Multifunctional up/down-conversion luminescence of core/shell nanocomposite for self-monitored heating and fluorescence imaging

Highlights

• The C/S-4 were successfully synthesized via a stepwise metal-organic thermolysis process.

• The incompatibility of the DCL and PTT is solved by energy-blocked shells.

• The C/S-4 has potential application on noninvasive cancer therapy and fluorescence imaging.

Abstract

The simultaneous realization of real-time thermal sensing at physiological temperature range and fluorescence imaging during photothermal therapy (PTT) via single-component biocompatible nanocomposite could furthest avoid collateral damage and enhance phototherapeutic effect, which, up to now, is of great interest and still in a formidable challenge. Under near-infrared (NIR) light irradiation, Nd³⁺-doped nanoparticles (NPs) have emerged as candidates with outstanding properties such as down-conversion emissions in biological window (BW) and capable of light-to-heat conversion. However, these two properties associated with Nd³⁺ doping concentrations induce opposite changing trend and difficult to combine within one single nanocomposite. In this work, for breaking through the obstacles, core/shell NaLuF₄:1%Nd@NaLuF₄@NaLuF₄:15%Yb,3%Er@NaLuF₄:15%Yb@NaLuF₄:85%Nd 808 nm light-triggered co-enhancement up/down-conversion luminescence (UCL/DCL) nanocomposite was purposely designed with efficient heating, thermal sensing and fluorescence imaging concurrently. The core emits high quantum yield (QY) DCL in BW while the outermost layer could convert the absorbed photon into thermal energy and also transfer a fraction of energy inwards to internal layer with exciting the UCL (Nd→Yb→Er) for thermal sensing via thermally coupled levels ²H_11/2/⁴S_3/2 of Er using the fluorescence intensity ratio (FIR) method. The simultaneously enhanced UCL/DCL and thermal effect in the engineered nanocomposite are satisfactorily realized due to suppressing the interionic quenching owing to the inert two layers NaLuF₄ and NaLuF₄:15%Yb. Such smart designed nanocomposite has potential application on PTT-based noninvasive cancer therapy.

Introduction

In recent decades, the continuous development of nanotechnology has accelerated the progress in the fields of biomedical research and life science, which results in appearance of novel approaches and new materials for improvement of procedures in fluorescence imaging, diagnosis and therapy. Owing to intrinsic up/down-conversion luminescence (UCL/DCL) and inertness of physical/chemical properties, much scientific effort has been devoted to design, synthesis, characterization and application of lanthanide-activated nanoparticles (LANPs) that could be used as biosensors, biomarkers or phototherapeutic agents (PTAs) [[1], [2], [3], [4], [5]]. Hyperthermia, originated from externally induced temperature increasing and subsequently causing the thermal ablation of cancer cells, is a novel promising and developed noninvasively therapeutic method [6,7]. In general, different forms of energy such as ultrasound waves or microwave could be adopted to interplay with tissues and therefore deliver heat to a lesion. However, because of needing complicated operation steps and/or sophisticated equipment, the use of light (i.e., near-infrared (NIR) laser radiation) as external energy and converting into massive heat via PTAs for photothermal therapy (PTT) is now gained more research attention. In this regard, the real-time and accurate thermal feedback during PTT is extraordinary important to minimize collateral effect due to over/insufficient heating would inevitably cause irreversible damage to those around healthy tissues or ineffectual treatment to cancer cells, respectively [8,9]. In practice, real controlled PTT needs cleverly design of LANPs capable of self-monitored heating.

Typically, irradiation light is prone to be absorbed and/or scattered by living tissues, which decreases its potential application to just superficial organism. This shortcoming of light attenuation could be, to some extent, solved by selecting the light lying in the optical transparency window (biological window (BW)) [10,11]. Light located in NIR of 700–1100 nm not only provides lower autofluorescence and scattering but also enables deeper penetration and cutting down photodamage effect. Although the large absorption cross section of Yb³⁺ at 980 nm can efficiently transfer the absorbed NIR photon energy to codopants such as Ho³⁺, Tm³⁺ and Er³⁺ in LANPs, their real applications as optical nanothermometers (NTHs) or fluorescence imaging agents (FIAs) have been seriously restricted due to the maximum absorption of water in biological tissue is just overlapping with this value and would trigger overheating [8,12,13]. To solve this issue, choosing Nd³⁺ as sensitizer with broad absorption cross section at 808 nm to effectively active Yb³⁺ (Nd → Yb) is a feasible strategy to increase the penetration depth and minimize the laser-induced heating effect. Furthermore, the lower laser-induced damage at 808 nm irradiation with respect to that at 790 nm or other smaller wavelengths makes Nd³⁺-doped NPs more suitable for application at cellular level [14]. Meanwhile, Nd³⁺-doped NPs have relatively broad excitation bandwidth (>10 nm), which could avoid the impact of fluctuation by excitation wavelength (i.e., originated from diode temperature variation) [6,14].

On the other side, the aid of optical nanoprobes as FIAs have obviously promoted the understanding of structural and functional properties of biological system and now is far-reaching affecting on therapeutics and clinical diagnostics [3,10,11,13]. There are several preconditions for FIAs must be met before, which include good photostability, appropriate signal range to minimize light attenuation and photodamage, and high quantum yield (QY). Therefore, the FIAs need to have such optical properties that both excitation and emission signals must locate in the BW. Coincidentally, Nd³⁺-activated NPs are, again, suitable for these requirements via DCL process, due to both excitation and emission (ca. 850–930 nm) are in the BW [10,11]. Meanwhile, regarding the competitive relationship between DCL for FIAs (needs high QY) and PTT (nonradiative process, lower QY), it is top priority to design Nd³⁺-doped NPs with unique structure (i.e., core/shell with different concentrations of Nd in different layers or core), which could simultaneous achieve the co-enhancement of DCL FIAs and PTT effect. Besides, the Nd³⁺-doped NPs, when codoped with other lanthanide ions (i.e., Yb³⁺ and Er³⁺) and sensitized by Nd³⁺ (Nd → Yb → Er), could concurrently achieve the DCL and UCL processes. The energy transfer (ET) acting on Er³⁺ can lead to activation of Er³⁺ from its ground state up to its excited ²H_11/2/⁴S_3/2 thermal coupled levels [[15], [16], [17]], where the thermal sensitive UCL is generated and therefore realizing the real-time temperature sensing.

Accordingly, toward the fulfillment of the goal that developing all-in-one nanoplatform capable of fluorescence imaging, real-time and self-monitored PTT under a single beam 808 nm excitation, a four-layer Nd³⁺, Yb³⁺ and Er³⁺ codoped core/shell nanocomposite NaLuF₄:1%Nd@

NaLuF₄@NaLuF₄:15%Yb,3%Er@NaLuF₄:15%Yb@NaLuF₄:85%Nd (C/S-4) has smart designed and synthesized via a stepwise metal-organic thermolysis process. By reasonably arranging the shell configurations, the incompatibility of the DCL and PTT is solved by energy-blocked shells (#1 and #3), which achieves co-enhancement of fluorescence imaging and PTT effect. Meanwhile, the real-time accurate thermal sensing during PTT could be realized by temperature-sensitive UCL of Er³⁺. The idea of the designed C/S-4 and function of each part are shown in Scheme 1.