Multiparametric investigation of non functionalized-AGuIX nanoparticles in 3D human airway epithelium models demonstrates preferential targeting of tumor cells

Abstract

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.

Recent Progress and Trends in X-ray-Induced Photodynamic Therapy with Low Radiation Doses

“…For example, two RT sensitizers based on nanomaterials have been promoted to clinical trials, including the commercial product of NBTXR3 (Hensify) that was developed by Nanobiotix based on 50 nm-sized hafnium oxide nanoparticles and has recently been approved by European Medicines Agency (EMA) in trending adult soft tissue sarcoma, ,− and 15 other clinical trials underway. Meanwhile, the nanodrug of AGuIX developed by NH TherAguix based on a Gd-based nanoparticle has also entered a human phase 2 clinical trial on brain metastases, , as well as several phase 2 trials in nonsmall cell lung cancer, etc . Therefore, these successful works in RT present positive examples of nanomaterials to facilitate the clinical translation of X-PDT.…”

“…It could be inferred that the nanomaterials composed of heavy metals of Gd and Hf should be suitable candidates to move to clinical trials, while the rest should be further evaluated until the biocompatibility and safety are fully estimated. The leading reasons for Hf- or Gd-based nanomaterials for use as radiosensitizers are their strong interaction with X-rays and low cytotoxicity. ,− Other characteristics that the nanomaterials or candidates should maintain for clinical use include rational nanomaterial design (e.g., size smaller than 6 nm for rapid clearance by renal, spherical, or rod shape within 20–150 nm to allow metabolism through liver, neutral and negatively charged surface or biocompatible polymer modification) to guarantee long-term biodistribution, passive or active tumor targeting, sufficient tumor accumulation, microenvironment response, and efficient clearance with minimized toxicity risks. − Notably, the applications of Cu-Cy nanoformulations for X-PDT, gold clustoluminogens for X-PDT (1 Gy), as well as the AGuIX for clinical trials indicate that metal complexes-based nanoformulations contain huge potential. Under such circumstances, we infer that Zr- or Bi-based nanoformulations might be suitable translatable candidates for X-PDT because they both have strong interactions with X-rays and can form diverse types of complexes or ultrasmall nanostructures. , Of note, the preclinical or clinical toxicity should be always evaluated beyond the general hemolysis test, hematoxylin and eosin (H&E) staining or metabolomics, , or the procedures such as genotoxicity testing, carcinogenicity testing, neurotoxicity testing, etc .…”

Air−Liquid Interface Cultures of the Healthy and Diseased Human Respiratory Tract: Promises, Challenges, and Future Directions

“…[ 182 ] Hence, these models are widely used for toxicology studies, drug efficacy, and formulation screening ( Figure 3 ). [ 183–186 ]…”

“…Subsequently, this model has been used in a variety of other studies including specific tumor targeting and multiorgan chips. [ 195,196 ]…”