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. 2021 Nov 22;12(12):1925–1931. doi: 10.1021/acsmedchemlett.1c00492

Introducing the Tellurophene-Appended BODIPY: PDT Agent with Mass Cytometry Tracking Capabilities

Jacob W Campbell †, Matthew T Tung ‡, Roberto M Diaz-Rodriguez †, Katherine N Robertson §, Andrew A Beharry ‡,*, Alison Thompson †,*
PMCID: PMC8667306  PMID: 34917256

Abstract

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The synthesis and characterization of the first BODIPY appended to the five-membered heterocylic tellurophene [Te] moiety is reported. By incorporating tellurophene at the meso position, the tellurophene-appended boron-dipyrromethene dye (BODIPY) acts as a multimodal agent, becoming a potent photosensitizer with a mass cytometry tag. To synthesize the compound, we developed a method to enable late-stage Suzuki–Miyaura coupling by preparing and isolating tellurophene-2-BPin in a one-step procedure from the parent tellurophene. Coupling to a meso-substituted BODIPY functionalized with a pendant aryl bromide provides the desired tellurophene-appended BODIPY. This compound demonstrated a singlet oxygen quantum yield of 0.26 ± 0.01 and produced a light dose-dependent cytotoxicity with nanomolar IC50 values against 2D cultured HeLa cells and high efficacy against 3D cultured HeLa tumor spheroids, proving to be a strong photosensitizer. The presence of the tellurophene moiety could be detected using mass cytometry, thus showcasing the ability of a tellurophene-appended BODIPY as a novel photodynamic-therapy–mass-cytometry theranostic agent.

Keywords: Suzuki-coupled tellurophene, dual mass cytometry and PDT, singlet oxygen

Hybrid (or multimodal) cellular imaging and therapeutic techniques employ complementary modalities to maximize the resolution.1−3 Among the many approaches to multimodal functions (e.g., PET/CT,4 PET/MRI,3,5 lipid-based approaches,6−8 quantum dots,9−13 iron oxide nanoparticles,14−16 and macromolecular carriers),17,18 small-molecule probes2,19−21 stand out with advantages such as expedited clearance by the renal system, thus minimizing the toxicity associated with long-term liver retention, and facile tuning of properties through functionalization.1 Recent breakthroughs in multimodal small molecules involve systems that enable both diagnosis and treatment (i.e., theranostics) or enable in situ localization and treatment. This approach was first realized by tuning the fluorescence properties of dyes used in photodynamic therapy (PDT) such that cancerous cells could be located and given an accurately assessed payload of the drug.2 Herein the first mass cytometry/photosensitization multimodal agent incorporating tellurophene into a BODIPY scaffold designed for PDT is reported.

Mass cytometry (MC) is a clinically proven imaging technique that employs a small molecule appended with an isotopic mass label that can be tracked using mass spectrometry. Although a relative newcomer, MC is a valuable tool in the multimodal imaging field owing to the diversity of compounds in which a mass label can be installed.22−24 Modern MC experiments can display simultaneous measurements of over 40 cellular parameters at single-cell resolution and, when used in union with flow cytometry, can help fill the gaps in resolution encountered with less sophisticated imaging techniques.24

PDT is a clinically approved treatment used as an alternative to highly invasive surgeries or radiation therapies:25 in essence, a nontoxic sensitizer is activated by light of a therapeutically appropriate wavelength applied in a highly controlled manner. The photosensitized prodrug then interacts with oxygen to form cytotoxic singlet oxygen (1O2) and other reactive oxygen species (ROS) that effect death of cells in the immediate vicinity.26 Notable advantages of PDT include the repeatable application, cost effectiveness, and reduced drug resistance alongside flexible delivery modes such as topical application or injection.27 As such, combining multimodal imaging techniques with PDT has the benefit of enhancing localization of treatment through high-resolution imaging, and provides a method to monitor the time taken to accumulate in target tissues.2

