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Radiotherapy is a major therapeutic strategy for cancer treatment. Despite many technology advances in the last two decades, local control remains often suboptimal, especially in locally advanced tumours, which are often hypoxic, and radioresistant. In addition, irradiation of surrounding tissues and organs at risk usually precludes further dose escalation to minimize acute and late toxicities. Radiosensitizing agents such as chemotherapies targeting the DNA repair, or targeted monoclonal antibodies (cetuximab) have been shown to improve local control in many tumour types. More recently, radioenhancers have emerged as a new way to overcome the limitations of radiation. Here, we review the state of the art in this field and will focus on the past and ongoing clinical trials with the nanoparticles NBTXR3 and AGuIX®., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background and Purpose: Brain metastasis impacts greatly on patients' quality of life and survival. The phase I NANO-RAD trial assessed the safety and maximum tolerated dose of systemic administration of a novel gadolinium-based nanoparticle, AGuIX, in combination with whole brain radiotherapy in patients with multiple brain metastases not suitable for stereotactic radiotherapy., Materials and Methods: Patients with measurable brain metastases received escalating doses of AGuIX nanoparticles (15, 30, 50, 75, or 100 mg/kg intravenously) on the day of initiation of WBRT (30 Gy in 10 fractions) in 5 cohorts of 3 patients each. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events v4.03., Results: Fifteen patients with 354 metastases were included. No dose-limiting toxic effects were observed up to AGuIX 100 mg/kg. Plasma elimination half-life of AGuIX was similar for all groups (mean 1.3 h; range 0.8-3 h). Efficient targeting of metastases (T 1 MRI enhancement, tumor selectivity) and persistence of AGuIX contrast enhancement were observed in metastases from patients with primary melanoma, lung, breast, and colon cancers. The concentration of AGuIX in metastases after administration was proportional to the injected dose. Thirteen of 14 evaluable patients had a clinical benefit, with either stabilization or reduction of tumor volume. MRI analysis showed significant correlation between contrast enhancement and tumor response, thus supporting a radiosensitizing effect., Conclusion: Combining AGuIX with radiotherapy for patients with brain metastases is safe and feasible. AGuIX specifically targets brain metastases and is retained within tumors for up to 1 week; ongoing phase II studies will more definitively assess efficacy., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Interest of tumor targeting through EPR effect is still controversial due to intrinsic low targeting efficacy and rare translation to human cancers. Moreover, due to different reasons, it has generally been described for relatively large nanoparticles (NPs) (hydrodynamic diameter > 10 nm). In this review EPR effect will be discussed for ultrasmall NPs using the example of the AGuIX® NP (Activation and Guiding of Irradiation by X-ray) recently translated in clinic. AGuIX® NP is a 4 ± 2 nm hydrodynamic diameter polysiloxane based NP. Since AGuIX® NP biodistribution is monitored by magnetic resonance imaging (MRI) and its activation is triggered by irradiation upon X-rays, this NP is well adapted for a theranostic approach of radiotherapy cancer treatment. Here we show that AGuIX® NP is particularly well suited to benefit from EPR-mediated tumor targeting thanks to an ultrasmall size and efficacy under irradiation at small dose. Indeed, intravenously-injected AGuIX® NP into rodent cancer models passively reached the tumor and revealed no toxicity, favoured by renal clearance. Moreover, translation of AGuIX® NP accumulation and retention into humans carrying brain metastases was validated during a first-in-man phase Ib trial taking advantage of easy biodistribution monitoring by MRI., Competing Interests: Competing Interests: F.L. and O.T. have one patent (WO2011135101) protecting the AGuIX® NP, are employed by NH TherAguix owner of AGuIX® NP, and possess shares of this company. S.D. is employed by NH TherAguix and possesses shares of this company. Y.C. is employed by NH TherAguix., (© The author(s).)

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., (Copyright © 2019 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

AGuIX ® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.

