Solving radiotherapy’s biggest limitation. Medicine is now using physics every day to treat cancer patients. Nanotechnologies can help clinicians deliver safer and more efficacious treatments by shifting the intended effect from the macroscopic to the subcellular level.
NanoXray™, designed to resolve cancer therapy’s biggest drawback: destruction of healthy tissue and its subsequent deleterious side effects when a high dose of X-ray is necessary.
The core of a nanoXray nanoparticle is an inactive and inert substance—not a drug—that can subsequently be activated in order to locally (intratumor) increase the dose of a standard X-ray, which is then expected to lead to higher efficiency.
After nanoXray nanoparticles accumulate in the target tissues, a standard X-ray is applied that is intended to generate a local therapeutic effect, designed to destroy only the targeted tumor cells.
This mechanism suggests total control of the intended therapeutic effect.
The core of the nanoXray platform is nbtxr3—a dense, biocompatible nanoparticle, designed to infiltrate only the targeted tumor’s cells.
One inside the tumor’s cells, nbtxr3 nanoparticles have properties that convert incoming, standard X-ray radiation into an efficient emission of electrons responsible for the generation of free radicals.
The use of a particle size within the nanometer scale improves the dispersion and the diffusion of the effect within the tumor cells.
Nbtxr3 is mainly spherical in shape, which is a favorable morphology to enhancing cellular penetration. The mean hydrodynamic diameter is below 100 nm and characteristically centered on 70 nm.
Such range is relevant for a superior cellular penetration. Stability in physiological media is achieved by coating the nanoparticles with a surface-treating agent, which assures that the nanoparticles are stable in physiological fluids. From these various characteristics—low surface area, biocompatible coating, and the inorganic material that comprises nbtxr3—the nanoparticle nbtxr3 may be considered as reasonably inert, and therefore not a drug.
Nbtxr3 is to be activated in vivo in order to selectively destroy cancer cells upon exposure to irradiation.
The proposed physical and energetic mechanism of action of such a product is based on free radical creation and heat generation after standard X-ray absorption.
Nbtxr3 works according to an “on-off” activation/activity status. Thus, when the nanoparticles are not activated, they do not have any effect because they are inert.
Under standard X-ray irradiation, X-rays (photons and electrons) are absorbed by nbtxr3 nanoparticles exactly as ionizing radiations are absorbed by water molecules to create free radicals.
In both cases, X-ray energy will generate electrons with kinetic energy that will be released into the medium and will generate free radicals or heat.
Indeed, the nanoparticles do not react directly with any human recipient cell or tissue.
The free oxygen radicals generated by nbtxr3 are very reactive and trigger different types of damage to membranes, proteins and nucleic acids that lead to biological consequences, including cell inactivation and lethal processes.
This is particularly the case when heavily damaged DNA cannot be efficiently repaired, the tumor cells choosing therefore to enter an apoptotic cell death program.
Nbtxr3 should allow high doses of ROS with cytotoxic action in the tumor cells and therefore differential cell damage between healthy and malignant cells.
When the standard X-ray irradiation is “off”, the nanoXray nanoparticles return to their inactive state.
The process may be applied several times with the same nanoparticles. The process has been already validated in preclinical studies.
Tumor cell uptake
Nbtxr3 has been demonstrated to be uptaken by mammalian cancer cells. To confirm that the cellular uptake of nanoparticles is mediated through endosomes, transmission electron microscopy (TEM) analysis has been performed.
Performance: cell viability assay
Cell viability was measured after a 24 hour treatment period with, and without ,nbtxr3 , varying irradiation doses (up to 6 Gy). Nbtxr3 used in combination with radiotherapy has shown an increase in efficacy; 1 Gy corresponds to the efficacy of 3 Gy of radiotherapy alone.
Intratumor use
Nbtxr3 has been intratumorously injected to mice bearing a tumor. The time residency of nanoparticles in tumor is at least 15 days, with a good dispersion of the product.
Performance study of nbtxr3 in HCT116 tumor model
Nbtxr3 has been intratumorously injected to mice bearing tumors grafted on the flank. Local irradiation of tumor has been performed. Nbtxr3 leads to a total regression of tumor on all animals compared to 5% glucose-treated mice subjected to radiotherapy alone. After 60 days, 90% of animals are still tumor free when treated with nbtxr3 plus radiotherapy. The group with radiotherapy alone has shown growth of the tumor.
Systemic tolerance of nbtxr3
The tolerance of HCT116 tumor bearing Swiss nude to repeated administrations of nbtxr3 has been explored. This study has permitted the checking of potential acute toxic effects of the product after exaggerated injection compared to the planned one-injection use in humans.
Disclaimer: Based on previous data obtained and timeline for completion of safety studies on the first product, VARIOUS CLINICAL TRIALS ARE EXPECTED TO START IN 2009 and 2010. More information will be posted on this section of the web site.
Based on the existing technology and preclinical results, Nanobiotix is developing other nanomedicine programs beyond nanoXray that will sustain its pipeline and will expand the uses of nanoparticles in medicine.
- nanoMag : Magnetic particles for treatment and diagnostic of cancer
- nanoPDT : laser activated nanoparticles for cancer treatment
- Outside oncology field : Business and development collaboration with Malaysian Biotech Corp
- Activated drug delivery : Based on different modalities already in use in hospitals; drug-delivery systems (DDS) that can be externally triggered