AGuIX® from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine

International audienceAGuIX® 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

Pro-organic radical contrast agents (“pro-ORCAs”) for real-time MRI of pro-drug activation in biological systems

Nitroxide-based organic-radical contrast agents (ORCAs) are promising as safe next-generation magnetic resonance imaging (MRI) tools. Nevertheless, stimuli-responsive ORCAs that enable MRI monitoring of prodrug activation have not been reported; such systems could open new avenues for prodrug validation and image-guided drug delivery. Here, we introduce a novel “pro-ORCA” concept that addresses this challenge. By covalent conjugation of nitroxides and drug molecules (doxorubicin, DOX) to the same brush-arm star polymer (BASP) through chemically identical cleavable linkers, we demonstrate that pro-ORCA and prodrug activation, i.e., ORCA and DOX release, leads to significant changes in MRI contrast that correlate with cytotoxicity. This approach is shown to be general for a range of commonly used linker cleavage mechanisms (e.g., photolysis and hydrolysis) and release rates. Pro-ORCAs could find applications as research tools or clinically viable “reporter theranostics” for in vitro and in vivo MRI-correlated prodrug activation

TIRR regulates 53BP1 by masking its histone methyl-lysine binding function

53BP1 is a multi-functional double-strand break (DSB) repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumors to PARP inhibitors. Central to all 53BP1 activities is its recruitment to DSBs via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, TIRR (Tudor Interacting Repair Regulator) that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, ATM phosphorylates 53BP1 and recruits RIF1 to dissociate the 53BP1–TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to DSBs. Depletion of TIRR destabilizes 53BP1 in the nuclear soluble fraction and also alters the DSB-induced protein complex centering 53BP1. These findings identify TIRR as a new factor that influences DSB repair utilizing a unique mechanism of masking the histone methyl-lysine binding function of 53BP1

Clinically Translatable Transcrocetin Delivery Platform for Correction of Tumor Hypoxia and Enhancement of Radiation Therapy Effects

Improving the tumor reoxygenation to sensitize the tumor to radiation therapy is a cornerstone in radiation oncology. Here, the pre‐clinical development of a clinically transferable liposomal formulation encapsulating trans sodium crocetinate (NP TSC) is reported to improve oxygen diffusion through the tumor environment. Early pharmacokinetic analysis of the clinical trial of this molecule performed on 37 patients orient to define the optimal fixed dosage to use in a triple‐negative breast cancer model to validate the therapeutic combination of radiation therapy and NP TSC. Notably, it is reported that this formulation is non‐toxic in both humans and mice at the defined fixed concentration, provides a normalization of the tumor vasculature within 72 h window after systemic injection, leads to a transient increase (50% improvement) in the tumor oxygenation, and significantly improves the efficacy of both mono‐fractionated and fractionated radiation therapy treatment. Together, these findings support the introduction of a first‐in‐class therapeutic construct capable of tumor‐specific reoxygenation without associated toxicities

Nanoparticle Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy

More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies

Antibody-targeting of ultra-small nanoparticles enhances imaging sensitivity and enables longitudinal tracking of multiple myeloma

Monitoring malignant progression and disease recurrence post-therapy are central challenges to improving the outcomes of patients with multiple myeloma (MM). Whereas current detection methods that rely upon bone marrow examination allow for precise monitoring of minimal residual disease and can help to elucidate clonal evolution, they do not take into account the spatial heterogeneity of the tumor microenvironment. As such, they are uninformative as to the localization of malignant plasma cells and may lead to false negative results. With respect to the latter challenge, clinically-available imaging agents are neither sufficiently sensitive nor specific enough to detect minute plasma cell populations. Here, we sought to explore methods by which to improve detection of MM cells within their natural bone marrow environment, using whole-animal magnetic resonance imaging to longitudinally monitor early-stage disease as well as to enhance tumor detection after systemic therapy. We conducted a proof-of-concept study to demonstrate that ultra-small

Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein

Dynamic protein interaction networks such as DNA double-strand break (DSB) signaling are modulated by post-translational modifications. The DNA repair factor 53BP1 is a rare example of a protein whose post-translational modification-binding function can be switched on and off. 53BP1 is recruited to DSBs by recognizing histone lysine methylation within chromatin, an activity directly inhibited by the 53BP1-binding protein TIRR. X-ray crystal structures of TIRR and a designer protein bound to 53BP1 now reveal a unique regulatory mechanism in which an intricate binding area centered on an essential TIRR arginine residue blocks the methylated-chromatin-binding surface of 53BP1. A 53BP1 separation-of-function mutation that abolishes TIRR-mediated regulation in cells renders 53BP1 hyperactive in response to DSBs, highlighting the key inhibitory function of TIRR. This 53BP1 inhibition is relieved by TIRR-interacting RNA molecules, providing proof-of-principle of RNA-triggered 53BP1 recruitment to DSBs

The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma

The development of sensitive and non-invasive ‘‘liquid biopsies’’ presents new opportunities for longitudinal monitoring of tumor dissemination and clonal evolution. The number of circulating tumor cells (CTCs) is prognostic in multiple myeloma (MM), but there is little information on their genetic features. Here, we have analyzed the genomic landscape of CTCs from 29 MM patients, including eight cases with matched/paired bone marrow (BM) tumor cells. Our results show that 100% of clonal mutations in patient BM were detected in CTCs and that 99% of clonal mutations in CTCs were present in BM MM. These include typical driver mutations in MM such as in KRAS, NRAS, or BRAF. These data suggest that BM and CTC samples have similar clonal structures, as discordances between the two were restricted to subclonal mutations. Accordingly, our results pave the way for potentially less invasive mutation screening of MM patients through characterization of CTCs

AGuIX, a theranostic nanoparticle to improve image-guided radiation therapy : a proof ofconcept in pancreatic cancer

L'efficacité des nanoparticules AGuIX a été démontré avec des irradiations précliniques ou monoénergétiques pour les cancers du cerveau, tête et cou, et poumon. L'irradiation préclinique de faible énergie (220 kV), et l'irradiation clinique (6 MV) sont adaptées pour activer les nanoparticules. L'effet radiosensibilisant des nanoparticules métalliques étant principalement causé par effet photoélectrique, il est nécessaire d'utiliser des photons d'énergie proche de la raie K du gadolinium (50.2 keV) afin de créer une interaction avec les électrons de l'atome dans le but d'amplifier localement la dose autour des nanoparticules aboutissant à des effets biologiques menant à une augmentation de la mort cellulaire. Dans le cadre de cette thèse, nous avons réalisé une preuve de concept sur le cancer du pancréas, connu pour son faible taux de survie, avec machines précliniques et cliniques. Afin de relever le défi du passage en clinique, nous avons proposé une méthode pour créer un adoucissement du faisceau d'irradiation et démontré la possibilité d'utiliser les nanoparticles AGuIX pour un essai clinique. Les travaux de recherche ont été réalisés en trois temps : un calcul analytique permettant d'obtenir une information sur l'influence des différents paramètres d'irradiation, une confirmation de l'efficacité des nanoparticules avec faisceaux précliniques, et enfin une preuve de concept avec faisceaux cliniques. Notre étude avec faisceaux cliniques est la première étude réalisée démontrant l'efficacité de nanoparticules de gadolinium passivement ciblées vers la tumeur, et démontre qu'il est possible d'obtenir des résultats cliniques similaires à ceux obtenus en précliniquePrevious studies demonstrated AGuIX ability to act as an efficient radiosensitizer under the presence of preclinical radiations or monoenergetic radiation beams for multiple cancer models. The preclinical irradiation (220 kV) has been shown effective in activating high atomic number (Z) nanoparticles. The energy peak is close to the k-edge of the different high-Z elements used (50.2 keV for the gadolinium), leading to a strong photoelectric effect. Auger electrons generation and biological effects occur afterwards creating a local dose enhancement. However, clinical treatments use a higher energy beam (>6 MV). At these energy ranges, the photoelectric probability is less important, decreasing the direct interaction of the nanoparticles with the incoming photons. We performed a proof of concept on a pancreatic tumor model, known for its low survival rates, with preclinical and clinical radiation beams to evaluate the efficacy of the AGuIX. To increase the efficacy of the clinical radiation beam without modifying the nanoparticle structure in order to obtain a dose enhancement close to the one observed with the preclinical beam, we evaluated key clinical beam parameters to understand and increase the mechanisms of interaction between the incident photons and the high-Z nanoparticles. Hence, we evaluated analytically the impact of the radiation beam under different conditions of irradiation, confirming the potential of the AGuIX with a preclinical beam, and finally shown their significant efficacy under a clinical setup. This study is the first to evaluate the potential of a high-Z nanoparticle to act as radiosensitizer following low dose intravenous injection

