Nanotechnology X-ray Method Aims to Kill Cancer But Spare Healthy Tissue

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Radiation Therapy

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“Development of this technology has involved many scientific disciplines beyond oncology: physics, chemistry, biophysics, cellular biology, radiobiology, molecular biology, physical chemistry, and others.”

—Laurent Levy, MD

Nanotechnology X-ray Method Aims

to Kill Cancer But Spare Healthy Tissue

An Interview With Laurent Levy, PhD

Radiation, used to treat more than half of all cancers, can sometimes be as toxic to the body as it is to the tumor. Advances in nanomedicine, however, may soon make it possible for radiation oncologists and technicians to deliver doses of x-rays that are strong enough to destroy the cancer without damaging healthy tissues.

With a new device from Nanobiotixcalled NanoXray^TM, inert nanoparticles, between 100 and 1000 times smaller than the diameter of a human hair,are injected into the cancer and activated by a standard x-ray. These nanoparticles, called NBTXR3,absorb high levels of radiation. Once activated, these particles create electrons that, in turn, generate free radicals, which inflict irreversible damage to the cancerous cells and cause their destruction, while the surrounding cells receive a simple standard dose of radiation.

In early 2011, Nanobiotixplans tobegin clinical trials with NanoXray at the Gustave Roussy Institute, Paris, an international center of excellence in cancer treatment. The chief executive officer of Nanobiotix, Laurent Levy, PhD, has been working with nanotechnologies for more than a decade, developing practical applications, such as NanoXray. Levy is the president of the French Technology Platform ofNanomedicine and author of 35international publications and communications. Here, Levy discusses this new technology.

Please describe how the NanoXray works.

NanoXray is a technology in which crystallineand inert nanoparticles are designed to reach the tumor and then are activated by a standard x-ray. Once into the tumor, the nanoparticles accumulate in the cancer cell, and the x-ray activates the particles to release large amounts of energy in the cell. The electrons produced after the nanoparticles absorb a high level of x-rays generate large quantities of free radicals.

These free radicals inflict nonspecific,irreversible damage to the cancerous cell that leads to its destruction and multiplies the effects of radiation therapy. Due to their unique design and physical properties, the nanoparticles present in the cancerous tissues absorb a strong dose of x-rays, while healthy tissues receive a standard x-ray dose.

What advantages over standard radiotherapy methods will NanoXray offer?

There are many potential benefits from this new approach to radiation therapy:First, it achieves a better local tumor control with an inert product. Secondly, it has a good safety profile demonstrated in animal models, and lastly, it delivers a higher dose to achieve total tumor control.

The product augments efficacy of radiation therapy. Radiation has been effective against cancer for more than 50 years, and nanoparticles emitted by NanoXray have been thoroughly investigated and found to cause no harm in noncancerous cells over long periods of time.

NanoXray could be combined with existing therapies, such as chemotherapy, surgery, and immunotherapy, and with molecularly targeted drugs. The device provides for “on/off” therapy. The inert nanoparticles are only rendered active when exposed to radiation. One injection of the nanoparticles should last through a course of several radiation therapy sessions, and the device works with all standard radiotherapy equipment.

Radiation oncologists and technicians can combine NanoXray with other approaches to improve radiation therapy outcomes, such as more focused imaging techniques and technologies that improve the focus of the radiation beam.

Is this considered platform technology?

Nanobiotixhas 3 products in the pipeline. The first (NBTXR3) will enter clinical trials in early 2011. This compound will be injected directly into the tumor.

A second nanoparticle (NBTXR-IV), currently being investigated in nonclinical studies, may be injected intravenously to treat other cancers where an intravenous injection is the optimum delivery route.

The third (NBTX TOPO) is being developed for use during surgery, to prepare the cancer site for follow-up radiotherapy, such as in breast cancer surgery. Based on the existing technology and preclinical results, Nanobiotix is developing other nanomedicine programs beyond NanoXray that will sustain its pipeline and expand the uses of nanoparticles in medicine.

Which cancer patients would be more likely to benefit from the NanoXray?

Given the universal nature of the mode of action of these particles, this technology could be applied to all radiotherapy applications, that is, 50% to 60% of patients with cancer, while maintaining an optimal standard of care. The potential expands beyond this application because the mode of action of the nanoparticle product is not specific and could, in the future,open new routes for radiotherapy.

Nanobiotix plans to address liver cancer, glioblastoma, rectal cancer, prostate cancer, non-small cell lung cancer, and breast cancer with various formulations of the product.

Describe the evidence supporting your contention that NBTXR3 not only delivers positive outcomes, but also shows superiority over standard therapies?

Nonclinical research indicates the treatment is safe, effective, and delivers a dose of radiation that is markedly higher than traditional radiation therapy. Nonclinical and preclinical research is completed, and this research paves the way for clinical trials to begin in Europe in early 2011. Preliminary research with the first NanoXray product (NBTXR3) in several animal models demonstrated a complete tumor regression and prolonged survival.

