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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.

Hadrontherapy presents the major advantage of improving tumor sterilization while sparing surrounding healthy tissues because of the particular ballistic (Bragg peak) of carbon ions. However, its efficacy is still limited in the most resistant cancers, such as grade III-IV head and neck squamous cell carcinoma (HNSCC), in which the association of carbon ions with gadolinium-based nanoparticles (AGuIX ® ) could be used as a Trojan horse. We report for the first time the radioenhancing effect of AGuIX ® when combined with carbon ion irradiation in human tumor cells. An increase in relative biological effectiveness (1.7) in three HNSCC cell lines (SQ20B, FaDu, and Cal33) was associated with a significant reduction in the radiation dose needed for killing cells. Radiosensitization goes through a higher number of unrepaired DNA double-strand breaks. These results underline the strong potential of AGuIX ® in sensitizing aggressive tumors to hadrontherapy and, therefore, improving local control while lowering acute/late toxicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Gadolinium based nanoparticles (GBNs, diameter 2.9±0.2nm), have promising biodistribution properties for theranostic use in-vivo. We aimed at demonstrating the radiosensitizing effect of these GBNs in experimental radioresistant human head and neck squamous cell carcinoma (SQ20B, FaDu and Cal33 cell lines). Combining 0.6mM GBNs with 250kV photon irradiation significantly decreased SQ20B cell survival, associated with an increase in non-reparable DNA double-strand breaks, the shortening of G2/M phase blockage, and the inhibition of cell proliferation, each contributing to the commitment of late apoptosis. Similarly, radiation resistance was overcome for SQ20B stem-like cells, as well as for FaDu and Cal33 cell lines. Using a SQ20B tumor-bearing mouse model, combination of GBNs with 10Gy irradiation significantly delayed tumor growth with an increase in late apoptosis and a decrease in cell proliferation. These results suggest that GBNs could be envisioned as adjuvant to radiotherapy for HNSCC tumors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Gadolinium-based nanoparticles are novel objects with interesting physical properties, allowing their use for diagnostic and therapeutic applications. Gadolinium-based nanoparticles were imaged following intravenous injection in healthy rats and rats grafted with 9L gliosarcoma tumors using magnetic resonance imaging and scintigraphic imaging. Quantitative biodistribution using gamma-counting of each sampled organ confirmed that these nanoparticles were rapidly cleared essentially by renal excretion. Accumulation of these nanoparticles in 9L gliosarcoma tumors implanted in the rat brain was quantitated. This passive and long-duration accumulation of gadolinium-based nanoparticles in tumor, which is related to disruption of the blood-brain barrier, is in good agreement with the use of these nanoparticles as radiosensitizers for brain tumors.

Ultrasmall gadolinium based particles have been functionalized with positively charged pyridinium quaternary ammonium and labelled with (111)In. Evidence of their active targeting properties towards proteoglycans has been demonstrated in vivo after intravenous injection into rats opening thus a route to cancer imaging and therapy.

Small Rigid Platforms (SRPs) are sub-5 nanometre gadolinium based nanoparticles that have been developed for multimodal imaging and theranostic applications. They are composed of a polysiloxane network surrounded by gadolinium chelates. A covalent coupling with quinoxaline derivatives has been performed. Such derivatives have proven their affinity for melanin frequently expressed in primary melanoma cases. Three different quinoxaline derivatives have been synthesised and coupled to the nanoparticles. The affinity of the grafted nanoparticles for melanin has then been shown in vitro by surface plasmon resonance on a homemade melanin grafted gold chip.

Ultrasmall gadolinium-based nanoparticles (GBNs) induce both a positive contrast for magnetic resonance imaging and a radiosentizing effect. The exploitation of these characteristics leads to a greater increase in lifespan of rats bearing brain tumors since the radiosensitizing effect of GBNs can be activated by X-ray microbeams when the gadolinium content is, at the same time, sufficiently high in the tumor and low in the surrounding healthy tissue. GBNs exhibit therefore an interesting potential for image-guided radiotherapy.

