Construction of a novel fluorescent nanoenzyme based on lanthanides for tumor theranostics

Abstract

Traditional lanthanide fluorides lack therapeutic efficacy against tumors, thus limiting their applications in biomedicine. In this study, we introduce a groundbreaking lanthanide-based nanomaterial known as ligand-free Ba_1.4Mn_0.6LuF₇: Yb³⁺/Er³⁺/Ho³⁺ (abbreviated as BMLF). This innovative material allows for the simultaneous tuning of upconversion luminescence emissions and Fenton-like reactions through the controlled release of Mn ions within the tumor microenvironment. BMLF exhibits dual functionality through integrating ratiometric fluorescence imaging for diagnosis and nanozyme-based catalytic therapy. These capabilities are successfully harnessed for tumor theranostics in vivo. This research presents a novel approach to leveraging lanthanide fluoride nanomaterials, transforming them into fluorescent nanoenzymes with theranostic potential.

Graphical abstract

Keywords

lanthanide fluoride / fluorescent nanoenzyme / tumor theranostics / controllable release

1 Introduction

Cancer has posed a serious threat to human well-being due to its rising incidence and mortality rates. In recent years, significant strides have been made in tumor theranostics, particularly with the rapid advancement of nanomedicine. Various nanomaterials combining imaging and anti-tumor functionalities have been developed to integrate tumor diagnosis and therapy. Lanthanide fluorides, among the plethora of nanomaterials available, have played a pivotal role in constructing nanocomposite systems for tumor theranostics, thanks to their upconversion luminescence (UCL) imaging capabilities and versatile material surface designs [1–4]. For example, Zhang et al. engineered core–shell nanocomposites by combining NaGdF₄: Tb@NaGdF₄: Ce@NaLuF₄ nanoparticles with Hf-porphyrin metal‒organic frameworks for photodynamic therapy (PDT) of tumors [5]. Thereinto, NaGdF₄: Tb@NaGdF₄: Ce@NaLuF₄ lanthanide fluorides acted as scintillators to activate the photosensitizer. In another study, Feng et al. introduced NaGdF₄: 2%Nd@NaLuF₄ along with doxorubicin into nanomicelles for imaging and chemotherapy. The NaGdF₄: 2%Nd@NaLuF₄ served as carriers and imaging agents [6]. Additionally, a multitude of other nanocomposite systems based on lanthanide fluorides have been developed, such as NaGdF₄: Lu/Yb/Er/Ce@GuMnSi, NaYF₄: Gd/Yb/Er@Cu_2−xS, NaGdF₄: Nd@Ce6, and NaYF₄: Tm/Yb@NaYF₄/Dox [7–11]. These innovative advancements highlight the versatility and potential of lanthanide fluorides in advancing the field of tumor theranostics.

In the abovementioned composite systems, lanthanide fluorides often serve as the core or platform for carrying tumor therapeutic agents such as photosensitizers, chemotherapy drugs, semiconductors, and photothermic agents [12–16]. However, lanthanide fluorides themselves are not directly therapeutic; instead, their primary functions lie in bioimaging diagnosis and conversion/delivery of exogenous energy to the carried therapeutic agents. This carrier strategy, though widely used, encounters several challenges such as complex preparation process, low carrying efficiency, concerns about nanocomposite biosafety, and lack of selectivity in damaging tumor tissues/cells [17–20]. Furthermore, employing this carrier strategy can alter the surface structure of lanthanide-based nanomaterials, potentially leading to the deterioration in physicochemical properties and the subsequent reduction of efficiencies in energy conversion and delivery [21–24]. Essentially, the limited development of inherent anti-tumor properties significantly hampers the biomedical application prospects of traditional lanthanide fluorides.

Addressing the challenges associated with traditional lanthanide fluorides, we have devised a new approach to systematically enhancing and regulating their inherent properties solely through the introduction of specific dopants, thereby transforming them into effective tumor therapeutic agents. Building upon this strategy and drawing from our prior research, we present a groundbreaking lanthanide fluoride nanomaterial, ligand-free Ba_1.4Mn_0.6LuF₇: Yb³⁺/Er³⁺/Ho³⁺ (hereafter denoted as BMLF), in this work. By simply doping Mn ions, BMLF achieves dual functionality as a ratiometric fluorescence imaging tool for diagnosis and a nanocatalytic agent for tumor therapy. This is made possible by the ability of Mn ions to enhance red band emissions and facilitate Fenton-like reactions [25–30]. The resulting BMLF holds immense promise as a potential fluorescent nanoenzyme for clinical tumor theranostics.

