A Platinum-Aluminum Bimetallic Salen Complex for Pro-senescence Cancer Therapy.

Cell senescence is defined as irreversible cell cycle arrest, which can be triggered by telomere shortening or by various types of genotoxic stress. Induction of senescence is emerging as a new strategy for the treatment of cancer, especially when sequentially combined with a second senolytic drug capable of killing the resulting senescent cells, however severely suffering from the undesired off-target side effects from the senolytic drugs. Here, we prepare a bimetalic platinum-aluminum salen complex (Alumiplatin) for cancer therapy-a combination of pro-senesence chemotherapy with in situ senotherapy to avoid the side effects. The aluminum salen moiety, as a G-quadruplex stabilizer, enhances the salen's ability to induce cancer cell senescence and this phenotype is in turn sensitive to the cytotoxic activity of the monofunctional platinum moiety. It exhibits an excellent capability for inducing senescence, a potent cytotoxic activity against cancer cells both in vitro and in vivo, and an improved safety profile compared to cisplatin. Therefore, Alumiplatin may be a good candidate to be further developed into safe and effective anticancer agents. This novel combination of cell senescence inducers with genotoxic drugs revolutionizes the therapy options of designing multi-targeting anticancer agents to improve the efficacy of anticancer therapies.

Gallium Triggers Ferroptosis through a Synergistic Mechanism.

The gallium ion (Ga3+ ) has long been believed to disrupt ferric homeostasis in the body by competing with iron cofactors in metalloproteins, ultimately leading to cell death. This study revealed that through an indirect pathway, gallium can trigger ferroptosis, a type of non-apoptotic cell death regulated by iron. This is exemplified by the gallium complex of the salen ligand (Ga-1); we found that Ga-1 acts as an effective anion transporter that can affect the pH gradient and change membrane permeability, leading to mitochondrial dysfunction and the release of ferrous iron from the electron transfer chain (ETC). In addition, Ga-1 also targeted protein disulfide isomerases (PDIs) located in the endoplasmic reticulum (ER) membrane, preventing the repair of the antioxidant glutathione (GSH) system and thus enforcing ferroptosis. Finally, a combination treatment of Ga-1 and dietary polyunsaturated fatty acids (PUFAs), which enhances lipid peroxidation during ferroptosis, showed a synergistic therapeutic effect both in vitro and in vivo. This study provided us with a strategy to synergistically induce Ferroptosis in tumor cells, thereby enhancing the anti-neoplastic effect.

Biomimetically constructing a hypoxia-activated programmable phototheranostics at the molecular level.

The hypoxic microenvironment is considered the preponderant initiator to trigger a cascade of progression and metastasis of tumors, also being the major obstacle for oxygen consumption therapeutics, including photodynamic therapy (PDT). In this work, we report a programmable strategy at the molecular level to modulate the reciprocal interplay between tumor hypoxia, angiogenesis, and PDT outcomes by reinforcing synergistic action between a H2O2 scavenger, O2 generator and photosensitizer. The modular combination of a catalase biomimetic (tri-manganese cryptand, 1) and a photosensitizer (Ce6) allowed the rational design of a cascade reaction beginning with dismutation of H2O2 to O2 under hypoxic conditions to enhance photosensitization and finally photooxidation. Concurrently, this led to the decreased expression of the vascular endothelial growth factor (VEGF) and effectively reduced unwanted growth of blood vessels observed in the chick chorioallantois membrane (CAM). Notably, the proof-of-principle experiments using the tumor-bearing models proved successful in enhancing PDT efficacy, prolonging their life cycles, and improving immunity, which could be monitored by magnetic resonance imaging (MRI).

Bioinspired Design of seco-Chlorin Photosensitizers to Overcome Phototoxic Effects in Photodynamic Therapy.

Photodynamic therapy (PDT) is a non-invasive treatment modality against a range of cancers and nonmalignant diseases, however one must be aware of the risk of causing phototoxic reactions after treatment. We herein report a bioinspired design of next-generation photosensitizers (PSs) that not only effectively produce ROS but undergo fast metabolism after treatment to overcome undesirable side effects. We constructed a series of ß-pyrrolic ring-opening seco-chlorins, termed beidaphyrin (BP), beidapholactone (BPL), and their zinc(II) derivatives (ZnBP and ZnBPL), featuring intense near-infrared absorption and effective O2 photosensitization. Irradiation of ZnBPL led to a non-cytotoxic, metabolizable beidaphodiacetamide (ZnBPD) via in situ generated O2.- but not 1 O2 , as revealed by mechanistic studies including time-resolved absorption, kinetics, and isotope labeling. Furthermore, water-soluble ZnBPL showed an effective therapeutic outcome, fast metabolism, and negligible phototoxic reactions.