Boron-dipyrromethene dyes (BODIPYs, 4-disubstituted-4-bora-3a,4a-diaza-s-indacenes) have been exhaustively investigated with regard to their fluorescence quantum yield (Φf). More recently, BODIPYs have been tuned to facilitate intersystem crossing (ISC) from a singlet to a triplet excited state to enhance 1O2 production.28−30 The BODIPY core can be tuned via pyrrolic substitutions (at the α and/or β-positions) or meso substitution,29 making this molecular framework particularly well-suited for adaption as a combined MC/PDT agent. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of meso-aryl-substituted BODIPYs are primarily localized on the dipyrrolic core, and thus substituents appended to the meso-arene are projected to have little effect on the photoinduced 1O2 production. Therefore, substitution at the meso position offers promise for the incorporation of mass labels in a BODIPY equipped for monitoring via MC and PDT.31 Furthermore, with BODIPYs often exhibiting very high fluorescence quantum yields, any residual emission could be used for complementary fluorescence imaging. With bromo-activated meso-substituted BODIPYs serving as common coupling partners,32−38 and with these skeletons typically exhibiting poor fluorescence (e.g., Φf < 0.05)39,40 and therefore potentially favoring high 1O2 production, meso-aryl BODIPYs were selected for the investigation as bifunctional PDT/MC agents.

The prototypical mass label for MC is a heavy element with many available isotopes, such as to enable time/isotope-stamped administration and monitoring without altering the physiological uptake or metabolism.24 Although lanthanides are often used as MC labels, organotellurium motifs41,42 were identified as competent mass labels due to tellurium having a low toxicity profile, eight stable isotopes, no known biological role in prokaryotic or eukaryotic cells,42−44 and the potential to improve ISC through the heavy atom effect.45 There are a handful of reports of BODIPYs appended with alkyl or aryl telluroether functionalities,36−38,46−48 but many lack stability. Consequently, the five-membered heterocyclic tellurophene motif, hereafter abbreviated as [Te], was selected for attachment to the BODIPY framework. Early [Te] derivatization consisted of halogenation,49 acylation,50 and alkylation51 chemistry of annulated [Te]s due to the poor reputation regarding the instability of heavy chalcogenophenes:52 early stage incorporation of the requisite functionality was essential, yet limiting, in regards to the generation of analogs. More recently, elegant metallacycle transfer using prefunctionalized diynes has been used to prepare borylated tellurophenes for Suzuki–Miyaura coupling.53,54 However, although stannylation of the [Te] heterocycle and consequent Stille coupling is known,55,56 there are no reports of the borylation of the parent heterocycle. To efficiently prepare [Te]-appended BODIPYs, a method for the synthesis of [Te]-2-BPin from the parent unsubstituted [Te] was developed for coupling to a bromo-activated BODIPY via Suzuki–Miyaura methods (Scheme 1). Natural-abundance tellurium was used to enable methodology development, with the intention of using commercially available single-isotope elemental tellurium for applications work.

Scheme 1. Synthesis of 8-(4-(Tellurophenyl)phenyl)-BODIPY 4.

Scheme 1

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To prepare the parent [Te] heterocycle,41,57 we first reduced the elemental tellurium with sodium hydroxymethanesulfinate dihydrate (Rongalite) to form the water-soluble sodium telluride. Subsequent treatment with trimethylsilyl-capped 1,3-butadiyne gave 2,5-bis(trimethylsilyl)[Te], which was deprotected in situ to give crude [Te] 1.57 According to the literature procedure, treatment of the crude chalcogenophene with bromine gave 1,1-dibromo[Te] as an insoluble orange solid to enable purification by filtration. The reduction of 1,1-dibromo[Te] gave the parent [Te] 1. Given the anticipated crystallinity and versatility of coupling,58 [Te]-2-BPin 2 was selected as the target nucleophile for coupling to bromo-activated meso-aryl BODIPY 3, as shown in Scheme 1. Through the modification of procedures described for other heterocycles,59 the room-temperature lithiation of [Te] with n-butyllithium, followed by borylation employing 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, afforded [Te]-2-BPin 2 as a crystalline yellow solid in 72% yield after distillation. The slow evaporation of a diethyl ether solution of 2 gave long acicular crystals. The analysis of the corresponding crystallographic data confirmed the structure of 2 (Figure 1).

Figure 1.

