Juanjuan Huang

Highly Charged Ruthenium(II) Polypyridyl Complexes as Lysosome‐Localized Photosensitizers for Two‐Photon Photodynamic Therapy

Photodynamic therapy (PDT) is a noninvasive medical technique that has received increasing attention over the last years and been applied for the treatment of certain types of cancer. However, the currently clinically used PDT agents have several limitations, such as low water solubility, poor photostability, and limited selectivity towards cancer cells, aside from having very low two-photon cross-sections around 800 nm, which limits their potential use in TP-PDT. To tackle these drawbacks, three highly positively charged ruthenium(II) polypyridyl complexes were synthesized. These complexes selectively localize in the lysosomes, an ideal localization for PDT purposes. One of these complexes showed an impressive phototoxicity index upon irradiation at 800 nm in 3D HeLa multicellular tumor spheroids and thus holds great promise for applications in two-photon photodynamic therapy.

Noncovalent Ruthenium(II) Complexes–Single-Walled Carbon Nanotube Composites for Bimodal Photothermal and Photodynamic Therapy with Near-Infrared Irradiation

To enhance the efficacy and optimize the treatment of cancers, the integration of multimodal treatment strategies leading to synergistic effects is a promising approach. The coassembly of multifunctional agents for systematic therapies has received considerable interest in cancer treatment. Herein, Ru(II) complex-functionalized single-walled carbon nanotubes (Ru@SWCNTs) are developed as nanotemplates for bimodal photothermal and two-photon photodynamic therapy (PTT-TPPDT). SWCNTs have the ability to load a great amount of Ru(II) complexes (Ru1 or Ru2) via noncovalent π-π interactions. The loaded Ru(II) complexes are efficiently released by the photothermal effect of irradiation from an 808 nm diode laser (0.25 W/cm(2)). The released Ru(II) complexes produce singlet oxygen species ((1)O2) upon two-photon laser irradiation (808 nm, 0.25 W/cm(2)) and can be used as a two-photon photodynamic therapy (TPPDT) agent. Based on the combination of photothermal therapy and two-photon photodynamic therapy, Ru@SWCNTs have greater anticancer efficacies than either PDT using Ru(II) complexes or PTT using SWCNTs in two-dimensional (2D) cancer cell and three-dimensional (3D) multicellular tumor spheroid (MCTS) models. Furthermore, in vivo tumor ablation is achieved with excellent treatment efficacy under a diode laser (808 nm) irradiation at the power density of 0.25 W/cm(2) for 5 min. This study examines an efficacious bimodal PTT and TPPDT nanoplat form for the development of cancer therapeutics.

Real-time tracking mitochondrial dynamic remodeling with two-photon phosphorescent iridium (III) complexes.

Mitochondrial fission and fusion control the shape, size, number, and function of mitochondria in the cells of organisms from yeast to mammals. The disruption of mitochondrial fission and fusion is involved in severe human diseases such as Parkinsons disease, Alzheimers disease, metabolic diseases, and cancers. Agents that can real-time track the mitochondrial dynamics are of great importance. However, the short excitation wavelengths and rapidly photo-bleaching properties of commercial mitochondrial dyes render them unsuitable for tracking mitochondrial dynamics. Thus, mitochondrial targeting agents that exhibit superior photo-stability under continual light irradiation, deep tissue penetration and at intrinsically high three-dimensional resolutions are urgently needed. Two-photon-excited compounds employ low-energy near-infrared light and have emerged as a non-invasive tool for real-time cell imaging. Here, cyclometalated Ir(III) complexes (Ir1-Ir5) are demonstrated as one- and two-photon phosphorescent probes for the real-time imaging and tracking of mitochondrial fission and fusion. The results indicate that Ir2 is well suited for two-photon phosphorescent tracking of mitochondrial fission and fusion in living cells and in Caenorhabditis elegans (C. elegans). This study provides a practical use for mitochondrial targeting two-photon phosphorescent Ir(III) complexes.

A dendritic nano-sized hexanuclear ruthenium(II) complex as a one- and two-photon luminescent tracking non-viral gene vector

Fluorescent tracking gene delivery could provide us with a better understanding of the critical steps in the transfection process. However, for in vivo tracking applications, a small diameter (<10 nm) is one of the rigorous requirements for tracking vectors. Herein, we have demonstrated a new paradigm for two-photon tracking gene delivery based on a dendritic nano-sized hexanuclear ruthenium(II) polypyridyl complex. Because this metallodendrimer has a multivalent periphery, the complex, which is 6.1 nm, showed high stability and excellent dispersibility and could stepwise condense DNA in vitro. With the outstanding photochemical properties of Ru(II) polypyridyl, this complex could track gene delivery in vivo using one- and two-photon imaging.