2 Experimental

2.1 Materials

NH₄F (99.99%), BaCl₂ (99.99%), LnCl₃·6H₂O (Ln = Yb, Er, Ho, and Lu), MnCl₂ (99.99%), oleic acid (OA), ethanol, and HCl were purchased from Sigma-Aldrich. All these chemicals are of analytical grade.

2.2 Synthesis of Ba_2−xMn_xLuF₇: Yb³⁺/Er³⁺/Ho³⁺ (B_2−xM_xLF) capped with OA

0.6 g NaOH, 10 mL alcohol, and 20 mL OA were added into a beaker and agitated to form a homogeneous solution. Then, x mmol MnCl₂ (0 ≤ x ≤ 0.8), (2−x) mmol BaCl₂, 1 mmol LuCl₃, 0.2 mmol YbCl₃, 0.002 mmol ErCl₃, 0.002 mmol HoCl₃, and 4 mmol NH₄F aqueous solutions were added into such a solution and stirred for 30 min. Subsequently, the mixture was transferred into a 50 mL stainless teflon-lined autoclave followed by heating at 200 °C for 24 h. After the completeness of the reaction, the products were collected, washed with ethanol/deionized water, and finally dried.

2.3 Synthesis of BMLF

BMLF was obtained by the removal of OA capping the surface of nanocrystals through acid treatment. In detail, 112 μL HCl (35%, 12 mol·L⁻¹) was added into 15 mL absolute ethanol to prepare an acidic ethanol solution (pH = 4) at first. Then 30 mg OA-capped B_1.4M_0.6LF was dispersed in such an acidic ethanol solution followed by stirring for 20 min. Subsequently, the products were collected through centrifugation. After washing several times with ethanol and distilled water, the resulted BMLF was finally dried.

3 Results and discussion

3.1 Characterizations of BMLF

The schematic representation of B_2−xM_xLF nanocrystals is shown in Fig.1(a). Firstly, we prepared a series of OA-capped B_2−xM_xLF samples with different molar ratios of Mn/Ba according to previous reports [31]. Subsequently, we optimized the Mn-doping to obtain ligand-free B_2−xM_xLF, which was then subjected to acid treatment to remove the OA capping from its surface for further experimentation. Characterizations of OA-capped B_2−xM_xLF samples were conducted using X-ray diffraction (XRD) and UCL spectroscopy. XRD analyses revealed that the positions of diffraction peaks for as-synthesized products remained consistent, which exhited a pure phase structure when the content of doped Mn was below 0.7 (x < 0.7) (Fig.1(b)). Corresponding UCL spectra of OA-capped B_2−xM_xLF samples displayed evident green and red emission regions (520‒575 nm and 650‒685 nm, respectively) under the 980 nm irradiation (Fig.1(c)). As the Mn-doped content increased, the intensity of green emission remained relatively constant, while that of red emission gradually increased, surpassing the green emission significantly at last (Fig.1(d)). Furthermore, the intensity ratio of red emission to green emission (I_red/I_green) improved by approximately 12.8 times, rising from 0.22 to 2.82 (Fig.1(e)). In summary, the introduction of moderate Mn ions into the host matrix of B_2−xM_xLF led to a remarkable enhancement in red emission while maintaining the stability of its phase structure.

Fig.1 (a) Schematic diagram for the preparation of B2−xMxLF nanocrystals. (b) XRD patterns and (c) UCL spectra of OA-capped B2−xMxLF samples. (d) Intensity variations of green and red emissions with x for B2−xMxLF. (e) Variation of the intensity ratio of red emission to green emission with x for B2−xMxLF.