Figure 1

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Side-on view of 2 highlighting the planarity of [Te].

The Suzuki–Miyaura coupling of 2 and the bromo-activated BODIPY 3 was catalyzed by employing a Pd(0)/XPhos system.60 The crude product mixture was filtered to remove the catalyst, and the filtrate was then subjected to chromatography on neutral alumina. Further purification by washing with pentane afforded 8-(4-(tellurophenyl)phenyl)-BODIPY 4 as a crimson-red, air-stable solid in 73% yield (Scheme 1). The slow diffusion of hexanes layered over a dichloromethane solution of 4 gave small single crystals. The analysis of the corresponding crystallographic data confirmed the structure of 4 (Figure 2).

Figure 2.

Figure 2

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Side-on view of compound 4. Disorder is removed for clarity.

The photophysical properties of 4 were determined in CH2Cl2 at room temperature by first exciting at 500 nm while monitoring the emission from 510 to 700 nm to determine the peak emission maximum (λemmax = 526 nm). The spectrofluorometer was then set to the excitation peak maximum and monitored from 350 to 521 nm to determine the peak absorbance maximum (λabsmax = 503 nm, Figure S1). The fluorescence quantum yield of 4 was determined to be weak (Φf = 0.01) using rhodamine B (Φf = 0.70 in ethanol) as a standard. This weak fluorescence is anticipated to originate from nonradiative decay of the singlet excited state as a result of the free rotation of the meso-aryl substituent in addition to the presence of tellurium; the latter is known to promote ISC from the excited singlet state to the excited triplet state via the heavy atom effect.45 Because populating the triplet state may result in the generation of ROS, this was evaluated via the irradiation of 4 in the presence of 1,3-diphenylisobenzofuran (DPBF), an 1O2 sensor. If 1O2 is produced, then DPBF forms an endoperoxide, causing a decrease in its absorbance at 410 nm.61 Experiments were performed in MeOH containing 2% DMSO. Under these conditions, DPBF was monomeric and reactive,61 and 4 exhibited only slight shifts in λmax compared with aqueous solutions (Figure S22). Concentrations of compound 4 were determined by calculating extinction coefficients (ε = 54 822 M–1cm–1) in DMSO (Figure S23). Compound 4 demonstrated a decrease in absorbance after irradiation compared with background irradiation of DPBF alone, with a singlet oxygen quantum yield (ΦΔ) of 0.26 ± 0.01 (Figure S24).

Although DPBF is selective for 1O2 and is commonly used to determine ΦΔ,62,63 it has been shown to react with other ROS, such as hydroxyl radicals and peroxides.61,64 To ensure that the degradation of DPBF was at least partially caused by 1O2, excess NaN3, a 1O2 quencher,61 was used in the DPBF assay, whereby solutions containing NaN3 degraded DPBF at a significantly slower rate, confirming that 4 was indeed generating 1O2 (Figure S25). Furthermore, minimal photobleaching under these irradiation conditions was observed (Figure S26), demonstrating the high photostability of 4 in MeOH. Precursor 3 generated minimal amounts of 1O2, indicating that the tellurophene moiety is critical to the photosensitization exhibited by 4 (Figure S27).

Given the ability of 4 to generate 1O2 upon treatment with light, the capability to exert photocytotoxicity in cancer cells was explored. HeLa cells were incubated with varying concentrations of 4 in reduced serum media (Opti-MEM) for 3 h, then either kept in the dark or irradiated for 5 min before culturing overnight. After this time, the cell viability was determined using a standard MTT assay. Compound 4 exerted some dark toxicity >100 nM but high phototoxicity <100 nM, yielding a phototoxic index of ∼80 (dark IC50 = 1.35 μM/light IC50 = 0.017 μM (7.08 J/cm2)). The irradiation of 4 for shorter times (1 or 3 min) produced the expected light dose dependency on photocytotoxicity (Figure 3). No background phototoxicity was observed upon the irradiation of untreated cells (Figure S28).

Figure 3.