Mitochondrial Dynamics Tracking with Two-Photon Phosphorescent Terpyridyl Iridium(III) Complexes

Mitochondrial dynamics, including fission and fusion, control the morphology and function of mitochondria, and disruption of mitochondrial dynamics leads to Parkinson’s disease, Alzheimer’s disease, metabolic diseases, and cancers. Currently, many types of commercial mitochondria probes are available, but high excitation energy and low photo-stability render them unsuitable for tracking mitochondrial dynamics in living cells. Therefore, mitochondrial targeting agents that exhibit superior anti-photo-bleaching ability, deep tissue penetration and intrinsically high three-dimensional resolutions are urgently needed. Two-photon-excited compounds that use low-energy near-infrared excitation lasers have emerged as non-invasive tools for cell imaging. In this work, terpyridyl cyclometalated Ir(III) complexes (Ir1-Ir3) are demonstrated as one- and two-photon phosphorescent probes for real-time imaging and tracking of mitochondrial morphology changes in living cells.

Crossfire for Two-Photon Photodynamic Therapy with Fluorinated Ruthenium (II) Photosensitizers

Synergistic photodynamic therapy (PDT) that combines photosensitizers (PSs) to attack different key sites in cancer cells is very attractive. However, the use of multiple PSs may increase dark cytotoxicity. Additionally, realizing the multiple vein passage of several PSs through dosing could be a challenge in clinical treatment. To address these issues, a novel strategy that enables a single PS to ablate two key sites (i.e., cytomembranes on the outside and mitochondria on the inside) of cancer cells synergistically was proposed. Five new fluorinated ruthenium (II) complexes (Ru1-Ru5), which possessed excellent two-photon properties and good singlet oxygen quantum yields, were designed and synthesized. When incubated with HeLa cells, the complexes were observed on the cytomembranes at first. With an extension of the treatment time, both the cytomembranes and mitochondria were lit up by the complexes. Under two-photon laser irradiation, the mitochondria and cytomembranes were ablated simultaneously, and the HeLa cells were destroyed effectively by the complexes, whether the cells were in a monolayer or in multicellular spheroids. With the largest phototoxicity index under the two-photon laser, Ru4 was used for two-photon PDT of in vivo xenograft tumors and successfully inhibited the growth of the tumors. Our results emphasized that the strategy of attacking two key sites with a single PS is an efficient method for PDT.

Enhancing the photothermal stability and photothermal efficacy of AuNRs and AuNTs by grafting with Ru(II) complexes

Gold nanorods (AuNRs) and nanostars (AuNTs) were widely applied in photothermal cancer therapy recently. However, due to the photothermal effect, naked AuNRs and AuNTs easily melt into gold spheres. This drawback results in loss of the characteristic near-infrared (NIR) surface plasmon resonance (SPR) and limits their therapeutic applications. In this paper, we reported that ruthenium(ii) complex-functionalized AuNRs (AuNRs@Ru) and AuNTs (AuNTs@Ru) exhibit higher photothermal stability and photothermal efficiency than naked AuNRs and AuNTs. AuNRs@Ru and AuNTs@Ru maintain the morphology and NIR SPR absorption of gold nanoparticles upon 0.25 W cm-2 laser irradiation, which is lower than the maximal permissible exposure of skin as per ANSI regulation (0.33 W cm-2 at 808 nm). Further photothermal therapy studies on three-dimensional (3D) HeLa spheroids and an in vivo tumor model show that AuNRs@Ru and AuNTs@Ru are more effective for the photothermal destruction of tumors than AuNRs and AuNTs.

Interfering with DNA High‐Order Structures using Chiral Ruthenium(II) Complexes

In this work, it was found that DNA can undergo B-Z transformational changes and compaction in the presence of DNA intercalators such as ruthenium(II) polypyridyl complexes. The link between B-Z transition and condensation is weak but can be strengthened under certain circumstances with slight alterations to the structures of the ruthenium(II) complexes. Here, following on from previous research, this work reports a series of ruthenium(II) complexes with imidazophenanthroline ligands, which vary in size and planarity. The complexes exhibit distinct effects on DNA structures, ranging from little impact to the transformation of DNA secondary structures to the formation of higher-order DNA structures. Further studies on DNA morphological changes induced by chiral ruthenium(II) complexes are observed by atomic force microscopy and transmission electron microscopy.