Two Ru(II) compounds with aggregation induced emission as promising photosensitizers for photodynamic therapy

https://doi.org/10.1016/j.jinorgbio.2020.111233Get rights and content

Highlights

  • 1,3-Di(2H-tetrazol-5-yl)benzene (Hphbtz) was prepared.

  • 2,2′-Bipyridine (bipy) and 1,10-phenanthroline (phen) were chosen.

  • [Ru(Hphbtz)(bipy)2][PF6] (1) and [Ru(Hphbtz)(phen)2][PF6] (2) were prepared.

  • The nanoparticles (NPs) show aggregation induced emission (AIE).

  • Both NPs can effectively inhibit cell proliferation and migration in vitro.

Abstract

Design and preparation of photosensitizers (PSs) play an important role in photodynamic therapy (PDT). PDT mainly relies on the production of toxic reactive oxygen species (ROS) of the PSs. Conventional fluorophores, however, often suffer from aggregation caused quenching (ACQ), which limits the potential of PSs as fluorescent imaging agents. Molecules with aggregation-induced emission (AIE) properties maintain high fluorescence and dispersity in aqueous solutions, overcoming the ACQ effect. Ruthenium (II)-based AIE compounds are highly biocompatible molecules and can be used for response cell imaging. In the current study, two novel Ru(II)-based AIE compounds with main ligands 1,3-di(2H-tetrazol-5-yl)benzene (Hphbtz) by changing auxiliary ligand 2,2′-bipyridine (bipy) and 1,10-phenanthroline (phen) have been successfully synthesized and characterized, [Ru(Hphbtz)(bipy)2][PF6] (1) and [Ru(Hphbtz)(phen)2][PF6] (2). The NPs show strong intra-cellular fluorescence and also simultaneously exhibited potent cytotoxic activity. These compounds can self-assemble to form nanoparticles (NPs) by nanoprecipitation. The compounds are found to exhibit a high AIE property with emission maxima at 353 nm and 380 nm, respectively. And the compounds have the low IC50 (half maximal inhibitory concentration) of only 15 μg/mL (1.94 μM) and 13 μg/mL (1.58 μM) on HeLa cells, respectively. Meanwhile, negligible dark toxicity has been also observed for these NPs. The results show that [Ru(Hphbtz)(bipy)2][PF6] (1) and [Ru(Hphbtz)(phen)2][PF6] (2) NPs can inhibit cell proliferation in vitro, and may be potential candidates for photodynamic therapy.

Introduction

Photodynamic therapy (PDT) is a widely accepted method of tumor elimination, which can effectively treat various deep tissue tumors [[1], [2], [3], [4], [5], [6]]. Today, PDT is rapidly developing for cancer treatment in clinical trial and has been combined with other modalities, such as surgery, radiotherapy and chemotherapy [[7], [8], [9], [10], [11]]. PDT mainly relies on the production of toxic reactive oxygen species (ROS), including singlet oxygen (1O2), superoxide radicals, hydroxyl radicals etc, to induce cell death [[12], [13], [14], [15], [16], [17], [18]].

Most photosensitizers (PSs) exhibit strong luminescence in their diluted solutions, but this tends to be weakened or quenched at higher concentrations, a phenomenon known as ‘Aggregation-Caused Quenching (ACQ). The ACQ effect limits their potential as fluorescence imaging agent. Therefore, it is urgent to develop PSs that maintain high fluorescence and dispersibility in aqueous solutions. Aggregation-induced emission (known as AIE), opposite to ACQ, was firstly discovered by B.Z. Tang et al. [19]. Molecules with AIE properties have been investigated for various biological applications, including PDT, bio-imaging and so on [[20], [21]]. Investigation on AIE molecules mainly focuses on organic compounds while that of inorganic compounds are far from satisfactory.

