Ratiometric nanothermometer in vivo based on triplet-sensitized upconversion

Ratiometric nanothermometer in vivo based on triplet-sensitized upconversion

Though luminescence imaging is a promising approach for contactless thermometry in vivo, the low thermal sensitivity of existing thermometers limits its potential. Here, we develop a high-sensitivity ratiometric nanothermometer based on triplet-sensitized upconversion.

Temperature is a fundamental parameter, and accurate temperature sensing is very important for the widespread scientific researches. Particularly, temperature is an essential factor that counts for living system where complicated vital activities are usually temperature dependent. In vivo temperature mapping based on non-contact optical approach will benefit for revealing the physiological phenomena behind with minimized influence to the organism. For the endotherms, the temperature changes slightly in a specific area due to thermoregulation mechanism in biology, however, the temperature varies in different regions of the body. To be qualified for the mapping of overall body temperature variations, the luminescent thermometer should be very sensitive over a wide physiological temperature range. Eventhough recently some sensitive temperature probes have been widely developed, most of them are actually not appropriate for thermometry in vivo, which mainly due to the biological incompatibility and the inevitable background noise resulted from excitation light of high-energy photons. Therefore, a highly sensitive thermometer capable of monitoring the slight temperature variation in vivo is still urgently needed.

Upconversion based on anti-Stokes process that can avoid auto-fluorescence of biological systems, is a promising technique for the development of thermometer in vivo. However, the lanthanide-doped upconversion nanophosphors (UCNPs) generally showed moderate thermal sensitivity and resolution, as well as poor luminescence efficiency. As the most effective anti-Stokes process, upconversion based on triplet-triplet annihilation (TTA) is potentially thermosensitive. Because TTA-upconversion involves multiple energy transfer in the component annihilator & sensitizer dyad, which requires the temperature-sensitive diffusion factor. Nevertheless, the example of thermometer in vivo based on TTA-upconversion technique has not been reported, which is hampered by significant challenges such as irregular temperature response or low thermal sensitivity in the physiological circumstance, and serious concentration dependence.

To address the issues, we have made several pivotal upgrades to TTA system, the deactivation suppression and ratiometric calibration for instance. Notably, diffusion enhancement at higher temperature is a positive factor for the TTA-upconversion process, while thermal deactivation is a negative factor. The competitive effect between deactivation and diffusion factors would probably result in irregular thermal responses of the TTA system. We took a simple but effective strategy to mitigate thermal deactivation effect, which was equivalent to the amplification of positive diffusion effect. The design pushed the limit of thermosensitive TTA system where phase transition or polymer-chain softening was generally required to enhance the diffusion effect. For the TTA dyad directly in liquid solvent, a sharp and continuous enhancement of TTA-upconversion luminescence was achieved over the physiological temperature range. In order to minimize influence from biological environment and to enable concentration-independent output of indicating signals, the TTA dyad was encapsulated with a thermal-insensitive reference to construct a ratiometric nanothermometer with state-of-the-art sensitivity for thermometry in vivo.

The ratiometric nanothermometer could accurately detect the slight temperature changes in living mice caused by surrounding temperature variation and internal inflammation reaction. We hope this work can enrich the applications of upconversion materials, especially for nanomedicine and life science.

For more detail, please go to https://www.nature.com/articles/s41467-018-05160-1.

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