Nonaromatic Organonickel(II) Phototheranostics.

Earth-abundant metal-based theranostics, agents that integrate diagnostic and therapeutic functions within the same molecule, may hold the key to the development of low-cost personalized medicines. Here, we report a set of O-linked nonaromatic benzitripyrrin (C^N^N^N) macrocyclic organonickel(II) complexes, Ni-1-4, containing strong σ-donating M-C bonds. Complexes Ni-1-4 are characterized by a square-planar coordination geometry as inferred from the structural studies of Ni-1. They integrate photothermal therapy, photothermal imaging, and photoacoustic imaging (PAI) within one system. This makes them attractive as potential phototheranostics. Relative to traditional Ni(II) porphyrins, such as F20TPP (tetrapentafluorophenylporphyrin), the lowest energy absorption of Ni-1 is shifted into the near infrared region, presumably as a consequence of Ni-C bonding. Ultrafast transient absorption spectroscopy combined with theoretical calculations revealed that, upon photoexcitation, a higher population of ligand-centered and 3MLCT states is seen in Ni-1 relative to NiTPBP (TPBP = 6,11,16,21-tetraphenylbenziporphyrin). Encapsulating Ni-1 in 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) afforded nanoparticles, Ni-1@DSPE, displaying red-shifted absorption features, as well as good photothermal conversion efficiency (∼45%) in aqueous media. Proof-of-principle experiments involving thrombus treatment were carried out both in vitro and in vivo. It was found that Ni-1@DSPE in combination with 785 nm photo-irradiation for 3 min (0.3 W/cm2) proved successful in removing blood clots from a mouse thrombus model as monitored by photoacoustic imaging (PAI). The present work highlights the promise of organonickel(II) complexes as potential theranostics and the benefits that can accrue from manipulating the excited-state features of early transition-metal complexes via, for example, interrupting π-conjugation pathways.

Gadolinium(III) Porphyrinoid Phototheranostics.

Molecular phototheranostics as an emerging field of modern precision medicine has recently attracted increasing research attention owing to non-invasiveness, high precision, and controllable nature of light. In this work, we reported promising gadolinium (Gd3+ ) porphyrinoids as phototheranostic agents for magnetic resonance imaging (MRI) and photodynamic therapy (PDT). The synthesized Gd-1-4-Glu featured with meso-glycosylation and ß-lactonization to endow good biocompatibility and improved photophysical properties. In particular, ß-lactonization of glycosylated Gd3+ porphyrinoids substantially red-shifted Q band absorption to near-infrared (NIR) region and boosted generation of reactive oxygen species including 1 O2 , and some radical species that engaged in both type II and type I PDT pathways. In addition, the number and regioisomerism of ß-oxazolone moieties was observed to play an essential role in improving longitude relaxivity (r1 ) of Gd-1-4-Glu of up to 4.3±0.2 mM-1 s-1 by affecting environmental water exchange. Taking Gd-4-Glu as a promising complex, we further achieved real-time T1 -weighted MRI and PDT on HeLa tumour mice in vivo, revealing the appealing potential of Gd3+ porphyrinoids in phototheranostics.

Split and Use: Structural Isomers for Diagnosis and Therapy.

Diagnostics and therapeutics are generally separate entities in medicine. Theranostics, agents that provide for both modalities, are being developed. However, they often require complex syntheses so as to incorporate within one molecular structure both diagnostic and therapeutic elements. Moreover, their use is often complicated by the disparate dosage requirements for diagnosis and therapy. Herein, we report that closely related porphyrinoid regioisomers produced from the same 1,3-dipolar cycloaddition reaction give rise to products that as their corresponding ytterbium(III) complexes may be split and used for the separate biological functions that are required for theranostics. Specifically, the cis isomer is luminescent and suitable for NIR imaging, while the trans isomer produces singlet oxygen with a good quantum yield and is thus attractive for use in photodynamic therapy (PDT). Both in vitro and in vivo experiments provide support for the complementary biological functions of the two regioisomers. The present study reveals how ostensibly related regioisomers may be used to switch between diagnosis and therapy. More broadly, it serves to highlight a new approach to creating paired sets of molecules that may be used in combination as effective theranostics.

