Accurate In Vivo Nanothermometry through NIR‐II Lanthanide Luminescence Lifetime

Abstract

importance to unravel the complexity of these systems and to impact a multitude of technological applications ranging from integrated photonic devices to precise medicine. [1-3] Thermocouples and thermistors dominate the market but are inappropriate to probe temperature in live biological systems as physical contact with measured samples is a prerequisite, which disturbs the measurements at sub-millimeter scales. [4] Alternatively, luminescence nanothermometry is emerging as a noninvasive spectroscopic method that allow to probe temperature variation at nanometric spatial resolution and in remote distance, spurring wide interests. [5,6] The contactless and high-resolution nature makes them ideal candidates for temperature evaluation in the early diagnosis of several diseases as well as for providing real-time temperature feedback in thermal (hypothermia or hyperthermia) therapies of malignant cancers. [7-9] Indeed, the potential clinical and preclinical applications fuel a fast development of luminescence nanothermometers particularly for in vivo studies in the nearinfrared (NIR) range. [10] Light in the first biological window (NIR-I, 750-950 nm) or the second biological window (NIR-II, 1000-1700 nm) is known to have minimized scattering and absorption, thus allowing for maximized light Luminescence nanothermometry is promising for noninvasive probing of temperature in biological microenvironment at nanometric spatial resolution. Yet, wavelength-and temperature-dependent absorption and scattering of tissues distort measured spectral profile, rendering conventional luminescence nanothermometers (ratiometric, intensity, band shape, or spectral shift) problematic for in vivo temperature determination. Here, a class of lanthanide-based nanothermometers, which are able to provide precise and reliable temperature readouts at varied tissue depths through NIR-II luminescence lifetime, are described. To achieve this, an inert core/ active shell/inert shell structure of tiny nanoparticles (size, 13.5 nm) is devised, in which thermosensitive lanthanide pairs (ytterbium and neodymium) are spatially confined in the thin middle shell (sodium yttrium fluoride, 1 nm), ensuring being homogenously close to the surrounding environment while protected by the outmost calcium fluoride shell (CaF 2 , ≈2.5 nm) that shields out bioactive milieu interferences. This ternary structure enables the nanothermometers to consistently resolve temperature changes at depths of up to 4 mm in biological tissues, having a high relative temperature sensitivity of 1.4-1.1% °C −1 in the physiological temperature range of 10-64 °C. These lifetime-based thermosensitive nanoprobes allow for in vivo diagnosis of murine inflammation, mapping out the precise temperature distribution profile of nanoprobes-interrogated area.

NIR-II Upconversion Photoluminescence of Er3+ Doped LiYF4 and NaY(Gd)F4 Core-Shell Nanoparticles

“…Liu et al synthesized Er and Ho co-doped NPs with both excitation and emission in the NIR-II window as a sensor for inflammation dynamic detection ( Liu et al, 2018 ). The time-gate imaging technique in the NIR-II window was realized in a NaYF 4 : Yb, Nd@CaF 2 core shell structure with outstanding brightness ( Tan et al, 2020 ). Er 3+ ion is known as an outstanding imaging agent for NIR-II range, since it can be excited around 1550 nm due to the 4 I 15/2 → 4 I 13/2 transition ( Chen et al, 2011 ; Shao et al, 2014 ; Cheng et al, 2018 ).…”

NIR luminescence lifetime nanothermometry based on phonon assisted Yb3+–Nd3+energy transfer

“…As it has been recently demonstrated, the energy transfer relaying on the absorption of phonon could be the appropriate direction to follow 32 . Therefore, in this manuscript a comprehensive and detailed investigation on the thermal dependence of phonon mediated energy transfer between Yb 3+ and Nd 3+ ions is performed in order to develop a highly sensitive luminescent thermometer based on the kinetics of the Yb 3+ ions.…”

“…It needs to be noted that the additional nonradiative quenching processes associated with ligands attached to the nanoparticle surface may reduce the emission intensity and reduce the susceptibility of the Yb 3+ lifetimes to temperature variations. Therefore, as recently proposed the Chen et al32 , the passivation of the nanoparticle surface by optically inactive shell layer may improve the thermometric properties of such thermographic phosphor. Thus the relative sensitivity of 1.4%/K at 283K was achieved for NaYF 4 @NaYF 4 :Yb 3+ ,Nd 3+ @CaF 2[32]…”

“…Therefore, as recently proposed the Chen et al32 , the passivation of the nanoparticle surface by optically inactive shell layer may improve the thermometric properties of such thermographic phosphor. Thus the relative sensitivity of 1.4%/K at 283K was achieved for NaYF 4 @NaYF 4 :Yb 3+ ,Nd 3+ @CaF 2[32]…”

Recent advances in design of lanthanide-containing NIR-II luminescent nanoprobes

“…The inner 4f-4f transitions of these Ln 3+ are insensitive to outer environment due to the effective shielding of 4f orbitals by the filled 5s and 5p orbitals, which results in sharp and tunable emissions with high photostability. As a new generation of NIR-II probes, Ln 3+ -containing nanoparticles (NPs) show great potential for multiplexed sensing, time-gated detection, and high-resolution imaging ( Naczynski et al., 2014 ; Tan et al., 2020 ; Yu et al., 2008 ; Zhang et al., 2015 ; Wang et al., 2017a ; Huang et al., 2015 ).…”