Nanometric hybrid gadolinium oxide particles (Gado-6Si-NP) for diagnostic and therapeutic applications (mean diameter 3-4 nm) were obtained by encapsulating Gd(2)O(3) cores within a polysiloxane shell, which carries organic fluorophore (Cy 5) and is derivatized by a hydrophilic carboxylic layer. As residency time in the living body and methods of waste elimination are crucial to defining a good nanoparticle candidate and moving forward with steps for validation, this study was aimed at evaluating the biodistribution of these multimodal Gado-6Si-NP in rodents. Gado-6Si-NP were imaged following intravenous injection in control Wistar rats and mice using MRI (7 T), optical fluorescent imaging, and SPECT. A clear correlation was observed among MRI, optical imaging, and SPECT regarding the renal elimination. Quantitative biodistribution using gamma-counting of each sampled organ confirmed that these nanoparticles circulated freely in the blood pool and were rapidly cleared by renal excretion without accumulation in liver and RES uptake. These results demonstrate that Gado-6Si-NP display optimal biodistribution properties, enabling them to be developed as multimodal agents for in vivo imaging and theragnostics, especially in oncological applications.

Functionalized gold nanoparticles were applied as contrast agents for both in vivo X-ray and magnetic resonance imaging. These particles were obtained by encapsulating gold cores within a multilayered organic shell which is composed of gadolinium chelates bound to each other through disulfide bonds. The contrast enhancement in MRI stems from the presence of gadolinium ions which are entrapped in the organic shell, whereas the gold core provides a strong X-ray absorption. This study revealed that these particles suited for dual modality imaging freely circulate in the blood vessels without undesirable accumulation in the lungs, spleen, and liver.

Luminescent hybrid nanoparticles with a paramagnetic Gd2O3 core were applied as contrast agents for both in vivo fluorescence and magnetic resonance imaging. These hybrid particles were obtained by encapsulating Gd2O3 cores within a polysiloxane shell which carries organic fluorophores and carboxylated PEG covalently tethered to the inorganic network. Longitudinal proton relaxivities of these particles are higher than the positive contrast agents like Gd-DOTA which are commonly used for clinical magnetic resonance imaging. Moreover these particles can be followed up by fluorescence imaging. This study revealed that these particles suited for dual modality imaging freely circulate in the blood vessels without undesirable accumulation in lungs and liver.

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.

Hadrontherapy presents the major advantage of improving tumor sterilization while sparing surrounding healthy tissues because of the particular ballistic (Bragg peak) of carbon ions. However, its efficacy is still limited in the most resistant cancers, such as grade III-IV head and neck squamous cell carcinoma (HNSCC), in which the association of carbon ions with gadolinium-based nanoparticles (AGuIX ® ) could be used as a Trojan horse. We report for the first time the radioenhancing effect of AGuIX ® when combined with carbon ion irradiation in human tumor cells. An increase in relative biological effectiveness (1.7) in three HNSCC cell lines (SQ20B, FaDu, and Cal33) was associated with a significant reduction in the radiation dose needed for killing cells. Radiosensitization goes through a higher number of unrepaired DNA double-strand breaks. These results underline the strong potential of AGuIX ® in sensitizing aggressive tumors to hadrontherapy and, therefore, improving local control while lowering acute/late toxicity. [ABSTRACT FROM AUTHOR]