Rational design of an "all-in-one" phototheranostic.

We report here porphodilactol derivatives and their corresponding metal complexes. These systems show promise as "all-in-one" phototheranostics and are predicated on a design strategy that involves controlling the relationship between intersystem crossing (ISC) and photothermal conversion efficiency following photoexcitation. The requisite balance was achieved by tuning the aromaticity of these porphyrinoid derivatives and forming complexes with one of two lanthanide cations, namely Gd3+ and Lu3+. The net result led to a metalloporphodilactol system, Gd-trans-2, with seemingly optimal ISC efficiency, photothermal conversion efficiency and fluorescence properties, as well as good chemical stability. Encapsulation of Gd-trans-2 within mesoporous silica nanoparticles (MSN) allowed its evaluation for tumour diagnosis and therapy. It was found to be effective as an "all-in-one" phototheranostic that allowed for NIR fluorescence/photoacoustic dual-modal imaging while providing an excellent combined PTT/PDT therapeutic efficacy in vitro and in vivo in 4T1-tumour-bearing mice.

A Gallium(III) Complex that Engages Protein Disulfide Isomerase A3 (PDIA3) as an Anticancer Target.

Gallium(III)-based drugs have gained momentum in cancer therapy due to their iron-dependent anticancer activity. Judicious choice of ligands is critical for improved oral bioavailability, antitumor efficacy, and distinct mechanisms from simple GaIII salts. We describe GaIII complexes with planar tetradentate salen ligands [salen=2,3-bis[(4-dialkylamino-2-hydroxybenzylidene)amino]but-2-enedinitrile)] and labile axial solvent ligands, which display tumor growth inhibition in vitro and in vivo comparable to cisplatin. Confocal fluorescence microscopy, western blotting, mRNA profiling, chemical proteomics, and surface plasmon resonance (SPR) studies provide compelling evidence that PDIA3, a member of the protein disulfide isomerase (PDI) family involved in endoplasmic reticulum (ER) stress, is a direct target of Ga-1. This work offers a new route to designing and synthesizing Ga-based drugs, and also reveals that PDIA3 is an important anticancer target.

Unusual near infrared (NIR) fluorescent palladium(ii) macrocyclic complexes containing M-C bonds with bioimaging capability.

Near infrared (NIR) luminescent metal complexes are promising probes in bioimaging and biosensing, however they generally suffer from oxygen interference arising from heavy metal effects. We designed new tetradentate macrocyclic benzitripyrrin (C^N^N^N) ligands by combination of M-C bond formation and reducing the π-conjugation to achieve NIR fluorescent Pd complexes (700-1000 nm) with quantum yields up to 14%. To understand the origin of NIR fluorescence, detailed analyses by density functional theory/time-dependent density functional theory (DFT/TDDFT) calculations together with femtosecond and nanosecond transient absorption spectroscopies suggest that M-C bond formation indeed leads to destabilization of the d-d excited state and less effective quenching of emission; and importantly, small spin-orbital coupling (SOC) and the large singlet-triplet energy gap are the primary causes of the non-population of triplet states. Comparison of PdII and PtII analogues shows that the non-radiative channel of the out-plane vibration of the tripyrrin plane effectively quenches the fluorescence of the PtII complex but not the PdII congener. We also demonstrate the proof-of-concept applications of PdII complexes (Pd-1 and Pd-3) encapsulated in silica nanoparticles, in both in vitro and in vivo bioimaging experiments without oxygen interference. Moreover, pH-induced reversible switching of NIR fluorescence was achieved even intracellularly using the Pd complex (Pd-2), which shows the potential to further develop perspective stimuli-responsive NIR materials.

Gadolinium(III) Porpholactones as Efficient and Robust Singlet Oxygen Photosensitizers.

Construction of Gd(III) photosensitizers is important for designing theranostic agents owing to the unique properties arising from seven unpaired f electrons of the Gd(3+) ion. Combining these with the advantages of porpholactones with tunable NIR absorption, we herein report the synthesis of Gd(III) complexes Gd-1-4 (1, porphyrin; 2, porpholactone; 3 and 4, cis- and trans-porphodilactone, respectively) and investigated their function as singlet oxygen ((1) O2 ) photosensitizers. These Gd complexes displayed (1) O2 quantum yields (ΦΔ s) from 0.64-0.99 with the order Gd-1