"The idea is to cluster gadolinium into nanoparticles to use for MR guidance and to boost X-ray irradiation," Sancey explained. "The use of gadolinium nanoparticles can also help to pre-select patients that may be responsive to treatment, allowing adjustment of their treatment protocol."

The nanoparticles in question – called AGuIX – are formed from a polysiloxane network surrounded by gadolinium chelates. Sancey emphasized that the gadolinium atoms are safely entrapped, with a low (though not zero) risk of release from the nanoparticles. The nanoparticles can also be freeze-dried for long-term storage, she said.

Preclinical assessment

The team FENNEC and its collaborators first examined the use of AGuIX nanoparticles in animals, demonstrating that injection of the nanoparticles enabled MR visualization of previously unseen tumours. While most of the nanoparticles were rapidly cleared by the kidneys, some were retained in the tumour for 24 to 72 hours after injection.

In vitro studies revealed a 30–40% increase in cell death in cells treated with AGuIX plus radiotherapy, compared with those receiving only radiation. To examine radiosensitization in viv, the researchers irradiated rats bearing 9L tumours, with and without nanoparticles. Intravenous injection of low doses of AGuIX, 24 hours before radiotherapy, strongly increased survival. The 60-day survival of animals treated with nanoparticles, for example, was approximately 67%, compared with 29% for those receiving radiotherapy alone. Similar results were seen in tests on mice bearing B16F10 tumours.

The team also performed preclinical toxicity studies on rats and nonhuman primates. Except for a minimal and reversible modification in the rodent's kidneys, they observed no differences in any clinical parameters versus a control group, for both species, at human equivalent doses from 60 to 145 mg/kg.

The first clinical trial

These results paved the way for the team to design the first clinical trial in humans. This trial – conducted by the recently created start-up NH TherAguix – will include patients with multiple (three or more) brain metastases from melanoma, lung or breast tumours, who are being treated with 30 Gy of radiotherapy over 10 sessions. Phase I will examine the safety and pharmacokinetics of adding pre-injection of nanoparticles to the patients' existing clinical protocol.

The researchers plan to perform a dose escalation study, with the first three patients receiving a dose of 15 mg/kg. This dose will then be ramped to 30, 50, 75 and a maximum of 100 mg/kg, with three patients receiving each dose. The maximum tolerated dose will then be used for a future Phase II trial.

Sancey told the AAPM delegates that the first patient in the trial had been treated a few days earlier, and that NH TherAguix will shortly announce details regarding the first patients included in the trial. She noted that possible future trials may include patients with glioma, and pancreatic, uterine and prostate cancers. It may also be possible to treat lung tumours using AGuIX nanoparticles delivered via an aerosol.

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