Are you referring to the biological effects of a Hafnium radioisotope?

Liposarcomas are tumors derived from primitive mesenchymal cells that undergo adipose differentiation and constitute approximately 10% of all soft tissue sarcomas. Nearly one-third of cases arise in visceral spaces, and there is an association between site of primary tumor and histologic subtypes. Despite an aggressive multi disciplinary treatment (surgery, chemotherapy and radiation therapy), the rate of recurrence of more than 50% remains very high and results in diffuse metastatic disease and the death of the patients.

The effectiveness of radiotherapy in eradicating a tumor principally depends on the total dose of radiation administered. Therefore, to achieve the intended therapeutic benefit, local or locoregional side effects related to radiotherapy are controlled by precisely defining ballistics and also by fractionating the doses of delivered radiation. The index for estimating the dose of radiation that can treat a tumor effectively while staying within the safety range is known as the therapeutic window.

Radiation dose deposit within tissues is linked to their ability to absorb/interact with x-rays. This absorption depends on electron density (mainly water in the case of tissues) and the energy used. Introduction of material with higher electron density into the x ray pathway can increase absorption as compared with water. Utilization of nanoparticles has a particular advantage as they are able to achieve a large dispersion within tumor tissue and closely interact with specific subcellular structures.

The NBTXR3 product is intended for IT injection. NBTXR3 is a nonpyrogen, sterile, white aqueous dispersion of hafnium oxide nanoparticles coated with a biocompatible agent that provides the nanoparticles with a negative surface charge and ensures their stability in aqueous solution at pH values of between 6 and 8.

 On the basis of hafnium oxide material properties, crystalline hafnium oxide nanoparticles were chosen for their promising benefit:risk ratio for human healthcare. Hafnium presents a high atomic number (Z = 72), which is crucial for efficient hafnium oxide nanoparticle–ionizing radiation interactions. Hafnium oxide nanoparticles are expected to have inert behavior in bio-logical media, low solubility, absence of redox phenomena or electron transfer and no marked surface acido-basicity. In other words, their inert behavior, demonstrated in several biological systems has suggested the relevance of hafnium oxide selection.

The nanoparticles are capable of enlarging the therapeutic window owing to two prominent characteristics: their capacity to deposit high energy within tumors when the ionizing radiation source (Co-60/Ir-192 or accelerator) is ‘on’, and their chemically inert behavior in cellular and subcellular systems, demonstrated by very good local and systemic tolerance, thus decreasing potential health hazards.

Antitumor activities demonstrated marked advantage in terms of survival, tumor-specific growth delay and local control in both mesenchymal and epithelial human tumor xenografted models using high-energy source, when compared with radiation therapy alone.

The data support the use of this new type of high-atomic-number nanoparticle as an innovative approach in anticancer therapy, with an on/off mode of action through successive fractions of radiation therapy using current radiotherapy equipment available in hospitals.

Dear Dr Mushtaq Ahmad. Thank you very much for your erudite and scholarly discussions on NBTRX3 (aka PEP503). I may not fully understand the radiophysics of this particular material since I am a medical pathologist. Our university is embarking on a possible collaborative trial on the use of this implantable medical device on human soft tissue liposarcomas. Although I do understand that te mode of sction is basically identical to that of radiotherapy, i.e.- energy absorption-electrons emission-free radical generation-cellular damage-subsequent action/effects on cells. I do hope I got this correctly? I am identified as the lead person in charge for evaluation of pathologic response, if ever this project is approved and granted for collaboration with our University. I'd appreciate furthur enlightenment. With warmest regards- Rowen T. Yolo, M.D. University of Santo Tomas Hospital Benavides Cancer Institute, Manila, Philippines

Dear Professor Edward Russak. I am referring to NBTXR3 (aka PEP503) as a nonpyrogen, sterile, white aqueous dispersion of hafnium oxide nanoparticles coated with a biocompatible agent.

Dr Mushtaq Ahmad, 

Forgive me for my ignorance, can you pls explain the reason why hafnium oxide nanoparticles is coated with a biocompatible agent? I understand though by your reply is that this will provide stability in acqueous solution. Second question is how is this material activided? Once inplanted into the tissue, a predetermined dose of radiation will be bombarded in order to activate this material? Thank you again for your kind response.

The nanoparticles toxicological issues are of most importance when designing a nanomaterial. The potential toxicity of engineered nanomaterials developed for diagnostic or therapeutic application is to be considered and encompasses phenomena such as release of toxic species into biological media, redox phenomena, electron transfer and reactive oxygen species (ROS) production. Also, adsorption of proteins on the nanoparticles surface may trigger various adverse phenomena such as change in protein conformation and subsequent loss of enzyme activity, fibrillation, or exposure to new antigenic epitopes. Pharmacokinetics is a determinant parameter of efficacy and safety prediction. Nanoparticles, which are not or only poorly degraded, after being captured by mononuclear phagocytic cells, can be entrapped in the reticuloendothelial system (RES) where they accumulate and can induce undesirable side effects.

Nanoparticle surface coating (functionalization) is perceived has an attractive approach to improve nanoparticles safety by playing different roles such as preventing nanoparticles bioreactivity and nanoparticles dissolution. Indeed, the coating of nanoparticles with a protective shell appears as an effective means of reducing their toxicity. Suitable shell materials include biocompatible organic or inorganic substances such as PolyEthyleneGlycol compounds (PEG compounds), silica (Si02) and biocompatible polymers. However, these coatings are environmentally labile or degradable and an initially non-toxic material may become hazardous after shedding its coat, when the core of the nanoparticle is exposed to the body.

Cobalt-60 or Iridium-192 or Accelerator may be used to radiate the nanoparicles, which will act as radiosensitizer. Monte Carlo calculations showed 9 times increase of doses to tumor. Once the radioactve sources or accelerator is focused on nanomaterial, process of dose delivery starts. No radioactive material will be produced in nanomaterial, and when radioactive sources or accelerator is switched off, dose delivery to tumor shall stop. 

Dear Dr Ahmad. Once again thank you very much for your kind and scholarly  response. Your contributions are well taken and I assure you that your inputs will be appropriately acknowledged once the project is approved and realized. With warmest regards.