Heterometallic Ru-Pt metallacycle for two-photon photodynamic therapy

Abstract

As an effective and noninvasive treatment of various diseases, photodynamic therapy (PTD) relies on the combination of light, a photosensitizer, and oxygen to generate cytotoxic reactive oxygen species that can damage malignant tissue. Much attention has been paid to covalent modifications of the photosensitizers to improve their photophysical properties and to optimize the pathway of the photosensitizers interacting with cells within the target tissue. Herein we report the design and synthesis of a supramolecular heterometallic Ru-Pt metallacycle via coordination-driven self-assembly. While inheriting the excellent photostability and two-photon absorption characteristics of the Ru(II) polypyridyl precursor, the metallacycle also exhibits red-shifted luminescence to the near-infrared region, a larger two-photon absorption cross-section, and higher singlet oxygen generation efficiency, making it an excellent candidate as a photosensitizer for PTD. Cellular studies reveal that the metallacycle selectively accumulates in mitochondria and nuclei upon internalization. As a result, singlet oxygen generated by photoexcitation of the metallacycle can efficiently trigger cell death via the simultaneous damage to mitochondrial function and intranuclear DNA. In vivo studies on tumor-bearing mice show that the metallacycle can efficiently inhibit tumor growth under a low light dose with minimal side effects. The supramolecular approach presented in this work provides a paradigm for the development of PDT agents with high efficacy.

Keywords: mitochondria; nucleus; photodynamic therapy; supramolecular coordination complex; two-photon absorption.

Fig. 1.

Synthesis of heterometallic Ru–Pt metallacycle 1.

Fig. 2.

Photophyscial properties of metallacycle 1. (A) Emission spectrum of 1. (B) Two-photon absorption cross-sections of 1 at different excitation wavelengths from 780 to 880 nm.

Fig. 3.

Colocalization images of 1 with LTG, Hoechst, and MTDR with corresponding correlation coefficients. (Scale bars: 20 μm.)

Fig. 4.

Two-photon PDT in vivo. The mice were randomly allocated into four different treatments: (i) physiological saline (control), (ii) physiological saline and two-photon laser irradiation (light), (iii) 1-injected only (1), and (iv) 1-injected and subjected to two-photon laser irradiation (1 + Light). (A) In vivo tumor growth inhibition curves for mice with four different treatments. (B) Average body weights of tumor-bearing mice with four different treatments. (C) Representative photographs of A549 tumors in mice with four different treatments. (D) Histological examination of tumors with four treatments after PDT. (Scale bars: 50 μm.)