Photothermal therapy is an up-and-coming tumour ablation technique that is less invasive than chemotherapy or surgery. Here, optical radiation is absorbed and transformed into heat that is then used to thermally denature proteins and DNA in cells, and coagulate tissue. This irreversibly damages the targeted diseased cells, while minimizing damage to surrounding healthy tissue.

Gold nanoparticles are particularly interesting as anticancer agents in this respect because they are non-toxic and biocompatible, and because they absorb light at near-infrared wavelengths (of around 800 nm). Light of this wavelength can penetrate deeply into soft biological tissue.

The best types of gold nanostructure for tumour therapy are silica-cored gold nanoshells. However, the problem with these is that, at present, they can only be fabricated with diameters greater than 100 nm. Particles smaller than this would be better because they could be more easily taken up by tumour sites and more rapidly eliminated by the body via natural processes.

Absorbing light with an efficiency of 77%

Multilayered gold nanoparticles comprising gold/silica/gold, also known as nanomatryoshkas, can, for their part, be made smaller than 100 nm. These structures consist of a gold nanoparticle core, coated with a thin silica layer, surrounded by a final outer thin gold shell. Thanks to strong coupling between plasmons supported by the gold core and the gold shells (a phenomenon called plasmon hybridization), the plasmon resonance can be tuned to the near-infrared region in particles that are smaller than the standard SiO2/Au nanoshells normally employed in such therapies. The result is that these structures absorb light with an efficiency of 77% compared with just an efficiency of 15% for the Au nanoshells.

A team led by Naomi Halas and Amit Joshi has now directly compared sub-100 nm Au nanomatryoshkas and Au nanoshells with a diameter of around 150 nm for photothermally treating highly aggressive triple negative breast cancer tumours in mice. This type of cancer, which accounts for around 15% of all breast cancers, is often fatal and resistant to conventional treatments.

“We found that with the same dose of gold injected into the diseased mice, the smaller SiO2-Au nanomatryoshkas could accumulate in greater amounts in the tumours,” says Joshi. “The key challenge here was to reproduce the near-infrared plasmon resonance of conventional 150 nm sized Au shells in a geometry that was just 100 nm across, but with the same material composition.”

83% of mice tumour free after a single photothermal treatment

The fact that tumour sites take up greater quantities of Au nanomatryoshkas dramatically increases treatment efficiency, with 83% of mice tumour free after a single photothermal treatment, he added. To compare, only 33% remained tumour free after treatment with an equivalent dose of Au nanoshells.

“Our work shows that that nanoparticle size matters when it comes to photothermal therapy efficiency for equivalent systematically delivered doses of gold,” he told nanotechweb.org.

The researchers chose to study triple negative breast cancer, which, if left untreated, is actually 100% fatal in mice within 28 days. This type of cancer lacks oestrogen, progesterone and HER2 receptors and can thus not easily be targeted by conventional molecular medical treatments. The only way to deliver nanoparticles into such tumours following intravenous injection is to make the irregular, leaky bloody vessels in the tumour more permeable and to make the tumour hold onto the particles for longer, explains Joshi.

Directly comparing the two types of nanostructure

“Since the time the nanoparticles stay in the body (their so-called half-life) is controlled to a great extent by the surface charge on the nanoparticles themselves, we developed ‘stealth’ coating techniques to produce Au nanoshells and Au nanomatryoshkas with nearly identical surface charges,” explained Joshi. “This was so we could directly compare the two types of nanostructure. The stealth coatings were based on polyethylene glycol (PEG) molecules and we treated mice with human triple negative breast cancer xenografts with equivalent doses of Au nanoshells, Au nanomatryoshkas and salt solutions as a control. We treated the mice in a single session lasting five minutes with 3 W of 808 nm laser light.”

The researchers found that the tumours in the control mice did not diminish at all after treatment and that the animals died within two weeks.

Spurred on by its preliminary results, the team says that it is now busy further developing its Au nanomatryoshkas and exploiting the silica space in their interiors for packing in fluorescent and MRI contrast agents. “With near-infrared fluorescence and MRI signals, Au nanomatryoshkas will be visible in both microsurgery and in non-invasive whole body pre-operative imaging,” said Joshi. “This labelling strategy will open up new avenues for image-guided and minimally invasive light-based therapeutic interventions for a variety of cancers and metastases.”

The research is detailed in ACS Nano DOI: 10.1021/nn501871d.