Intratumoral injection of NBTXR3 nanoparticles activated via standard radiation therapy led to complete tumor regression and showed survival benefit in mice bearing human cancer cells. The preclinical study showed that an intratumoral injection of NBTXR3 nanoparticles activated via standard radiation therapy led to complete tumor regression in mice at 60 days, and showed significant survival advantages. NanoXray used in combination with radiotherapy should help it to achieve a better local control and should not compete with other products.

Are there adverse effects with NanoXray therapy and, if so, how would they be managed?

NBTXR3 nanoparticles are designed to be safe and effective treatment for radiosensitive and radioresistant tumors. Two years ago, Nanobiotix commenced a large safety assessment program in animals to acquire knowledge about NBTXR3's biodistribution, excretion, and potential toxicology effects in healthy and tumor-bearing animals.

Despite the intended use of NBTXR3 as a local injection directly into a tumor, NBTXR3 was tested in animals as a systemic injection into the vein in order to mimic a clinical situation of accidental and massive passage of NBTXR3 nanoparticles into the bloodstream during the procedure of intratumor injection.

Preclinical tolerance studies in terms of animal survival, behavior, and pathological assessment indicated capture by the reticulo-endothelial system and negligible toxicity, even for dose-maximization situations in which NBTXR3 was injected by intravenous route on 5 consecutive days.

Results suggested absence of any indolent disease characteristics in male and female animals. Excretion studies following intravenous administration showed identical data for male and female animals, with NBTXR3 very slowly eliminated by feces per plan and no presence of NBTXR3 in urine. For the systemic administrations, NBTXR3 nanoparticles underwent endocytosis mainly in the mononuclear phagocyte system. There was no evidence of blood/brain barrier rupture. Also, no presence of inflammation or degenerative change was found in toxicology study.

What trials are underway or planned? What has been identified as the primary endpoint of these trials?

In early 2011, Nanobiotix will begin clinical trials with NBTXR3, the first NanoXray product. The trial’s first indication will be on soft tissue sarcomas, a rare form of cancer that develops in different tissues such as in fat, muscle, and others. The primary endpoints of this trial are to demonstrate feasibility and the innocuity of the treatment in humans.

What technological advances made the NanoXray possible?

The nanoparticle used in NanoXray technology is an inactive and inert substance (not a drug), measuring 50 nanometers in diameter—up to 1000 times smaller than the diameter of a human hair.

The nanoparticle comprises a crystalline inorganic core and a coating layer that protects the core from unintended biological interactions within the body. Development of this technology has involved many scientific disciplines beyond oncology: physics, chemistry, biophysics, cellular biology, radiobiology, molecular biology, physical chemistry, and others. The ability to design, qualify, and manufacture such nanoparticles have been key factors in the development.

Describe how those advances were used to develop this technique?

I have worked in the nanotechnology field for 15 years as a scientist, but also as an entrepreneur. I started with my PhD in nanotechnology, where I explored the impact of scale on the physical properties of nanomaterials—in other words, how to design and reduce the size of a material to tune and exploit its new properties.

After this step, I thought about using the unique properties of nanoparticles to kill cancer cells. I had to go to the US (University at Buffalo, The State University of New York) to find a multidisciplinary team that could explore the concept of how to combine biology, nanomaterial, chemistry, and physics to develop nanomedicine applications. At this time the concept was very new, and everything needed to be done. Later, when we created Nanobiotix, we had to expend our knowledge to take the technology to the next level and make it industrial.

What materials form the nanoparticles used in the NanoXray, and how are the nanoparticles manufactured?

NanoXray compounds are based on crystalline HfO2 nanoparticles. A specific manufacturing process has been developed that is scalable, ensures batch-to-batch reproducibility, and allows flexible manufacturing of several products. Successive NBTXR3 batches have been successfully validated and qualified. The current process produces sufficient materials for the completion of preclinical development, clinical trials, and potentially, initial commercialization. A manufacturer with GMP [good manufacturing processes] and injectable-product capabilities handles the production.

What stage of the development cycle are you in, and when do you think this product will be ready to submit for FDA and/or EMEA approval? When will it reach the market?

The NanoXray therapeutics, due to their physical mechanism of action, have been classified as class III medical devices by some of the regulatory authorities in EU countries. The first Nanobiotix product, NBTXR3 for intratumoral injection, is planned to launch around 2014, but of course this always depends on development orientation and timelines, which may vary depending on clinical results.

What major challenges have you and your company faced thus far in developing this technology?

As any young innovative healthcare company, Nanobiotix went through “classical” steps combining technological development, finding the right financing, executing manufacturing, defining the regulatory pathway, finding the right people, and so on, On top of that, Nanobiotix faces major challenges, as long as it is not a classical biotech player, involved in molecule development: We still have to educate, excite, and endorse to help our target audiences to think out of the box. These are very important tasks since we want this technology to benefit to patient as soon as possible.

More Info» http://www.nanobiotix.com/