Figure 3

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Cell viability with 4. HeLa cells were incubated with 0–7.9 μM 4 for 3 h and left either in the dark or irradiated for the given duration with a 525 nm green lamp (23.60 mW/cm2) IC50 for dark conditions = 1.35 μM, 1 min irradiation = 0.094 μM (1.42 J/cm2), 3 min irradiation = 0.053 μM (4.25 J/cm2), and 5 min irradiation = 0.017 μM (7.08 J/cm2). Experiments were conducted in triplicate.

The ability of 4 to exert phototoxicity by producing ROS was confirmed by intracellular imaging using the general ROS sensor, 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA). DCFDA is cell-permeable, and upon deacetylation by intracellular esterases and reaction with ROS, a green fluorescent product is produced.65 HeLa cells treated with 4 (25 nM) and DCFDA (10 μM) produced strong green fluorescence after irradiation, whereas fluorescence was not observed when the treatment occurred in the absence of light (Figure 4). Control experiments with DCFDA (10 μM) alone or 4 (25 nM) alone, with/without irradiation (Figure S29), produced no fluorescence, further demonstrating that irradiation of cells treated with 4 is needed to produce ROS (Figure 4).

Figure 4.

Figure 4

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ROS generation in HeLa cells using DCFDA. HeLa cells were incubated with 4 (25 μM) and DCFDA (10 μM), and fluorescence was monitored before and after 5 min irradiations with a 525 nm green lamp (23.60 mW/cm2). Green fluorescence indicates the production of ROS in cells. 20× magnification, scale bar = 50 μm.

The mechanism of cell death was explored using Annexin V-FITC and propidium iodide (PI) staining. Annexin V binds phosphatidylserine, which is naturally found on the cytosolic side of the plasma membrane of healthy cells.66 However, during apoptosis, phosphatidylserine translocates to the extracellular side of the plasma membrane, allowing Annexin V to bind and exhibit green fluorescence localized at the cell membrane.66 PI is a noncell permeable dye that fluoresces red when bound to DNA and is used as an indicator for cells dying by necrosis or in the late stages of apoptosis.66,67 Cells were treated with 4 (1.25 μM) and irradiated for 5 min, then incubated for 4 h and stained using the Annexin V/PI staining kit. Green fluorescence was observed, indicating Annexin V binding, but minimal red fluorescence was observed (Figure 5), thus indicating the mechanism of death caused by light-activated 4 to be through apoptosis.

Figure 5.

Figure 5

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Mechanism of cell death. HeLa cells with no 4 (top) or after incubation with 4 (1.25 μM) and irradiated with a 525 nm green lamp (bottom, 23.60 mW/cm2) were stained with Annexin V-FITC and PI 4 h post-treatment. Green fluorescence was observed only after treatment, showcasing that cell death occurred through apoptotic pathways. 10× magnification, scale bar = 100 μm.

3D cell cultures have been shown to represent the microenvironment within tumors by mimicking the tumor morphology and physiology more accurately compared with 2D cell cultures.68 HeLa spheroids were grown in Opti-MEM and incubated in the absence and presence (100 nM) of 4 for 3 h to investigate the potential of compound 4 as a therapeutic agent for solid tumors. This concentration was chosen to match that resulting in the maximum phototoxic index observed in 2D cell cultures. Spheroids were then left in the dark or irradiated with a 525 nm green lamp (23.60 mW/cm2) for 5 min and cultured overnight in the dark. The ReadyProbes cell viability imaging kit (blue/green) was used to determine the cytotoxicity: all cells have nuclei stained with blue fluorescence, whereas only dead cells exhibit green fluorescence. Spheroids treated with 4 and irradiated exhibited cell death (i.e., bright green fluorescence) compared with controls containing 4 without irradiation or untreated spheroids with/without irradiation (Figure 6).

Figure 6.

Figure 6

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Cell viability of HeLa cell spheroids. HeLa spheroids treated with/without 100 nM 4 under 5 min irradiations (525 nm, 23.60 mW/cm2) or dark conditions. (top row) Bright-field images of HeLa spheroids; (middle row) nuclear staining of all cells; and (bottom row) cell death monitored by green fluorescence. Only spheroids treated with 100 nM of 4 and irradiated exhibited significant cell death (10× magnification, scale bars = 100 μm).

