against cancer.Published online 2023 Dec 11.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10713951/
Extrait sur nbtxr3:
ROS-generating nanoplatforms towards clinical trial
Prior to clinical use, several points of nanoplatform design need deep investigation and also optimization. Specific pharmacokinetic parameters such as biodistribution and elimination, biocompatibility and residual toxicity need a greater attention compared to what has been know up to nowadays [105]. Other important aspect that needs to be taken into consideration is the huge need to have specific preclinical studies, since normally less than 1% of the NPs administered in a systemic way are able to reach their final target, due to kidney clearance and reticuloendothelial system clearance [106]. Furthermore, tumor architecture possesses an irregular vascular architecture structure that leads to a not homogeneous nanoplatform distribution and therefore treatment. Also, the intrinsic toxicity of materials that are frequently present into these nanoplatforms, to increase the ROS yield, show in vivo toxicities [106]. Although substantial progress has been made in this therapeutic area in recent years to overcome their main limitations and so to close the gap between bench and bedside, with more nanocomposite structures being developed with remarkable results in in vivo animal models, clinical translation remains a critical issue. Indeed, it should be noted that a small number of nanomedicines approved as ROS-based therapies have currently entered clinical trials. The most prominent example is the radio-enhancer NBTXR3 developed from the French company Nanobiotix [107, 108]. NBTXR3 is a hafnium oxide nanoparticle (HaO2 NP) with a high atomic number (Z = 72) which make it an efficient radiosensitizer. Because NBTXR3 is physically and chemically inert in biological medium, it can be used safely in biomedical applications. When NBTXR3 reaches tumor tissues and gets RT, its high electron density increases the likelihood that it will interact with the incoming radiation, causing more energy to be deposited inside the irradiated tissues than RT alone and resulting in tumour cell death. Preclinical research has revealed that using NBTXR3 during RT an excellent antitumor activity can be obtained and may enhance patient outcomes in a variety of cancer types [109, 110]. The phase 1 NBTXR3 clinical trial indicated that combining NBTXR3 with RT was a viable therapy strategy [110–112]. In addition, in a multicenter, randomized, controlled phase II/III clinical trial (NCT02379845), the combination of NBTXR3 with RT resulted in excellent radiological and pathologic responses in patients with locally advanced soft tissue sarcoma [111]. However, although other examples can be reported within the therapeutic area covered by this review (e.g., NCT04559685, NCT04845919), as far as we know this is still the only example of nanomedicine approved for ROS-based cytotoxic therapies [113–115]. By considering the translation of ROS-generating nanoplatforms from pre-clinical models to clinical trials, several issues can be further postulated. Many pre-clinical research on ROS-based cancer therapy focuses on creating animal models, which normally have a perfect therapeutic effect in tumor treatment. However, the understanding of the interactions between the ROS-based nanomedicines and the biological environment in vivo are still suffering of a deep and complete knowledge. Furthermore, significant differences are still present in the organizational structures and biological behaviors between experimental animal models and human physiological environments. Crucial is to specifically investigate the efficacy and safety of ROS-based nanoplatforms before moving to the patients [116]. The nanoplatforms used in laboratory and the one that move to clinical stage, are still produced in a small-scale, characterized by drug stability and reproducibility within different batches. Therefore, the shift to a large-scale production involved an increase in testing costs that can burden pharmaceutical companies and researchers [116].