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According to Fig.1(c), OA-capped B_1.4M_0.6LF had the intensest red region emission, which could be further developed to fluorescence bio-probes. Therefore, OA-capped B_1.4M_0.6LF was selected to be further processed to prepare BMLF by removing OA capped on the surface, which could expose Mn on the surface of nanocrystals and obtain excellent water-solubility for better biological applications. Firstly, we characterized the properties of BMLF. According to Fourier transform infrared spectroscopy (FTIR) results in Fig.2(a), the characteristic peaks of OA centered at ~2700 (2793)/1640/1356 cm⁻¹ respectively stemming from the stretching vibration of −CH₃, the stretch of carbonyl (C=O), and the stretch of symmetric −COO− disappeared in the spectrum of BMLF, which indicated that capped OA had been successfully removed from the surface of nanocrystals. XRD results demonstrated that the diffraction peaks of BMLF were unchanged, suggesting its remaining pure phase after the removal of OA (Fig.2(b)). Transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HRTEM) images also verified that BMLF had an almost pure tetragonal phase structure (Fig.2(c) and 2(d)). In addition, it could be detected from the energy dispersive spectroscopy (EDS) result in Fig. S1 (included by ESM of Appendix) that BMLF contained elements of Ba, Mn, Lu, F, Yb, Er, and Ho. The dynamic light scattering (DLS) result showed that the diameter distribution of BMLF was mostly concentrated at around 10.5 nm (Fig.2(e)). EDS and X-ray photoelectron spectroscopy (XPS) analyses (Figs. S1 and 2(f)) confirmed the presence of the Mn element in nanocrystals, indicating the successful doping of Mn. For the high-resolution XPS result of Mn 2p (Fig.2(g)), two peaks at 654.0 and 642.4 eV were assigned to spin states of Mn 2p_1/2 and Mn 2p_3/2, respectively, and the spin-energy separation gap was calculated to be 11.6 eV, indicating the existence of the Mn(II) state in BMLF. Meanwhile, the UCL spectrum of BMLF remained unchanged, which still possessed 521/542 nm green and intense 654 nm red emission bands respectively stemming from the ²H_11/2/⁴S_3/2 → ⁴I_15/2 transition of Er³⁺ and the ⁵F₅ → ⁵I₈ transition of Ho³⁺ under the 980 nm laser irradiation (Fig.2(h)). Moreover, UCL decay durations of BMLF were 57.73/59.28/97.84 μs when captured at 521/542/654 nm, respectively (Fig.2(i)). The above measurement results comprehensively demonstrated that OA molecules had been successfully removed from BMLF and the physicochemical properties of BMLF remained essentially unchanged.

Fig.2 (a) FTIR spectra and (b) XRD patterns of ligand-free and OA-capped B1.4M0.6LF samples. (c) TEM and (d) HRTEM images of BMLF. (e) DLS result of BMLF. (f) Survey XPS spectrum and (g) high-resolution Mn(II) 2p XPS spectrum of BMLF. (h) UCL spectrum of BMLF. (i) UCL decay curves of BMLF measured at different excitation wavelengths.

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Since Mn²⁺ was exposed on the surface of BMLF, we speculated that endogenous H₂O₂ in the tumor microenvironment (TME) could directly oxidize Mn²⁺ to Mn⁴⁺ through a Fenton-like reaction, resulting in the production of highly toxic •OH, the release of Mn⁴⁺ from BMLF, and the UCL change of BMLF. As a result, Mn⁴⁺ could also be changed into Mn²⁺ through the redox reaction with GSH, and generated Mn²⁺ further participated in the Fenton reaction process with H₂O₂ to generate •OH and Mn⁴⁺, which would lead to an auto-regenerative reaction cycle. To verify the above speculation, a in vitro color-change experiment was carried out using 3, 3′, 5, 5′-tetramethylbenzidine (TMB) and DTNB as the indicators. As shown in Fig.3(a), the solution color obviously changed under the BMLF effect, indicating the generation of reactive oxygen species (ROS) and the depletion of GSH. The above phenomenon was further investigated through ultraviolet‒visible (UV–vis) absorption spectroscopy. As shown in Fig.3(b) and 3(c), after incubation of TMB with BMLF in the presence of H₂O₂, oxidized TMB obviously had a characteristic peak at 655 nm, which became stronger with the prolonging of time. In addition, GSH could be degraded well by BMLF and the GSH consumption was greatly enhanced as time went on (Fig.3(d) and 3(e)). Notably, the red emission band intensity of BMLF decreased gradually with the release of Mn²⁺, while its green emission band intensity was almost unchanged upon the 980 nm laser excitation (Fig.3(f)). The intensity variations of red and green emissions were depicted in Fig.3(f), and the relationship between I_red/I_green and time was also shown in Fig. S3(a) (included by ESM of Appendix). The chromaticity coordinates corresponding to Fig.3(f) also showed that the UCL of BMLF gradually shifted to the green area from the yellow area (Fig.3(g) and S3(b)). Additionally, the inductively coupled plasma optical emission spectrometry (ICP-OES) result demonstrated that Mn²⁺ ions were released from BMLF in the H₂O₂ solution (Fig.3(h)). Benefiting from such a redox reaction, BMLF is expected to be developed as a novel fluorescence nanoenzyme for cancer theranostics.