Monitoring tellurium by mass cytometry would confirm the presence of 4 within cells, provide time points for accumulation, and demonstrate the potential to couple PDT to MC for cancer theranostic applications. To prepare cells for MC, we treated HeLa cells with 4 (25–4000 nM) for 3 h in the dark. Then, following a modified Maxpar cell surface staining protocol, we prepared and analyzed cells using a Helios CyTOF system with 75 000 events collected per concentration. Just before the collection of data, cells were treated with industry-standard EQ calibration beads, and data were normalized to account for signal drifts. Signals arising from 130Te, the most abundant isotope of Te, were analyzed. A positive linear relationship was observed between the 130Te signal intensity and increasing concentrations of 4, thereby confirming the presence of the tellurophene-appended BODIPY within the HeLa cells and showcasing its potential as a theranostic probe (Figure 7, Figure S30).

Figure 7.

Figure 7

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Mass cytometry of 4 within HeLa cells. Overlayed histogram of 130Te signals with increasing concentrations of 4 (25 nM (red), 250 nM (blue), 1000 nM (orange), and 4000 nM (green)). Cells were incubated with different concentrations of 4 for 3 h before cells were prepared for MC.

To conclude, an efficient synthesis of a tellurophene-appended BODIPY is reported. The method uses borylated tellurophene and lends itself to coupling this motif to other biologically relevant species. The tellurophene-appended BODIPY is a capable photosensitizer and generates 1O2. This compound demonstrated nanomolar IC50 under irradiation in HeLa cells, killing cells via apoptosis, with a large phototoxic index (∼80). High efficacy against 3D-cultured HeLa spheroids was also demonstrated, illustrating its capability as a potent photosensitizer. Mass cytometry studies confirmed the presence of Te within HeLa cells, further supporting the potential of tellurophene-appended BODIPYs as theranostic agents. Future work will involve the development of tellurophene-appended BODIPYs with optimized photophysical properties and the introduction of selectivity toward cancer cells to further demonstrate their suitability as multimodal imaging and treatment agents.

Acknowledgments

We thank Dr. Michael Lumsden and Mr. Xiao Feng (both at Dalhousie University) for sharing their expertise in NMR spectroscopy and mass spectrometry, respectively. We thank Mrs. Tina Chen and Mr. Joe Cozzarin from the Centre for Advanced Single Cell Analysis – SickKids Research Institute for their help with the mass cytometry data acquisition. We thank Dr. Craig Smith for providing 4,4-difluoro-8-(phenyl(4-pinacolatoboron))-4-bora-3a,4a-diaza-s-indacene used in an alternative synthesis of 4. A.T. and A.A.B. thank Professor Mark Nitz (Toronto) for helping to initiate this collaboration.

Glossary

Abbreviations

PDT

photodynamic therapy

MC

mass cytometry

1O2

singlet oxygen

ROS

reactive oxygen species

Φf

fluorescence quantum yield

ISC

intersystem crossing

DPBF

1,3-diphenylisobenzofuran

ΦΔ

singlet oxygen quantum yield

DCFDA

2′,7′-dichlorodihydrofluorescein diacetate

PI

propidium iodide

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00492.

  • Preparation and characterization of compounds; crystallographic methods and data; images of NMR spectra, details and data corresponding to PDT and MC evaluation (PDF)

  • Crystallographic information for CCDC 2092927 (CIF)

  • Crystallographic information for CCDC 2092928 (CIF)

Author Contributions

∥ J.W.C. and M.T.T. contributed equally.

This work was supported by NSERC of Canada via Discovery Grants and the CREATE Training Program in BioActives (510963) and the Queen Elizabeth II – Graduate Scholarship in Science and Technology.

The authors declare no competing financial interest.

Supplementary Material

ml1c00492_si_002.pdf (2.6MB, pdf)
ml1c00492_si_003.cif (4.1MB, cif)
ml1c00492_si_004.cif (6.8MB, cif)

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ml1c00492_si_002.pdf (2.6MB, pdf)
ml1c00492_si_003.cif (4.1MB, cif)
ml1c00492_si_004.cif (6.8MB, cif)

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