Abstract 2665: NBTXR3 hafnium oxide nanoparticle activated by ionizing radiation demonstrates marked radio-enhancement and antitumor effect via high energy deposit in human soft tissue sarcoma

Abstract

Local and systemic control of Soft Tissue Sarcoma (STS) remains a clinical challenge. Radiation therapy is part of the standard of care of STS. The narrowness of its therapeutic window represents the main concern for different clinical settings. Thus, local delivery of radiation doses is critical to ensure optimal benefit-risk ratio. NBTXR3, biocompatible hafnium oxide nanoparticles were designed as therapeutics to be activated by ionizing radiation to achieve tumor control by enhancement of local energy deposition. A global non clinical program was implemented in mesenchymal tumor models. In vitro clonogenic survival assays were performed in two human fibrosarcoma cell lines (HT1080 and Hs913t) and a human liposarcoma cell line (SW872) to evaluate the cellular response to radiation-activated NBTXR3 at increasing concentrations. A marked radio-enhancement was observed in human STS cell lines with dose enhancement factors estimated at 4 Gy ranging from 1.48 up to 5.36 according to NBTXR3 concentrations. Further, in human immortalized MRC5V1 fibroblasts, no significant decrease in clonogenic surviving fraction was observed upon activation of NBTXR3 under similar conditions suggesting a differential radiation response between fibroblasts and fibrosarcoma, liposarcoma cell lines. This differential radiation response was further confirmed between HT1080 fibrosarcoma cell line and MRC5V1 fibroblasts upon activation of NBTXR3 at increasing concentration using high energy gamma-rays. Mechanistic studies have demonstrated in HT1080 cells that NBTXR3 activation induces an increase of 53BP1 foci associated with more “complex” DNA damages than ionizing radiation alone. The level of unrepaired DNA damages was also estimated by flow cytometry analysis showing a higher level of gamma-H2AX at 48h following NBTXR3 activation than after radiotherapy alone. DNA fragmentation and Annexin V staining have demonstrated that these unrepaired DNA damages upon NBTXR3 activation induces apoptosis in HT1080 fibrosarcoma cells. In vivo, tolerance and tumor growth delay were investigated in two human xenografted tumor models, HT1080 fibrosarcoma and a patient derived liposarcoma LPS80T3 (poorly differentiated grade 3). No toxicity related to NBTXR3 was reported. In both models, a significant advantage was demonstrated in terms of tumor growth inhibition and survival when compared to radiation therapy alone. These findings establish a novel approach of treatment, which may be applied to a broad range of tumors. Therefore, incrementing the amount of energy deposited within the tumor through the activation of NBTXR3 crystalline nanoparticles constitutes a revolutionary approach for future clinical investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2665. doi:10.1158/1538-7445.AM2011-2665

Metal-based NanoEnhancers for Future Radiotherapy: Radiosensitizing and Synergistic Effects on Tumor Cells

“…NBTXR3 were designed for direct local intratumoral injection and subsequent radiosensitization 6 , 137 . Subsequently, it has been demonstrated by Monte Carlo simulation that NBTXR3 crystalline nanoparticles exposed to high-energy photons could promote a significant radiation dose enhancement, and the obvious radiosensitizing effects of NBTXR3 in vitro and in vivo were presented 138 - 140 . Also, nonclinical toxicology evaluation of this agent showed a good tolerance.…”

A Facile One-Pot Synthesis of Versatile PEGylated Platinum Nanoflowers and Their Application in Radiation Therapy

“…It was reported that nanoparticles with surface charge corresponding to a potential less than 20 mV can provide sufficient stabilization when using large molecular weight stabilizers (PEG-diamine), which act mainly by steric stabilization [46]. Moreover, to investigate the stability of Pt NFs in aqueous solution with different pH values (3)(4)(5)(6)(7)(8)(9)(10)(11), the sizes and zeta potential of Pt NFs were studied (see supporting information Figure S1). The hydrodynamic diameter of Pt NFs remained similar as the pH changes, with no visible precipitation.…”

“…Nanoparticles containing other heavy elements, for example, 50-nm crystalline HfO2 NPs (NBTXR3, Nanobiotix, Paris, France), were also developed. It has been demonstrated that these NPs exposed to high-energy photons induce a significant radiation dose enhancement as shown in vitro and in vivo [9][10][11].…”

Review of clinical applications of radiation-enhancing nanoparticles

“…The free radicals generated by the electrons ejected from the metal-based NP and from water are highly reactive and tend to break the covalent bonds of molecules they encounter. In fact, an increase in cell death mechanisms such as apoptosis, necrosis and autophagy has been demonstrated when irradiated cells enter into contact with NP [ 2 ]. Nanoparticles with a physical mode of action were able to enhance pathway activity of cancer cells via increased DNA damage, compared to RT alone [ 3 ].…”