Olivier Tillement

Claude Bernard University Lyon 1 | UCBL

Background: The introduction of magnetic resonance (MR)-guided radiation treatment planning has opened a new space for theranostic nanoparticles to reduce acute toxicity while improving local control. In this work, second-generation AGuIX ® nanoparticles (AGuIX-Bi) are synthesized and validated. AGuIX-Bi are shown to maintain MR positive contrast w...

Loosely bound iron, due to its contribution to oxidative stress and inflammation, has become an important therapeutic target for many diseases. A water-soluble chitosan-based polymer exhibiting both antioxidant and chelating properties due to the dual functionalization with DOTAGA and DFO has been developed to extract this iron therefore preventing...

Ultrasmall nanoparticles (USNs) (nanoparticles with hydrodynamic diameter <10 nm) are being widely developed pre‐clinically and started to emerge in clinical trials over the last decade. Most of these USNs display the same features including short retention time in the blood, rapid renal clearance, and relie on passive targeting strategy to reach t...

Clinical trials incorporating metallic nanoparticles (NPs) have recently begun. Radiotherapy planning does not take into account NPs concentrations observed in the patients' target volumes. In the framework of the NANOCOL clinical trial including patients treated for locally advanced cervical cancers, this study proposes a complete method to evalua...

Rose Bengal is a well-known photosensitizer used in the treatment of several diseases [1, 2]. This photosensitizer produces a large amount of singlet oxygen upon specific illumination, which allows its use in photodynamic therapy [3]. The work to be presented highlights the passive tumor targeting by coupling Rose Bengal to nanoparticles in clinica...

Heavy metals present a threat to human health, even at minimal concentrations within the body. One source of exposure is due to the consumption of low-level contaminated foodstuff and water. Lead and cadmium have been shown to be absorbed by and accumulate within organs like the kidneys and liver, and they have also been associated to many diseases...

Cerenkov-induced photodynamic therapy (CR-PDT) with the use of Gallium-68 (68Ga) as an unsealed radioactive source has been proposed as an alternative strategy to X-ray-induced photodynamic therapy (X-PDT). This new strategy still aims to produce a photodynamic effect with the use of nanoparticles, namely, AGuIX. Recently, we replaced Gd from the A...

Purpose: Chondrosarcomas (CHSs), which represent 20% of primary bone tumors in adults, are mostly resistant to radio- and chemotherapy. It is therefore essential that new therapeutic approaches, targeted to the tumour, be developed to improve the prognosis of patients. The effectiveness, as a radiosensitizing agent, of gadolinium oxide nanoparticl...

Glioblastoma is considered the most common malignant primary tumor of central nervous system. In spite of the current standard and multimodal treatment, the prognosis of glioblastoma is poor. For this reason, new therapeutic approaches need to be developed to improve the survival time of the glioblastoma patient. In this study, we performed a precl...

In the frame of radiotherapy treatment of cancer, radioresistance remains a major issue that still needs solutions to be overcome. To effectively improve the radiosensitivity of tumors and reduce the damage of radiation to neighboring normal tissues, radiosensitizers have been given increasing attention in recent years. As nanoparticles based on th...

Avec environ 19,3 millions de nouveaux cas et près de 10,0 millions de décès survenus en 2020, le cancer est l’une des causes majeures de mortalité dans le monde. Le nombre de nouveaux cas ne devrait pas cesser d’augmenter : 47 % de nouveaux cas (28,4 millions) attendus d’ici 2040 [1]. La recherche dans le développement de nouveaux outils de diagno...

Radiotherapy suffers from its high-dose radiation-induced systemic toxicity and radioresistance caused by the immunosuppressive tumor microenvironment. Immunotherapy using checkpoint blocking in solid tumors shows limited anticancer efficacy due to insufficient T-cell infiltration and inadequate systemic immune responses. Activation and guiding of...

In the frame of radiotherapy treatment of cancer, radioresistance remains a major issue that still needs solutions to be overcome. To effectively improve the radiosensitivity of tumors and reduce the damage of radiation to neighboring normal tissues, radiosensitizers have been given increasing attention in recent years. As nanoparticles based on th...

An emerging target to overcome cancer resistance to treatments is copper, which is upregulated in a wide variety of tumors and may be associated with cancer progression and metastases. The aim of this study was to develop a multimodal ultrasmall nanoparticle, CuPRiX, based on the clinical AGuIX nanoparticle made of the polysiloxane matrix on which...

During recent decades, ultrasmall inorganic nanoparticles have attracted considerable interest due to their favorable biodistribution, pharmacokinetics and theranostic properties. In particular, AGuIX nanoparticles made of polysiloxane and gadolinium chelates were successfully translated to the clinics. In an aqueous medium, these nanoparticles are...

Correction for ‘Quantifying nanotherapeutic penetration using a hydrogel-based microsystem as a new 3D in vitro platform’ by Saba Goodarzi et al. , Lab Chip , 2021, 21 , 2495–2510, DOI: 10.1039/D1LC00192B.

