RESEARCH

Sep 27, 2010

Nanotechnology: impacting radiotherapy

The use of nanotechnology for medical applications is a rapidly expanding field.

Increasing numbers of novel diagnostic and therapeutic schemes are emerging,
including many in the area of cancer medicine. At the recent ESTRO 29 meeting in
Barcelona, Spain, a dedicated symposium examined the potential impact of
nanotechnology on radiotherapy.

Kicking off proceedings, Dag Rune Olsen from the University of Bergen in Norway
described the rationale. Nanomedicine, he explained, is the interaction of cellular and
molecular components with nanoparticles. Such particles can be made of lipids,
polymers, semiconductors or metals, and created in the form of particles, shells, rods,
tubes or quantum dots, among others.

The linking factor is scale – such particles are up to 100 nm in size, similar dimensions
to large biological molecules and structures inside cells. "The advantage of nanoscale
technology in cancer medicine is that if the particles are less than 50 nm, they can
enter cells," Olsen explained. "If they're less than 20 nm, they can also transmit out of
small blood vessels."

The potential of nanomedicine for cancer treatment includes early-stage diagnostics,

personalized therapies and rapid drug development. "It may be years until we know if
these are clinically valid, but many different approaches are being looked at," said
Olsen. He pointed out that fundamental biological features of tumours, such as their
leaky vasculature, can be exploited to enable preferential uptake of nanoparticles.

Olsen went on to look more closely at some specific applications of nanotechnology

within radiotherapy, including target volume delineation, radiation sensitization,
combined chemo- and radiotherapy schemes, and radiation protection of normal
tissue. "Along these lines, I would think that nanotechnology could potentially play a
role in radiation oncology," he said.

Employing nanoparticle-enhanced imaging techniques to better define target volumes,

for example, could enhance the quality of the ensuing radiation treatment. Olsen

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described the development of multifunctional polymer vesicles that act as MRI
contrast agents, while simultaneously delivering targeted chemotherapy.

He also mentioned the application of liposomes as drug carriers, in which localized

release of their content – such as cytotoxic agents – is stimulated via exposure to
ultrasound, heat or changes in pH. One example is Caelyx, a liposome carrier
containing the cancer drug doxorubicin. Targeted delivery is enabled by exploiting the
enhanced permeability of the leaky tumour vasculature.

Quantum dots, meanwhile, have been shown to increase the sensitivity of cells to
ionizing radiation. The quantum dots – semiconductor-based nanoparticles – increase
the absorption of incident X-ray or gamma radiation, inducing electron ejection and
generating free radicals. These free radicals increase cellular damage and, ultimately,
induce cell death.

Olsen also told delegates about the use of nanoparticles to protect normal tissue
during radiation treatment. Nanoparticles of amifostine, for example, have been
shown to provide significant protection from acute whole-body gamma irradiation
injury in mice. He concluded by mentioning some unresolved issues that need to be
addressed in the near future. These include further work on selective targeting of
cancer cells, methods of nanoparticle delivery and studies into long-term toxicity.

The radiosensitizer effect

Next up, Eric Deutsch from Institut Gustave-Roussy in France took a closer look at one
of the applications described by Olsen – the use of high-density nanoparticles to
increase the efficacy of radiation therapy.

Research has already shown that gold nanoparticles can enhance the efficacy of low-
energy X-rays in irradiated cells. However, for use in humans, the key consideration is
safety. "High atomic-number atoms are used to increase the interaction with ionizing
radiation," Deutsch explained. "But one problem is choosing the highest-Z
nanoparticles with the lowest toxicity profile."

To address this issue, Deutsch and colleagues have used inert, biocompatible
nanoparticles comprising a dense hafnium oxide core surrounded by a thin amorphous
coating (hafnium has an atomic number of 72). The researchers integrated the

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nanoparticles – which are around 70 nm in diameter – into tumour cells. The particles
were taken up by the tumour cells and significantly increased cell killing following
exposure to ionizing radiation.

Deutsch noted that unlike gold nanoparticles, the hafnium oxide particles also appear
effective for use with higher-energy X-rays, such as those used in linac-based
radiotherapy. "You have increased energy deposited with these nanoparticles, both at
low kilovoltage energies and also at 6 MV," he said.

In vivo studies examining the use of this nanoparticle in mice revealed negligible local
leakage after intratumoural injection. Comparisons of tumour exposure to local
irradiation with and without nanoparticles, or treatment with nanoparticles alone,
revealed a significant enhancement of tumour growth delay in the nanoparticles-plus-
irradiation group.

Deutsch re-emphasized the importance of preclinical toxicity assessment prior to

clinical transfer. "At this stage, we can say that the toxicity of the nanoparticles
remains very weak, close to zero," he said. "We think that the advantage of hafnium is
its strong stability."

The hafnium oxide nanoparticle technology is being commercialized under the name
nanoXray, by the Paris-based company Nanobiotix. Deutsch says that phase I clinical
studies are planned for 2011.