Feel the heat

One significant source of radioresistance is the presence of hypoxic regions within the tumour. Mild hyperthermia (heating to around 43 °C) can enhance vascular perfusion and reduce hypoxia, but has not been employed clinically as only invasive methods of generating and monitoring heat were previously available.

Gold nanoshells, on the other hand, provide a non-invasive way to generate mild hyperthermia. The heat is created when such particles are exposed to a suitable wavelength of light. "If you take a dielectric silica core and coat it with a thin gold layer, then the nanoshell will absorb light and convert it to heat," Krishnan explained. The absorption wavelength can be tuned by adjusting the core–shell ratio. A 150 nm particle with a shell thickness of 15 nm, for example, will absorb near-infrared light, which penetrates 2–3 cm into tissue.

For therapeutic applications, gold nanoshells offer many advantages: they are biocompatible, have a high absorption cross-section, and the surface can be easily conjugated with biomolecules. At 150 nm in diameter, the nanoshells are "rather bulky for a nanoparticle," Krishnan noted. But when injected, they can pass through leaky tumour blood vessels and accumulate preferentially within tumours.

Krishnan described a study examining tumour volume in mice treated with radiotherapy, nanoshell-induced hyperthermia or both, for up to 28 days. "Radiation slowed the growth of the tumour, but radiation plus hyperthermia slowed it down further," he said.

To understand more about how this enhancement process works, Krishnan and colleagues used non-invasive MR thermometry to visualize heating in vivo, in tumour-bearing mice. They found that the nanoshells induced two tumour vascular-focused effects. Initially, the heat enhanced vascular perfusion, reducing the size of the radioresistant hypoxic core and increasing the tumour's sensitivity to radiation. Subsequent irradiation induced vascular disruption and extensive necrosis.

Krishnan cited his previous work in which gold nanoshell-induced heating was shown to sensitize cancer stem cells to radiation. Radiotherapy alone killed sensitive tumour cells, but a subpopulation of resistant cancer stem cells were harder to treat and increased in relative proportion after irradiation. Combining radiotherapy with hyperthermia, however, also effectively killed the cancer stem cells.

Boost the dose

Another way to use nanoparticles to augment radiotherapy efficacy is to exploit physical dose enhancement. High-Z materials such as gold strongly absorb ionizing radiation and when irradiated with kilovoltage X-rays, emit photoelectrons and Auger electrons. As gold nanoparticles accumulate preferentially within the tumour, irradiation leads to increased energy deposition within the tumour and enhanced cell killing.

For example, a group of mice bearing subcutaneous tumours treated with 1.9 nm diameter gold particles and radiotherapy had a one-year survival rate of 86%. This compared with 20% in mice receiving just radiation and 0% in those treated with gold alone. "They used very small gold nanoparticles, introduced them though the tail vein and irradiated," Krishnan said. "And the tumours don't come back."

Krishnan noted that this dose enhancement can also be heightened via biological targeting. "Instead of giving large amounts of gold, we propose using smaller amounts but placing it closer to the DNA," he explained.

This approach involves using 25 nm-long gold nanorods conjugated to peptides or antibodies. The conjugation does not increase tumour accumulation, but causes internalization of the nanorods into cell cytoplasm or even nuclei. Krishnan said that this distribution requires 1000 times less gold. "In principle, this could be possible for clinical use," he noted.

An in vivo study examining tumour volume following treatment demonstrated that injection of gold nanorods conjugated with Cetuximab (an antibody used to treat bowel or head-and-neck cancer) followed by irradiation induced significant reduction in tumour regrowth up to 28 days later. Injecting Cetuximab or unconjugated nanorods, plus irradiation, resulted in some growth delay, but no more than observed with irradiation alone. Cetuximab or nanorods (conjugated or unconjugated) without irradiation did not improve on control results.

The challenge with this approach is the need to use different particles for different types of cancer. So is there a nanoparticle-based treatment that will work with any tumour?

The bubble bursts

With this thought in mind, Krishnan rounded off his presentation by describing the use of heat-sensitive liposomes to deliver gold nanoparticles deep into a tumour. Liposomes containing 5 nm gold spheres are delivered into the perivascular space and focused ultrasound used to generate mild hyperthermia, which bursts the liposomes and delivers the gold into the tumour. The deep penetration of the nanoparticles improves radiosensitization, independent of hyperthermic enhancement.

"We noted that without hyperthermia, the gold is located more in the tumour periphery, but after hyperthermia, it goes into the core of the tumour," Krishnan added. "In principle, this could be a class solution for a variety of tumours accessible by ultrasound."

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