X-ray-induced Photodynamic Therapy (X-PDT) is an alternative strategy to improve Photo Dynamic Therapy (PDT) for cancer treatment1 PDT consists in the transfer of light-photon to a photosensitizer which in turn produces singlet oxygen and reactive species. The photo reactions depend mainly on the photosensitizer, light and the presence of molecular...

In this article, we report the conception and the use of dialysis-based medical device for the extraction of metals. The medical device is obtained by addition in the dialysate of a functionalized chitosan that can chelate endogenous metals like iron or copper. This water-soluble functionalized chitosan is obtained after controlled reacetylation an...

Current clinical imaging modalities for the sensitive and specific detection of multiple myeloma (MM) rely on nonspecific imaging contrast agents based on gadolinium chelates for magnetic resonance imaging (MRI) or for ¹⁸F-FDG-directed and combined positron emission tomography (PET) and computed tomography (CT) scans. These tracers are not, however...

Introduction et objectifs Le cancer broncho-pulmonaire demeure un problème de santé publique. Le gold standard du traitement est la chirurgie pouvant être remplacée et/ou associée à de la radiothérapie. La contrainte principale étant les effets délétères de la radiothérapie sur le tissu sain environnant. L’utilisation de nouveaux agents radio-sensi...

The knowledge of the fate of metal-containing nanoparticles in biological media in aqueous media is of utmost importance for the future use of these promising theranostic agents for clinical applications. A methodology based on the combination of TDA-ICP-MS and CE-ICP-MS was applied to study the degradation pathway of AGuIX, a phase 2 clinical ultr...

In this article, we report the conception and the use of dialysis based medical device for extraction of metals. The medical device is obtained by addition in the dialysate of a functionnalized chitosan that can chelate endogenous metals like iron or copper. The water soluble functionnalized chitosan is obtained after controlled reacetylation and a...

AGuIX are emerging radiosensitizing nanoparticles (NPs) for precision radiotherapy (RT) under clinical evaluation (Phase 2). Despite being accompanied by MRI thanks to the presence of gadolinium (Gd) at its surface, more sensitive and quantifiable imaging technique should further leverage the full potential of this technology. In this study, it is...

Anti-cancer therapies (radiotherapy, chemotherapy, etc.) are limited by their significant drawbacks. Today, photodynamic therapy (PDT) represents a real revival and success in the world of cancer therapy. Nevertheless certain limitations remain. One of those limitations is the lack of selectivity of most of the photosensitizers. Our teams have deve...

The huge gap between 2D in vitro assays used for drug screening, and the in vivo 3D-physiological environment hampered reliable predictions for the route and accumulation of nanotherapeutics in vivo....

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 suitabl...

Characterizing nanoparticles (NPs) distribution in multiple and complex metastases is of fundamental relevance for the development of radiological protocols based on NPs administration. In the literature, there have been advances in monitoring NPs in tissues. However, the lack of 3D information is still an issue. X-ray phase-contrast tomography (XP...

X-ray-induced photodynamic therapy is based on the energy transfer from a nanoscintillator to a photosensitizer molecule, whose activation leads to singlet oxygen and radical species generation, triggering cancer cells to cell death. Herein, we synthesized ultra-small nanoparticle chelated with Terbium (Tb) as a nanoscintillator and 5-(4-carboxyphe...

2D cell cultures are commonly used to rapidly evaluate the therapeutic potential of various treatments on living cells. However, the effects of the extracellular matrix (ECM) including the 3D arrangement of cells and the complex physiology of native environment are missing, which makes these models far from in vivo conditions. 3D cell models have e...

Gadolinium-based radiosensitizing AGuIX nanoparticles (AGuIX) currently tested two phase 2 clinical trials in association with radiotherapy for the treatment of brain metastases. Here, excitatory/inhibitory neurotransmission was assessed in rat cortex nerve terminals in the presence of AGuIX and their constituents (DOTAGA and DOTAGA/Gd³⁺) at concen...

Despite progress in therapeutic strategies and understanding of cancer cell biology, there is a large attrition of promising therapeutics into the clinic. One predominant reason is the huge gap between 2D in-vitro assays used for drug screening, and the in-vivo 3D-physiological environment. This is particularly important for a specific category of...

During past decade, special focus has been laid on ultrasmall nanoparticles for nanomedicine and eventual clinical translation. To achieve such translation, a lot of challenges have to be solved. Among them, size determination is a particularly tricky one. In this aim, we have developed a simple hyphenation between Taylor dispersion analysis and in...

Radiotherapy is the main treatment for cancer patients. A major concern in radiotherapy is the radiation resistance of some tumors, such as human nonsmall cell lung cancer. However, the radiation dose delivered to the tumors is often limited by the possibility of collateral damage to surrounding healthy tissues. A new and efficient gadolinium-based...