Gadolinium based nanoparticles (GBNs, diameter 2.9 ± 0.2 nm), have promising biodistribution properties for theranostic use in-vivo. We aimed at demonstrating the radiosensitizing effect of these GBNs in experimental radioresistant human head and neck squamous cell carcinoma (SQ20B, FaDu and Cal33 cell lines). Combining 0.6 mM GBNs with 250 kV photon irradiation significantly decreased SQ20B cell survival, associated with an increase in non-reparable DNA double-strand breaks, the shortening of G2/M phase blockage, and the inhibition of cell proliferation, each contributing to the commitment of late apoptosis. Similarly, radiation resistance was overcome for SQ20B stem-like cells, as well as for FaDu and Cal33 cell lines. Using a SQ20B tumor-bearing mouse model, combination of GBNs with 10 Gy irradiation significantly delayed tumor growth with an increase in late apoptosis and a decrease in cell proliferation. These results suggest that GBNs could be envisioned as adjuvant to radiotherapy for HNSCC tumors. From the Clinical Editor Gadolinium-based nanoparticles are studied as radiosensitizing theranostic agents to address head and neck squamous cell carcinoma in this novel study, demonstrating a promising adjuvant to radiotherapy for these often treatment resistant tumors. [ABSTRACT FROM AUTHOR]

This work takes place in the “cartilage targeting strategy”, consisting in using the quaternary ammonium (QA) function as a vector to proteoglycans (PGs) of extracellular matrix (ECM). The objective was to demonstrate that QA could address gadolinium based small rigid platforms (SRP) to PG-rich tumors. SRP were functionalized with QA, radiolabeled with 111 Indium and evaluated for biodistribution in vivo , respectively to non functionalized SRP, in two experimental models: (i) the HEMCSS human xenograft model; (ii) the Swarm rat chondrosarcoma (SRC) orthotopic model. The contribution of cellular uptake to tumoral accumulation of nano-objects was also determined from in vitro binding. In the SRC model expressing a highly and homogeneously distributed PG content, tumor accumulation and retention of SRP@QA were increased by 40% as compared to non-functionalized SRP. When considering the radiosensitizing potential of gadolinium based SRP, these results provide hopes for the radiobiological approach of highly resistant tumor such as chondrosarcoma. From the Clinical Editor In this study, gadolinium-based complexing DOTA-surfaced small polysiloxane nanoparticles were functionalized with quaternary ammonium derivatives that target the extracellular matrix of chondrosarcoma. The authors demonstrate in a rat model that the use of these constructs results in a 40% increase of tumor accumulation and retention compared to non-functionalized (and otherwise same) platforms. Similar approaches would be welcome additions to the clinical armamentarium addressing chondrosarcoma. [ABSTRACT FROM AUTHOR]

Background: Gadolinium nanoparticles (Gd-NP) combined with radiotherapy are investigated for radiation dose enhancement in radiotherapy treatment. Indeed, NPs concentrated in a tumor could enhance its radiosensitization. The noninvasive quantification of the NP concentration is a crucial task for radiotherapy treatment planning and post-treatment monitoring as it will determine the absorbed dose. In this work, we evaluate the achievable accuracy of in vivo SPECT-based Gd-NP organ concentration on rats. Methods: Gd-NPs were labeled with 111In radionuclide. SPECT images have been acquired on phantom and rats, with various Gd-NP injections. Images have been calibrated and corrected for attenuation, scatter, and partial volume effect. Image-based estimations were compared to both inductively coupled plasma mass spectrometer (ICP-MS) for Gd concentration and ex vivo organ activity measured by gamma counter. Results: The accuracy for the Gd mass measurements in organ was within 10% for activity above 2 MBq or concentrations above ∼ 3–4 MBq/mL. The Gd mass calculation is based on In-Gd coefficient which defines the Gd detection limit. It was found to be in a range from 2 mg/MBq to 2 µg/MBq depending on the proportions of initial injection preparations. Measurement was also impaired by free Gd and 111In formed during metabolic processes. Conclusions: Even if SPECT image quantification remains challenging mostly due to partial volume effect, this study shows that it has potential for the Gd mass measurements in organ. The main limitation of the method is its indirectness, and a special care should be taken if the organ of interest could be influenced by different clearance rate of free Gd and 111In formed by metabolic processes. We also discuss the practical aspects, potential, and limitations of Gd-NP in vivo image quantification with a SPECT. [ABSTRACT FROM AUTHOR]