A new efficient type of gadolinium-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy (RT). These new particles consist of a polysiloxane network surrounded by a number of gadolinium chelates, usually 10. Owing to their small size (<5 nm), AGuIX typically exhibit biodistributions that are almost ideal for diagnostic and therapeutic purposes. For example, although a significant proportion of these particles accumulate in tumours, the remainder is rapidly eliminated by the renal route. In addition, in the absence of irradiation, the nanoparticles are well tolerated even at very high dose (10 times more than the dose used for mouse treatment). AGuIX particles have been proven to act as efficient radiosensitizers in a large variety of experimental in vitro scenarios, including different radioresistant cell lines, irradiation energies and radiation sources (sensitizing enhancement ratio ranging from 1.1 to 2.5). Pre-clinical studies have also demonstrated the impact of these particles on different heterotopic and orthotopic tumours, with both intratumoural or intravenous injection routes. A significant therapeutical effect has been observed in all contexts. Furthermore, MRI monitoring was proven to efficiently aid in determining a RT protocol and assessing tumour evolution following treatment. The usual theoretical models, based on energy attenuation and macroscopic dose enhancement, cannot account for all the results that have been obtained. Only theoretical models, which take into account the Auger electron cascades that occur between the different atoms constituting the particle and the related high radical concentrations in the vicinity of the particle, provide an explanation for the complex cell damage and death observed.

Modern radiation therapy techniques provide effective treatments for solid tumors, but there remain challenges with delivering high doses to elusive tumors without causing toxicity to surrounding normal tissue. Pre-clinical trials have demonstrated the theranostic properties of a recently developed gadolinium-based nanoparticle (Gd-NP). The first in-human clinical trial was conducted to assess the safety and dose tolerance of intravenous Gd-NPs in combination with whole brain radiotherapy and showed favorable results, including a significant correlation between tumor uptake and therapeutic response. The second, double-blinded, in-human clinical trial is underway in the US and aims to evaluate if brain-directed stereotactic radiation in conjunction with NPs will improve local tumor control compared to radiation alone. The current work investigates uptake patterns in brain tumors of 23 patients as quantified by magnetization prepared 2 rapid gradient echo (MP2RAGE) T1 mapping. A phantom containing eight vials of NP-saline solutions at varying concentrations was created to examine the relationship between NP concentration and longitudinal relaxation (T1, in seconds). This relationship is known as relaxivity and is dependent on the contrast agent, field strength and T1 mapping sequence. A 3T MAGNETOM Vida scanner and MP2RAGE sequence were used to image the phantom and MP2RAGE T1 maps were calculated using Bloch equations (QMRLab software). Relaxivity was determined and applied to 23 patient T1 maps (pre- and post- Gd-NP administration) to calculate uptake on an individual tumor basis. Theranostic NP uptake was calculated for every voxel in each of 129 brain metastases and examined for patterns in quantity and distribution. Average individual tumor uptake ranged from 0.02-0.12 mg/ml, where average overall uptake was equal to 0.05 mg/ml. A relationship between tumor diameter and mean NP concentration was observed and best represented by a power-based curve (R2 = 0.92). In contrast, patients with suspected placebo administration appeared to have no uptake and therefore no relationship with tumor diameter. The distribution of NP concentration within the tumor was also examined; on average, linear uptake profiles through tumor centroids (ant-post, left-right) demonstrated roughly gaussian patterns of uptake with lower concentrations at the tumor edges and higher concentrations at the tumor center. This pattern indicates robust tumor penetration and may have implications for amplifying radiation dose to hypoxic tumors. Gd-NP uptake in brain metastases can be quantified using MP2RAGE T1 mapping. Uptake was determined for each voxel in each tumor volume, where a gaussian pattern of spatial concentrations was observed. This analysis procedure will be applied to the full data set, when available, to evaluate the impact of NP uptake (in conjunction with radiation therapy) within individual patients and individual tumors. [ABSTRACT FROM AUTHOR]

Proffered Papers: Proffered papers 27: Novel technologies OC-0561: Nano-Rad first in man study: AGuIX nanoparticles as radiosensitizing agent for radiotherapy C. Verry, S. Dufort, G. Le Duc, C. Mendoza, F. Lux, J. Arnaud, L. Sancey, A. Adolle, M. Gavard, F. Jover, S. Grand, C. Iriart, J. Villa, J. Balosso, O. Tillement. [Extracted from the article]