Critical Considerations on the Clinical Translation of Upconversion Nanoparticles (UCNPs): Recommendations from the European Upconversion Network (COST Action CM1403)

Abstract

The unique photoluminescent properties of upconversion nanoparticles (UCNPs) have attracted worldwide research interest and inspired many bioanalytical applications. The anti‐Stokes emission with long luminescence lifetimes, narrow and multiple absorption and emission bands, and excellent photostability enable background‐free and multiplexed detection in deep tissues. So far, however, in vitro and in vivo applications of UCNPs are restricted to the laboratory use due to safety concerns. Possible harmful effects may originate from the chemical composition but also from the small size of UCNPs. Potential end users must rely on well‐founded safety data. Thus, a risk to benefit assessment of the envisioned combined therapeutic and diagnostic (“theranostic”) applications is fundamentally important to bridge the translational gap between laboratory and clinics. The COST Action CM1403 “The European Upconversion Network—From the Design of Photon‐Upconverting Nanomaterials to Biomedical Applications” integrates research on UCNPs ranging from fundamental materials synthesis and research, detection instrumentation, biofunctionalization, and bioassay development to toxicity testing. Such an interdisciplinary approach is necessary for a better and safer theranostic use of UCNPs. Here, the status of nanotoxicity research on UCNPs is compared to other nanomaterials, and routes for the translation of UCNPs into clinical applications are delineated.

Designing Stimuli‐Responsive Upconversion Nanoparticles that Exploit the Tumor Microenvironment

“…UCNPs, whose clearance is dependent on their hydrodynamic diameter, can remain in the body for a duration of few days to several weeks. [ 123 ] Additional UCNP aspects need to be addressed for successful clinical translation, including: 1) comprehensive analysis of the physicochemical and biological properties important for clinical theranostics, 2) convenient and validated methods for rapid efficacy, quality and safety (EQS) evaluation of promising UCNPs drugs, and 3) robust infrastructure for efficient clinical translation of UCNP‐based products.…”

Assessing the protective effects of different surface coatings on NaYF4:Yb3+, Er3+ upconverting nanoparticles in buffer and DMEM

“…These properties make them attractive fluorescent reporters for life sciences applications such as bioimaging 9 , 10 , in-vitro and in-vivo detection of biomolecules 11 – 14 , drug delivery 15 , photodynamic therapy 2 , 9 , 10 , 16 , and biosensing 2 , 3 . Utilization in bioimaging and cellular studies requires, however, biocompatible particles that are sufficiently stable in diluted dispersions and have no acute or chronic toxicity under application-relevant conditions 17 – 21 . In the case of UCNP, this implies they should not release potentially toxic constituents such as fluoride and lanthanide ions.…”

“…However, there appeared an increasing number of reports recently on the dissolution of UCNP like NaYF 4 -based materials in aqueous environments under high dilution conditions 14 – 18 , leading to the release of fluoride and lanthanide ions 30 , 39 – 43 . This raised concerns of UCNP biocompatibility and triggered toxicity studies 17 .…”

Highly colloidally stable trimodal 125I-radiolabeled PEG-neridronate-coated upconversion/magnetic bioimaging nanoprobes

“…Lanthanide-based upconversion nanoparticles (UCNPs) have recently attracted extensive scientific interest due to their unique photoluminescence properties [11][12][13][14] . UCNPs are able to upconvert low-energy NIR irradiation into high-energy visible or ultraviolet (UV) light via anti-Stokes emission.…”