A metal-polyphenolic nanosystem with NIR-II fluorescence-guided combined photothermal therapy and radiotherapy.

Photothermal therapy (PTT) achieves substantive therapeutic progress in certain tumor types without exogenous agents but is hampered by the over-activated inflammatory response or tumor recurrence in some cases. Herein, we technically developed the metal-polyphenolic nanosystem with precise NIR-II fluorescence-imaging guidance for combining hafnium (Hf)-sensitized radiotherapy with PTT to regress tumor growth.

[Use of nanoparticles as radiosensitizing agents in radiotherapy: State of play]. / Utilisation de nanoparticules comme agent radiosensibilisant en radiothérapie : où en est-on ?

Nanomedicine has undergone significant development since the 2000s and it is only very recently that two metallic nanoparticles have emerged in clinical trials. The mechanism of these radiosensitizing agents is based on the presence of atoms with a high atomic number (Z) allowing a higher dose deposition into the tumor during irradiation. The first nanoparticle used in humans is NBTXR3, composed of hafnium (Z=79), with intratumor injection for the treatment of sarcoma. Another gadolinium-based nanoparticle (Z=64), AGuIX, has been used for intravenous injection in the treatment of brain metastases. The preliminary results are promising in terms of feasibility, safety and efficacy, as evidenced by the significant number of ongoing clinical trials. The upcoming challenges for the development of nanoparticles will be the targeting of cancer cells, their biodistribution into the body, their eventual toxicity and their industrial production. In the coming years, modalities of administration and optimal combinations with radiotherapy should be defined in connection with fundamental research.

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

BACKGROUND: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING: Nanobiotix SA.

Effect of TiF4, ZrF4, HfF4 and AmF on erosion and erosion/abrasion of enamel and dentin in situ.

OBJECTIVE: This in situ study aimed to analyse the impact of different tetrafluorides (TiF(4), ZrF(4) and HfF(4)) and AmF on erosion and erosion plus abrasion of enamel and dentin. DESIGN: Ten volunteers took part in this crossover and double-blind study performed in 8 phases of each 3 days. In each phase, 2 bovine enamel and 2 dentin specimens were fixed in intraoral appliances. One enamel and one dentin sample were pretreated once with TiF(4), ZrF(4), HfF(4) or AmF (all 0.5M F) for 60s, while the other samples remained unfluoridated and served as control. Then, all samples were subjected to either erosion only (4 times/day, 90 s) or to erosion and abrasion (2 times/day, 30 s/sample). Toothbrushing abrasion was performed 90 min after the first and last erosion with an electrical toothbrush and fluoridated toothpaste at 1.2N. After 3 days, enamel and dentin loss was assessed by profilometry (microm) and analysed by repeated measures ANOVA and paired t-test (p<0.05). RESULTS: All fluoride solutions reduced enamel and dentin loss significantly compared to the controls. Generally, eroded samples showed less wear than eroded and abraded samples. The protective potential of the fluorides was not significantly different and was only slightly, but mostly not significantly, decreased by abrasion. The protective effect of the fluoride solutions was similar in enamel and dentin. CONCLUSION: Tetrafluorides and AmF are able to reduce erosion and erosion plus abrasion in situ and are almost equally effective.

Efficacy of beta-diketonato complexes of titanium, zirconium, and hafnium against chemically induced autochthonous colonic tumors in rats.

Bis-beta-diketonato complexes of titanium, zirconium, and hafnium were tested against autochthonous colorectal tumors in rats. The model was found to reflect the clinical situation most closely. Of the compounds tested, budotitane was the most effective in terms of decrease in tumor weight and number and in increasing the lifespan of the treated animals. The therapeutic efficiency was superior to that of 5-fluorouracil, which so far has been the drug with the best activity in patients suffering from colon cancer.

[Tumor inhibition by metallocenes: effect of titanocene, zirconocene, and hafnocene dichlorides on Ehrlich ascites tumor in mice (author's transl)]. / Tumorhemmung durch Metallocene: Wirkung von Tianocen-, Zirconocen- und Hafnocen-dichlorid gegenüber Ehrlich-Aszites-Tumor der Maus.

The antitumor activity of the metallocene dichlorides TDC, ZDC, and HDC against Ehrlich ascites tumor in CF1 mice is investigated. A single i.p. injection of TDC in the optimum dose (30-60 mg/kg) 24 h p.t.t. achieves survival of 80-90% of the animals until day 180 p.t.t. without any tumor manifestation. This indicates an increase in the mean survival time of about 900% referred to the untreated animals. In contrast, ZDC and HDC exhibit no recognizable antineoplastic properties under equal experimental conditions. Assuming a similar mechanism of tumor inhibition for both DDP and the antineoplastic active metallocene dichlorides TDC, VDC, and MDC the comparatively increased non bonding Cl...Cl distance ("bite") of ZDC and HDC may be responsible for cancerostatic inactivity of the latter compounds.