhance circulation and to minimize the immune response, then injected them into mice containing colon cancer cells and allowed them to accumulate passively for 20 h. Measurement of tumor slices from the mice showed that there were roughly 3 million nanoshells per gram of tumor tissue.
As for OCT imaging, they conducted tests using a system from Cleveland-based Imalux Corp., selecting both tumor and normal tissue at least 2 cm away from the tumor site. For both types of tissue, they imaged the results after an injection of a nanoshell and a control solution. They found that the nanoshell-injected images had a 56 percent intensity increase, far larger and more statistically significant than the 16 percent increase using the control solution. In the case of normal tissue, there was no difference in the image intensity for control or nanoshell solutions.
Drezek noted that this outcome was expected because the accumulation in tumors had already been demonstrated. “The dual imaging/therapy in vivo demonstration is what was new here.”
For therapy, the investigators divided the mice into control and treatment groups: Some received treatment with nanoshells and a laser, some were untreated, and some were subjected to the laser after a control solution injection in a sham treatment. Using an 808-nm laser from Coherent Inc. of Santa Clara, Calif., they focused the beam to a 5-mm spot size and fired it for 3 min at a power density of 4 W/cm2 at the selected mice. They tracked tumor size and animal survival for seven weeks after treatment. Twelve days after treatment, the tumors had shrunk considerably, with the average tumor area cut in half. In contrast, the untreated and sham groups experienced tumor growth nearly quadrupling in size for the first group and nearly doubling for the sham-treatment mice.
As published in the July issue of Nano Letters, three weeks after treatment, the survival rate for the treated group was 80 percent whereas that for the other two groups was less than 10 percent. The median survival time for the sham-treatment group was 14 days and for the untreated group, 10 days. Drezek noted that this result was generally expected but that the specific configuration of this particular study had not been used before.
Nanospectra Biosciences Inc. of Houston is commercializing the nanoshell technology and is seeking regulatory approval to begin human trials for the treatment of head-and-neck tumors.
As for future research, Drezek noted that the move is toward more active targeting with techniques such as nanoshells linked to antibodies to improve specificity further. “This is the next step and is already under way,” she said.
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