Toward Clinical Transfer of Tumor-Targeted Ultrasmall Inorganic Nanoparticles

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 the tumor. Through this review, the development of AGuIX USNs is focused on because of their clinical usages as passively targeted USN but also because of their possible biofunctionalizations with peptides and monoclonal antibodies which are validated in various pre-clinical tumor models. As a result, the authors reviewed all the current biofunctionalization strategies that can be employed and confirmed based on a meta-analysis of the literature that biofunctionalized USNs pharmacokinetic and biodistribution profiles are dictated by the USNs and not the active targeting moiety. Additionally, it is demonstrated that such active targeting strategy improves the tumor targeting efficiency of the AGuIX USN but also increases their tumor retention time in comparison to the passively targeted AGuIX USNs, which may lead to an opportunity to reduce the number of injections/expend the therapeutic benefit of the drug product.