In vivo Realization of Dual Photodynamic and Photothermal Therapy for Melanoma by Mitochondria Targeting Dinuclear Ruthenium Complexes under Civil Infrared Low‐power Laser

Abstract

A series of dinuclear RuII complexes with extremely high TPA cross sections in the range of 800–900 nm have been designed. The amphiphilic complex Ru3 containing tert‐butyl groups has balanced performance in singlet oxygen generation and photothermal conversion and becomes the ideal drug candidate of the series. Ru3 targets mitochondria without penetrating the nucleus, which substantially increases its photodynamic therapy activity and reduces its dark cytotoxicity. Ru3 successfully suppresses melanoma tumor growth in vitro and in vivo with combined photodynamic and photothermal therapy under low light dose irradiation of an 808 nm low‐power laser, avoiding the known PDT resistance in melanoma. The excellent therapeutic effect of Ru3 facilitates its applications in further human trials for larger or deeper buried tumors, thereby becoming a prospective candidate for a new generation of low‐power IR‐driven dual PDT/PTT drugs.

More-Is-Better Strategy for Constructing Homoligand Polypyridyl Ruthenium Complexes as Photosensitizers for Infrared Two-Photon Photodynamic Therapy

“…σ 808 of HPRCs was 51–142 GM (1 GM = 10 –50 cm 4 s photon –1 ) as shown in Table , which was not only higher than the suggested value for optical imaging applications (0.1 GM) but also higher than similar mononuclear Ru­(II) , and Ir­(III) complexes at around 800 nm. Nevertheless, the σ 808 values of HPRCs are lower than some dinuclear Ru­(II), Os­(II), and Ir­(III) complexes. Ru1 showed the highest σ 808 , which could explain its remarkable photodynamic activity (Φ Δ808 ) under 808 nm excitation.…”

“…Recently, we designed a dinuclear Ru(II) complex 12 with remarkable TPA cross-section (TPACSs, σ) and photothermal conversion efficiency (PCE) in the IR region and realized its dual PDT and photothermal therapy (PTT) in vivo by using a low-power laser (LPL, 808 nm, 100 mW cm −2 ) with a tunable beam diameter (>1.0 cm) which has demonstrated good applicability in the antitumor phototherapy of upconverting nanoparticles. 14 Exploring promising Ru(II)-PSs with simpler structures and similar high phototherapy indexes (PIs) will undoubtedly be beneficial to pharmaceutical manufacturing.…”

“…Many Ru­(II) complexes have been successfully developed as PSs in PDT and photochemotherapy (PCT) for their long 3 ES lifetimes and high 1 O 2 quantum yields (Φ Δ ). , Although some good Ru­(II)-PSs like TLD1433, which entered a clinical trial in 2018, can be excited by red light (better than traditional blue light), even longer excitation wavelength, especially the infrared (IR) light, will be more practical for a deeper (typically >1 cm) and safer PDT. Ru­(II), Ir­(III), and Os­(II) complexes with distinct IR two-photon absorption (TPA) have exhibited versatile properties in antitumor phototherapy. ,− Currently, the two-photon (TP) excitation depends on lasers with extremely high energy density. The power exceeds the maximum allowable exposure value (0.33 W cm –2 ) under IR laser for human skin (ANSI Z136.1-2014).…”

Heterometallic ruthenium–osmium complexes: dual photodynamic and photothermal therapy for melanoma and drug-resistant lung tumourin vivo

“…Recently, we developed a series of IR low-power lasers (LPL, 100 mW cm −2 ) and excitable, single-molecule dual PDT/PTT antitumour homo-dinuclear Ru-Ru complexes by modulating the triple excited states ( 3 ESs) to a lower energy level for efficient energy transfer to oxygen, with convenient non-radiative (exothermic) decay. 12 Interestingly, their Os-Os counterparts have 3 ESs with an even lower energy, resulting in virtually all of their ESs energy decaying via heat release, thereby enhancing the PTT activity and eliminating the PDT activity. 13 In this study, a series of hetero-dinuclear Ru-Os complexes have been designed to combine the respective advantages of the Ru and Os structural units and regulate the ES energy distribution in radiation decay (luminescence), non-radiation decay (heat release), and energy transfer with oxygen, by which to maximise the utilisation of the ES energy of the dual PSs/PTAs in phototherapy (Fig.…”

NIR diagnostic imaging of triple-negative breast cancer and its lymph node metastasis for high-efficiency hypoxia-activated multimodal therapy

“…AAT has been con rmed to cut off the oxygen and nutrition supply to the tumor [30], which enhance the degree of hypoxia inside the tumor [31]. Coincidentally, photodynamic therapy (PDT) speci cally kills cancer cells in the presence of oxygen to generate reactive oxygen species (ROS) by photosensitizer under light irradiation [32], which also has the advantages of low systemic toxicity [33], low therapeutic resistance [34] and low invasiveness [35]. As PDT is highly oxygen-dependent, it can further lead to hypoxia in the tumor tissue [36,37].…”