Preclinical hazard evaluation strategy for nanomedicines

Abstract

The increasing nanomedicine usage has raised concerns about their possible impact on human health. Present evaluation strategies for nanomaterials rely on a case-by-case hazard assessment. They take into account material properties, biological interactions, and toxicological responses. Authorities have also emphasized that exposure route and intended use should be considered in the safety assessment of nanotherapeutics. In contrast to an individual assessment of nanomaterial hazards, we propose in the present work a novel and unique evaluation strategy designed to uncover potential adverse effects of such materials. We specifically focus on spherical engineered nanoparticles used as parenterally administered nanomedicines. Standardized assay protocols from the US Nanotechnology Characterization Laboratory as well as the EU Nanomedicine Characterisation Laboratory can be used for experimental data generation. We focus on both cellular uptake and intracellular persistence as main indicators for nanoparticle hazard potentials. Based on existing regulatory specifications defined by authorities such as the European Medicines Agency and the United States Food and Drug Administration, we provide a robust framework for application-oriented classification paired with intuitive decision making. The Hazard Evaluation Strategy (HES) for injectable nanoparticles is a three-tiered concept covering physicochemical characterization, nanoparticle (bio)interactions, and hazard assessment. It is cost-effective and can assist in the design and optimization of nanoparticles intended for therapeutic use. Furthermore, this concept is designed to be adaptable for alternative exposure and application scenarios. To the knowledge of the authors, the HES is unique in its methodology based on exclusion criteria. It is the first hazard evaluation strategy designed for nanotherapeutics.

A toxicity profile of the Pheroid® technology in rodents

“…The recently published recommendations by Siegerst and co-workers (2018) were taken into account where a step-by-step evaluation was done on this delivery system [41]. The physicochemical identity (particle size, distribution and endotoxin contamination) was characterized taking into account the constraints of the current drug delivery system with the aim of providing clear parameters for future products for intravenous administration.…”

The regulation of nanomaterials and nanomedicines for clinical application: current and future perspectives

“…44 When developing nanomedicines for clinical use, the mechanism and action of drug delivery requires considerable preclinical safety data before approval, including that of adverse effects. 48 The toxic effects of a high drug dose in the nano form may be that of toxicity of a particular cell or organ (something that may be lethal in patients with chronic kidney disease or diabetes) or the emergence of antibiotic resistance. Additionally, the size of the particles may pose a threat to patients given that they are more mobile than their larger counterparts.…”

Assessing the Safety of Nanomedicines: A Mini Review

“…The hazard evaluation strategy (HES) is a three-tiered concept that covers physiochemical characterization, NP interactions, and hazard assessment, this is adaptable to different exposures and applications. This was designed by Siegrist et al, 68 to test the suitability of injectable engineered NPs (ENPs). Nanomedicines can be very diverse in relation to many factors such as chemical identity, size, geometry, surface modifications, and intended clinical uses.…”

“…This is based on a three-tier approach combining physiochemical characterization, nanoparticle interaction, and hazard assessment. This testing strategy can identify potential safety risks of nanomedicines and can provide the basis for subsequent in vivo studies (modified from Siegrist et al 68 ).…”