Golden nanocages to put the heat on cancer cells

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In nanocage-injected mice (left), the surface of the tumor quickly became hot enough to kill cells - in buffer-injected mice (right), the temperature barely budged (Image: WUSTL)

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Cancer is a disease whose treatments are notoriously indiscriminate and nonspecific. Researchers have been searching for a highly targeted medical treatment that attacks cancer cells but leaves healthy tissue alone. The approach taken by scientists at Washington University in St. Louis (WUSTL) is to use "gold nanocages" that, when injected, selectively accumulate in tumors. When the tumors are later bathed in laser light, the surrounding tissue is barely warmed, but the nanocages convert light to heat, killing the malignant cells.

The new process nears similarities to one being developed at the University of California in Santa Cruz using hollow gold nanospheres and another in development at Rice University using exploding gold nanoparticles. Gold is an attractive substance for the researchers because it is inert in the body. Gold salts and gold colloids, (a type of mixture in which one substance is dispersed evenly through another), have been used to treat arthritis for over 100 years so it is believed the nanocages themselves will be nontoxic.

The nanocages are hollow boxes made by precipitating gold on silver nanoparticles. The silver simultaneously erodes from within the cube, entering solution through pores that open in the clipped corners of the cube.

To stop proteins depositing on the nanoparticles, which would result in them being captured by the immune system and dragged out of the bloodstream into the liver or spleen, the scientists coated the nanocages with a layer of PEG. PEG is a nontoxic chemical most people have encountered in the form of the laxatives GoLyTELY or MiraLAX. It resists the adsorption of proteins, in effect disguising the nanoparticles so that the immune system cannot recognize them. This allows them to circulate in the bloodstream long enough to accumulate in tumors.

A growing tumor must develop its own blood supply to prevent its core from being starved of oxygen and nutrients. But tumor vessels are as aberrant as tumor cells so they have irregular diameters and abnormal branching patterns, but most importantly, they have thin, leaky walls. The cells that line a tumor's blood vessel, normally packed so tightly they form a waterproof barrier, are disorganized and irregularly shaped, and there are gaps between them. The nanocages infiltrate through those gaps efficiently enough that they turn the surface of the normally pinkish tumor black.

The suspensions of the gold nanocages, which are roughly the same size as a virus particle, are not always yellow. They are colored by something called a surface Plasmon resonance. The resonance – and the color – can be tuned over a wide range of wavelengths by altering the thickness of the cages’ walls. In other words, their color and their ability to absorb light and convert it to heat can be precisely controlled.

For biomedical applications, the WUSTL scientists tune the cages to 800 nanometers, a wavelength that falls in a window of tissue transparency that lies between 750 and 900 nanometers, in the near-infrared part of the spectrum. Light in this sweet spot can penetrate as deep as several inches in the body (either from the skin or the interior of the gastrointestinal tract or other organ systems).

The conversion of light to heat arises from the same physical effect as the color. The resonance has two parts. At the resonant frequency, light is typically both scattered off the cages and absorbed by them. Controlling the cages' size tailors them to achieve maximum absorption.

Promising tests

In trialling the process mice bearing tumors on both flanks were randomly divided into two groups. The mice in one group were injected with the PEG-coated nanocages and those in the other with buffer solution. Several days later the right tumor of each animal was exposed to a diode laser for 10 minutes. The team employed several different noninvasive imaging techniques to follow the effects of the therapy.

During irradiation, thermal images of the mice were made with an infrared camera. As is true of cells in other animals that automatically regulate their body temperature, mouse cells function optimally only if the mouse's body temperature remains between 36.5 and 37.5 degrees Celsius (98 to 101 degrees Fahrenheit).

At temperatures above 42 degrees Celsius (107 degrees Fahrenheit) the cells begin to die as the proteins whose proper functioning maintains them begin to unfold. In the nanocage-injected mice, the skin surface temperature increased rapidly from 32 degrees Celsius to 54 degrees C (129 degrees F). In the buffer-injected mice, however, the surface temperature remained below 37 degrees Celsius (98.6 degrees Fahrenheit).

To see what effect this heating had on the tumors, the mice were injected with a radioactive tracer incorporated in a molecule similar to glucose. Positron emission and computerized tomography (PET and CT) scans were used to record the concentration of the glucose lookalike in body tissues; the higher the glucose uptake, the greater the metabolic activity.

The tumors of nanocage-injected mice were significantly fainter on the PET scans than those of buffer-injected mice, indicating that many tumor cells were no longer functioning. The tumors in the nanocage-treated mice were later found to have marked histological signs of cellular damage.

Despite the results, the researchers are dissatisfied with passive targeting. Although the tumors took up enough gold nanocages to give them a black cast, only 6 percent of the injected particles accumulated at the tumor site. They would like that number to be closer to 40 percent so that fewer particles would have to be injected. They plan to attach tailor-made ligands to the nanocages that recognize and lock onto receptors on the surface of the tumor cells.

In addition to designing nanocages that actively target the tumor cells, the team is considering loading the hollow particles with a cancer-fighting drug, so that the tumor would be attacked on two fronts. But the important achievement, from the point of view of cancer patients, is that any nanocage treatment would be narrowly targeted and thus avoid the side effects patients dread.

The research appears in the paper, Gold Nanocages as Photothermal Transducers for Cancer Treatment, published in the journal Small. The scientists at WUSTL have just received a five-year, US$2,129,873 grant from the National Cancer Institute to continue their work with photothermal therapy.

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