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.
Gadolinium based Small Rigid Plaforms (SRPs) have previously demonstrated their efficiency for multimodal imaging and radiosensitization. Since the RGD sequence is well-known to be highly selective for αvβ3 integrins, a cyclic pentapeptide containing the RGD motif (cRGDfK) has been grafted onto the SRP surface. An appropriate protocol led to the grafting of two targeting ligands per nano-object. The resulting nanoparticles have demonstrated a strong association with αvβ3 integrins in comparison with cRADfK grafted SRPs as negative control. Flow cytometry and fluorescence microscopy have also been used to highlight the ability of the nanoparticles to target efficiently HEK293(β3) and U87MG cells. Finally the grafted radiosensitizing nanoparticles were intravenously injected into Nude mice bearing subcutaneous U87MG tumors and the signal observed by optical imaging was twice as high for SRP-cRGDfK compared to their negative analogue.
In acute ischemic stroke, understanding the dynamics of blood–brain barrier injury is of particular importance for the prevention of symptomatic hemorrhagic transformation. However, the available techniques assessing blood–brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparticles cross the healthy or impaired blood–brain barrier through combined passive and active processes. Imaging and quantifying their transfer rate could better characterize blood–brain barrier damage and refine the delivery of neuroprotective agents.
We previously developed an original endovascular stroke model of acute ischemic stroke treated by mechanical thrombectomy followed by positron emission tomography-magnetic resonance imaging. Cerebral capillary permeability was quantified for two molecule sizes: small clinical gadolinium Gd-DOTA (< 1 nm), and AGuIX® nanoparticles (∼5 nm) used for brain theranostics.
On dynamic contrast-enhanced MRI, the baseline transfer constant Ktrans was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] x10−3 min−1, respectively, in normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] x10−3 min−1 in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, Ktrans for both Gd-DOTA and AGuIX® nanoparticles was significantly higher within the ischemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] x10−3 min−1 for Gd-DOTA and AGuIX® nanoparticles, respectively. With AGuIX® nanoparticles, Ktrans also increased within the ischemic growth areas, suggesting added value for AGuIX®. Finally, Ktrans was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A, n = 7) compared to placebo (n = 5).
Ktrans quantification with AGuIX® nanoparticles can monitor early blood–brain barrier damage and treatment effect in ischemic stroke after reperfusion.
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....
A novel and simple route to synthesize ultrasmall silica nanoparticles having hydrodynamic diameters under 10 nm for imaging and therapeutic applications.
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 exposed airway epithelia to liquid-apical gadolinium-based AGuIX® NPs in order to determine their safety profile. We used a multiparametric methodology to investigate the NP’s distribution over time in both healthy and tumor-bearing 3D models. AGuIX® NPs were able to target tumor cells in the absence of specific surface functionalization, without evidence of toxicity. Finally, we validated the therapeutic potential of this hybrid theranostic AGuIX® NPs upon radiation exposure in this model. In conclusion, 3D cell cultures can efficiently mimic the normal and tumor-bearing airway epitheliums, providing an ethical and accessible model for the investigation of nebulized NPs.
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.
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 emerging therapeutics: nanoparticles. The lack of physiological context hampered reliable predictions for the route and accumulation of those nanoparticles in-vivo. For such nanotherapeutics, Multi-Cellular Tumour Spheroids (MCTS) is emerging as a good alternative in-vitro model. However, the classical approaches to produce MCTS suffer from low yield, poor reproducibility and slow process, while spheroid-on-chip set-ups developed so far require a microfluidic practical knowledge difficult to transfer to a cell biology laboratory.We present here a simple yet highly flexible 3D-model microsystem consisting of agarose-based micro-wells. Fully compatible with the multi-well plates format conventionally used in cell biology, our simple process enables the formation of hundreds of reproducible spheroids in a single pipetting. It is compatible with live high-resolution optical microscopy and provides a user-friendly platform for in-situ immunostaining.As a proof-of-principle of the relevance of such in-vitro platform for the evaluation of nanoparticles, the aim of this study was to analyse the kinetic and localization of nanoparticles within colorectal cancer cells (HCT-116) MCTS. The nanoparticles chosen are sub-5 nm ultrasmall nanoparticles made of polysiloxane and gadolinium chelates that can be visualized in MRI and confocal microscopy (AGuIX®, currently implicated in clinical trials as effective radiosensitizers for radiotherapy). We show that the amount of AGuIX® nanoparticles within cells is largely different in 2D and 3D. Using our flexible agarose-based microsystems, we are able to resolve spatially and temporally the penetration and distribution of AGuIX® nanoparticles within tumour spheroids. The nanoparticles are first found in both extracellular and intracellular space of spheroids, within lysosomes compartment. While the extracellular part is washed away after few days, we evidenced trafficking of AGuIX® nanoparticles that are also found within mitochondria. Our agarose-based microsystem appears hence as a promising 3D in-vitro platform for investigation of nanotherapeutics transport, ahead of in-vivo studies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.