Fig.3 (a) Schematic illustration of the GSH catalytic degradation and ROS catalytic production of BMLF. UV–vis absorption spectra of (b) TMB with different additions and (c) TMB incubated with BMLF/H2O2 at different durations. (d) UV–vis absorption spectra of DTNB with different additions. (e) GSH depletion under the addition of BMLF at different durations. (f) UCL spectra and (g) CIE 1931xy chromaticity diagram of BMLF in the H2O2 solution with different time points. (h) ICP-OES result of released Mn from BMLF in the H2O2 solution.

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3.2 Application in bioimaging diagnosis for cancer cells/tumor

Before the biological application of BMLF, the assessment of its cytotoxicity is required. The cell viability of normal cells (MEF cells as an example) was measured through the methyl thiazolyl tetrazolium (MTT) assay. The MTT result (Fig.4(g)) showed that the cell viability of HeLa cells exceeded 88% under the co-incubation of 1000 µg·mL⁻¹ BMLF, indicating that BMLF possessed low cytotoxicity to normal cells. Afterwards, UCL imaging of live cells stained with BMLF was also studied. Confocal fluorescence imaging showed bright green/red emission fluorescence observed in cancer cells (HeLa cells as an example) stained with BMLF for 1 h (Fig.4(a)). With the prolonging of time, the intensity of red-emission fluorescence was gradually weakened, and the signal almost disappeared after staining for 10 h. In contrast, the intensity of green-emission fluorescence remained unchanged over time. Meanwhile, the interactive 2.5D surface plots and MFL corresponding to Fig.4(a) also more directly confirmed the above phenomenon (Fig.4(b)‒4(e)). Moreover, the intensity ratio of I_red/I_green gradually decreased from 1.49 to 0.1 (Fig.4(f)). Immediately following that, in vivo tumor UCL imaging situation of the tumor-bearing mice was further explored through the injection with BMLF. As shown in Fig.4(h), the bright UCL signal appeared at the tumor site of the injected mouse. It is noteworthy that the red-emission fluorescence signal changed with time and almost disappeared after about 10 h (Fig. S4 included by ESM of Appendix), while the green-emission fluorescence signal remained unchanged (Fig.4(h)). The reason for above experimental phenomenon is that Mn²⁺ in BMLF is reduced by overexpressed H₂O₂ in TME, leading to the UCL change of BMLF, corresponding to the results in Fig.3(f)–3(h). Therefore, BMLF can be applied to the UCL imaging diagnosis for tumors and monitoring the BMLF treatment process through the change of ratiometric fluorescence.

Fig.4 (a)(b) Confocal luminescence images and 2.5D surface plots of cancer cells stained with BMLF at different time points under the 980 nm laser irradiation (green and red emission filters: 500–600 nm and 630–700 nm, respectively). (c)(d)(e) Corresponding mean fluorescence intensities (MFIs) of confocal images. (f) Intensity ratios of red emission to green emission corresponding to confocal images at different durations. (g) Viabilities of MEF cells incubated with BMLF at various concentrations. (h) UCL imaging of tumor-bearing mice intravenously injected with BMLF at the tumor area (corresponding emission filter: 630‒700 nm and 500–600 nm).

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3.3 Application in therapy for tumor

In the previous characterization of BMLF, we found that BMLF could catalyze H₂O₂, leading to the generation of ROS and the release of Mn⁴⁺ which continuously degraded GSH (Fig.3(a)–3(e)). Next, the properties of BMLF would be further validated at the cellular level for the application of tumor therapy. The generation of intracellular ROS was visually detected using a 2',7'-dichlorodihydrofluorescein diacetate (H2-DCF-DA) fluorescent probe. The confocal images showed bright green fluorescence clearly observed in the BMLF-added group compared with that of the control one, which originated from green fluorescent DCF generated through the oxidation of nonfluorescent DCFH-DA, indicating the presence of a large amount of intracellular ROS (Fig.5(a), 5(b), and S5). Additionally, the interactive 2.5D surface plots corresponding to Fig.5(a) and 5(b) more directly confirmed the above phenomenon (Fig.5(c) and S6). The degradation capability of BMLF against intracellular GSH was evaluated using the GSH assay kit. The result revealed that intracellular GSH was successfully degraded after cancer cells were incubated with BMLF, and the GSH consumption was significantly increased with the enhancement of the BMLF concentration (Fig.4(d)). Overall, the detected results of ROS/GSH indicated that BMLF could induce lethal ROS generation and degrade overexpressed GSH in cancer cells, which was expected to act as the nanoenzyme for tumor chemodynamic therapy (CDT).