In recent years, ruthenium (II) coordination compounds have become promising anti-tumor and anti-metastatic drugs with the potential to resist drug resistance [[21], [22], [23], [24]]. Ruthenium (II) coordination compounds as two photon PSs are highly biocompatible molecules and can be used for near infrared response cell imaging and have AIE properties [25,26]. Members of a family of ruthenium (II) coordination compounds were synthesized by R. Lincoln et al., according to their photophysical and photobiological properties, and evaluated for their collective potential as photosensitizers (PSs) for photodynamic therapy [27]. Tetrazole-based ligands are capable of binding metal ions in a variety of coordination modes, bifunctional 5-substituted-tetrazolate ligands are likely to exhibit excellent bridging linkers. So that compelling topology structures can be constructed [[28], [29], [30], [31]]. In previous research, reported Ru(II) compounds based on tetrazole-based ligands were reported by our group with high phototoxicity, low dark toxicity and excellent bio-compatibility for photodynamic therapy [[32], [33], [34]].

In this article, we are devoted to investigating Ru(II)-tetrazole compounds derived from 1,3-di(2H-tetrazol-5-yl)benzene (Hphbtz), two compounds are obtained, namely, [Ru(Hphbtz)(bipy)2][PF6] (1) (bipy = 2,2′-bipyridine) and [Ru(Hphbtz)(phen)2][PF6] (2) (phen = 1,10-phenanthroline) as promising anti-tumor drugs. Meanwhile, the compounds 1 and 2 exhibit typical AIE feature. The AIE properties of compounds 1 and 2 are caused by the Ru-metal cluster center and the metal-to-ligand charge-transfer (MLCT) process. Nanoprecipitation with Polyethylene Glycol5000 (PEG5000) was used to prepare the nanoparticles (NPs) of compounds 1 and 2. Both NPs can be uptaken by HeLa cells and capable of generating ROS in vitro with 2,7-dichlorodihydrofluorescein diacetate (DCF-DA) as a probe. In vitro cytotoxicity study showed that [Ru(Hphbtz)(bipy)2][PF6] (1) and [Ru(Hphbtz)(phen)2][PF6] (2) NPs have a low IC50 (half maximal inhibitory concentration) of only 15.1 μg/mL (1.94 μM) and 13.2 μg/mL (1.58 μM) on HeLa cells, respectively (Scheme 1). In vitro study indicates that such NPs not only have high phototoxicity under irradiation, but also negligible dark toxicity. Besides, cell migration across a 2D artificial gap indicated that these NPs could inhibit the migration of cells.

Section snippets

Materials and apparatus

The ligands were prepared according to the literature methods [35,36]. General chemicals were commercially available reagents of analytical grade and used without further purification. The 1H NMR and 13C NMR spectra were performed on Bruker DRX NMR spectrometer (500 MHz) in DMSO-d6 at 298 K as the internal standard. The elemental analysis for C, H and N were obtained on a Carlo-Erba EA1110 CHNO-S microanalyzer. Photoluminescent spectra were collected on a Hitachi F-4600 spectrofluorometer.

Characterization of [Ru(Hphbtz)(bipy)2][PF6] (1) and [Ru(Hphbtz)(phen)2][PF6] (2)

The absorption spectra of [Ru(Hphbtz)(bipy)2][PF6] (1) and [Ru(Hphbtz)(phen)2][PF6] (2) in THF and their NPs are shown in Fig. 1a. Compound 1 in THF exhibits two peaks at 245 and 296 nm while compound 2 at 260 and 298 nm, respectively. In contrast, the absorption of compound 1 NPS showed peaks at 245 and 299 nm in water while that of compound 2 NPS exhibits 280, 301 nm. Difference in absorbance between THF and water due to aggregation of NPS and solvent effect. The fluorescence of NPs of 1 and 2

Conclusions

Two novel Ru(II)-based compounds with aggregation induced emission have been successfully synthesized by changing the auxiliary ligand. Nanoprecipitation was used to prepare the NPs of the two compounds. [Ru(Hphbtz)(bipy)2][PF6] (1) and [Ru(Hphbtz)(phen)2][PF6] (2) NPs have high phototoxicity as well as negligible dark toxicity. Besides, in vitro study shows that both NPs are able to effectively inhibit the migration of cells. The results show that these compounds may have great potential for

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

The authors acknowledge financial support from the Natural Science Foundation of China (Grant No. 81460119), National Natural Science Fundation of Jiangsu Province (Grant No. BK2012210), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (Grant No. 10KJB430001).

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