AGuIX, une nanoparticule théranostique pour améliorer la radiothérapie guidée par l’image : preuve de concept appliquée au cancer du pancréas

Previous studies demonstrated AGuIX ability to act as an efficient radiosensitizer under the presence of preclinical radiations or monoenergetic radiation beams for multiple cancer models. The preclinical irradiation (220 kV) has been shown effective in activating high atomic number (Z) nanoparticles. The energy peak is close to the k-edge of the different high-Z elements used (50.2 keV for the gadolinium), leading to a strong photoelectric effect. Auger electrons generation and biological effects occur afterwards creating a local dose enhancement. However, clinical treatments use a higher energy beam (>6 MV). At these energy ranges, the photoelectric probability is less important, decreasing the direct interaction of the nanoparticles with the incoming photons. We performed a proof of concept on a pancreatic tumor model, known for its low survival rates, with preclinical and clinical radiation beams to evaluate the efficacy of the AGuIX. To increase the efficacy of the clinical radiation beam without modifying the nanoparticle structure in order to obtain a dose enhancement close to the one observed with the preclinical beam, we evaluated key clinical beam parameters to understand and increase the mechanisms of interaction between the incident photons and the high-Z nanoparticles. Hence, we evaluated analytically the impact of the radiation beam under different conditions of irradiation, confirming the potential of the AGuIX with a preclinical beam, and finally shown their significant efficacy under a clinical setup. This study is the first to evaluate the potential of a high-Z nanoparticle to act as radiosensitizer following low dose intravenous injectionsL'efficacité des nanoparticules AGuIX a été démontré avec des irradiations précliniques ou monoénergétiques pour les cancers du cerveau, tête et cou, et poumon. L'irradiation préclinique de faible énergie (220 kV), et l'irradiation clinique (6 MV) sont adaptées pour activer les nanoparticules. L'effet radiosensibilisant des nanoparticules métalliques étant principalement causé par effet photoélectrique, il est nécessaire d'utiliser des photons d'énergie proche de la raie K du gadolinium (50.2 keV) afin de créer une interaction avec les électrons de l'atome dans le but d'amplifier localement la dose autour des nanoparticules aboutissant à des effets biologiques menant à une augmentation de la mort cellulaire. Dans le cadre de cette thèse, nous avons réalisé une preuve de concept sur le cancer du pancréas, connu pour son faible taux de survie, avec machines précliniques et cliniques. Afin de relever le défi du passage en clinique, nous avons proposé une méthode pour créer un adoucissement du faisceau d'irradiation et démontré la possibilité d'utiliser les nanoparticles AGuIX pour un essai clinique. Les travaux de recherche ont été réalisés en trois temps : un calcul analytique permettant d'obtenir une information sur l'influence des différents paramètres d'irradiation, une confirmation de l'efficacité des nanoparticules avec faisceaux précliniques, et enfin une preuve de concept avec faisceaux cliniques. Notre étude avec faisceaux cliniques est la première étude réalisée démontrant l'efficacité de nanoparticules de gadolinium passivement ciblées vers la tumeur, et démontre qu'il est possible d'obtenir des résultats cliniques similaires à ceux obtenus en précliniqu