Fig.5 (a)(b) Laser scanning confocal microscopy (LSCM) images and (c) corresponding interactive 2.5D surface plots of cancer cells stained with BMLF and DCFH-DA. (d) Intracellular GSH depletion with the addition of different BMLF concentrations. (e) Viabilities of cancer cells incubated with BMLF. (f) Representative photograph of ex vivo solid tumors in different groups (I: Control or II: BMLF treatment). (g) Time dependency of relative tumor volumes for tumor-bearing mice in different groups. (h) Average tumor masses in different groups. (i) Time dependency of body masses for tumor-bearing mice in different groups. (j) DAPI/TUNEL staining of tumors in different groups and corresponding merge images.

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Encouraged by above experimental results, the anticancer effect of BMLF was evaluated. The MTT assay results showed that BMLF had excellent effect on killing tumor cells, decreasing the viability of tumor cells to less than 40% with the concentration of BMLF at 800 µg·mL⁻¹ (Fig.5(e)), which was opposite to its low cytotoxicity toward normal cells (Fig.4(g)). Ulteriorly, the in vivo antitumor experiment of BMLF was carried out using tumor-bearing mice. As shown in Fig.5(g), the treatment with BMLF could obviously inhibit the tumor growth and the relative tumor volume only increased by ~5-fold compared with the ~14-fold increase of the control group after curation for 14 d. Meanwhile, similar results were obtained from the ex vivo solid tumor photograph and the tumor mass bar chart in Fig.5(f) and 5(h), respectively. After 14 d of curation, the tumors were subjected to a histological analysis. The TUNEL-stained images of tumor slices showed obvious cell apoptosis and serious damage in the BMLF-treated group compared to the negligible cell damage in the control group (Fig.5(j)). Moreover, the body mass of mice treated with BMLF had only a slight change (Fig.5(i)), and the hematoxylin and eosin (H&E) staining result clearly displayed that no evident damage/inflammation appeared in major organs (Fig.6). Thus, the above experimental results sufficiently demonstrated that BMLF had excellent antitumor efficacy and high therapeutic safety. Combining the resulted tumor imaging/therapy effects in this work, BMLF is expected to become a novel lanthanide-based fluorescent nanoenzyme for clinical tumor theranostics.

Fig.6 H&E staining images of histological sections derived from major organs of mice injected with BMLF (the sections from organs were taken at a magnification of 100×).

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4 Conclusions

In summary, a multifunctional BMLF nanomaterial was obatined through the simple solvothermal method. BMLF could produce a ratiometric change of the fluorescence emission, generate large amounts of ROS, and consume overexpressed GSH in TME. Importantly, the comprehensive experiment results indicated that BMLF successfully realized ratiometric fluorescence imaging diagnosis and nanocatalytic therapy for tumors in vivo. Therefore, it can be anticipated that the as-prepared BMLF would act as a novel fluorescent nanoenzyme for clinical tumor theranostics.

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Authors’ contributions

L.J.Xiang: writing-original draft, investigation, and writing –— review & editing; C.Y.Wang, Y.F.Mao, W.J.Li, and Y.Jiang: conceptualization, data curation, formal analysis, and project administration; Z.Huang and Z.F.Hu: project administration and supervision; Y.Wang: supervision, writing — review & editing. All authors have read and agreed to the published version of this manuscript.

Ethical statement

Animal experiments were approved by the Animal Ethics Committee of Anqing Normal University and performed in accordance with the Guidelines for Care and Use of Laboratory Animals of Anqing Normal University.

Declaration of competing interests

The authors declare that they have no competing interests.

Acknowledgements

This work was supported by Key project of the Natural Science Research in Universities of Anhui Province (No. 2023AH050510), Key Laboratory of Micro-nano Energy Materials and Application Technologies, University of Hunan Province (No. 2023HSKFJJ022), 2024 College Student Innovation and Entrepreneurship Training Project (X202410372053), Open Fund Projects of the Province Key Laboratory of the Biodiversity Study and Ecology Conservation in Southwest Anhui (Wsy202202), and 2019 University Excellent Talent Training Project (GXGWFX2019038, Z.H.).

Online appendix

Electronic supplementary material (ESM) can be found in the online version at https://doi.org/10.1007/s11706-024-0698-4 and https://journal.hep.com.cn/foms/EN/10.1007/s11706-024-0698-4 that includes Figs. S1–S6.

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