Smart radiotherapy biomaterials (SRBs) present a new opportunity to enhance image-guided radiotherapy while replacing routinely used inert radiotherapy biomaterials like fiducials. In this study the potential of SRBs loaded with gadolinium-based nanoparticles (GdNPs) is investigated for magnetic resonance imaging (MRI) contrast. GdNP release from S...

Background: Local recurrences of glioblastoma (GBM) after heavy standard treatments remain frequent and lead to a poor prognostic. Major challenges are the infiltrative part of the tumor tissue which is the ultimate cause of recurrence. The therapeutic arsenal faces the difficulty of eradicating this infiltrating part of the tumor tissue while inc...

Tumor targeting studies using metallic nanoparticles (NPs) have shown that the enhanced permeability and retention effect may not be sufficient to deliver the amount of intratumoral and intracellular NPs needed for effective in vivo radiosensitization. This work describes a pH-Low Insertion Peptide (pHLIP) targeted theranostic agent to enable image...

Purpose: This study aims at determining lung distribution of gadolinium-based polysiloxane nanoparticles, AGuIX® (small rigid platform - SRP), as a potential theranostic approach by the pulmonary route. Methods: First, the aerodynamic size distribution and the aerosol output rate were thoroughly characterized. Then, a multimodal approach using m...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Liquid deposit mimicking surface aerosolization in the airway is a promising strategy for targeting bronchopulmonary tumors with reduced doses of nanoparticle (NPs). In mimicking and studying such delivery approaches, the use of human in vitro 3D culture models can bridge the gap between 2D cell culture and small animal investigations. Here, we exp...

Purpose Heavy-metal chelators and inorganic nanoparticles (NPs) have been examined as potential radioenhancers to increase the efficacy of external beam radiation therapy of various cancers. Most of these agents have, unfortunately, displayed relatively poor pharmacokinetic properties, which limit the percentages of injected dose (%ID/g) that local...

The use of radiosensitizing nanoparticles with both imaging and therapeutic properties on the same nano-object is regarded as a major and promising approach to improve the effectiveness of radiotherapy. Here, we report the MRI findings of a phase 1 clinical trial with a single intravenous administration of Gd-based AGuIX nanoparticles, conducted in...

In an acute ischaemic stroke, understanding the dynamics of blood–brain barrier injury is of particular importance for the prevention of symptomatic haemorrhagic transformation. However, the available techniques assessing blood–brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparti...

The gadolinium-based nanoagent named AGuIX® is a unique radiosensitizer and contrast agent which improves the performance of radiotherapy and medical imaging. Currently tested in clinical trials, AGuIX® is administrated to patients via intravenous injection. The presence of nanoparticles in the blood stream may induce harmful effects due to undesir...

Glioblastoma is the most aggressive primary brain tumor leading to death in most of patients. It comprises almost 50–55% of all gliomas with an incidence rate of 2–3 per 100,000. Despite its rarity, overall mortality of glioblastoma is comparable to the most frequent tumors. The current standard treatment combines surgical resection, radiotherapy a...

This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z=22, to Bismuth, Z=83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug del...

Materials with a high atomic number (Z) are shown to cause an increase in the level of cell kill by ionizing radiation when introduced into tumor cells. This study uses in vitro experiments to investigate the differences in radiosensitization between two cell lines (MCF‐7 and U87) and three commercially available nanoparticles (gold, gadolinium, an...

Les nanoparticules (NP) contenant des éléments lourds attirent récemment beaucoup l’attention grâce à leur propriété radio-sensibilisante. Un défi dans ce nouveau domaine est la détermination d’une distribution intratumorale permettant de quantifier les NP au cours du temps. Ceci permet d’optimiser l’irradiation envoyée dans la zone tumorale en min...

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...

Radiation therapy is a mainstay in the therapeutic management of Head and Neck Squamous Cell Carcinoma (HNSCC). Despite significant progress in this field, radioresistance still accounts for most treatment failures. Gadolinium-based nanoparticles (GBNs) have shown great promises as radiosensitizers but the underlying sensitizing mechanism is still...

The authors would like to thank Mexbrain for providing the cerebrospinal fluid.

Low-intensity focused ultrasound (FUS), combined with microbubbles, is able to locally, and noninvasively, open the blood-brain barrier (BBB), allowing nanoparticles to enter the brain. We present here a study on the diffusion process of gadolinium-based MRI contrast agents within the brain extracellular space after ultrasound-induced BBB permeabil...

Effective drug delivery is restricted by pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, poorly-permeable blood vessels limit the intratumoral permeation and penetration of chemo or nanotherapeutic drugs. New and clinically viable strategies are urgently sought to breach the neoplastic barriers that prevent effectiv...

Purpose: The objective of this study is to evaluate the suitability and performance of ultra-short echo time (UTE) sequences for imaging and quantifying the deposition of nebulized MRI contrast agents in human-sized lungs. Methods: Nebulization of clinically used contrast agent or gadolinium-based nanoparticles were performed using a commercial...