Rational design of CT-coupled J-aggregation platform based on Aza-BODIPY for highly efficient phototherapy.

Supramolecular engineering is exceptionally appealing in the design of functional materials, and J-aggregates resulting from noncovalent interactions offer intriguing features. However, building J-aggregation platforms remains a significant challenge. Herein, we report 3,5-dithienyl Aza-BODIPYs with a donor-acceptor-donor (D-A-D) architecture as the first charge transfer (CT)-coupled J-aggregation BODIPY-type platform. The core acceptor moieties in one molecule interact with donor units in neighboring molecules to generate slip-stacked packing motifs, resulting in CT-coupled J-aggregation with a redshifted wavelength up to 886 nm and an absorption tail over 1100 nm. The J-aggregates show significant photoacoustic signals and high photothermal conversion efficiency of 66%. The results obtained in vivo show that the J-aggregates have the potential to be used for tumor photothermal ablation and photoacoustic imaging. This study not only demonstrates Aza-BODIPY with D-A-D as a novel CT-coupled J-aggregation platform for NIR phototherapy materials but also motivates further study on the design of J-aggregation.

Mitochondria-targeted BODIPY dyes for small molecule recognition, bio-imaging and photodynamic therapy.

Mitochondria are essential for a diverse array of biological functions. There is increasing research focus on developing efficient tools for mitochondria-targeted detection and treatment. BODIPY dyes, known for their structural versatility and excellent spectroscopic properties, are being actively explored in this context. Numerous studies have focused on developing innovative BODIPYs that utilize optical signals for imaging mitochondria. This review presents a comprehensive overview of the progress made in this field, aiming to investigate mitochondria-related biological events. It covers key factors such as design strategies, spectroscopic properties, and cytotoxicity, as well as mechanism to facilitate their future application in organelle imaging and targeted therapy. This work is anticipated to provide valuable insights for guiding future development and facilitating further investigation into mitochondria-related biological sensing and phototherapy.

Rubus Occidentalis and its bioactive compounds against cancer: From molecular mechanisms to translational advances.

BACKGROUND: Cancer ranks as the second leading cause of death globally, imposing a significant public health burden. The rise in cancer resistance to current therapeutic agents underscores the potential role of phytotherapy. Black raspberry (BRB, Rubus Occidentalis) is a fruit rich in anthocyanins, ellagic acid, and ellagitannins. Accumulating evidence suggests that BRB exhibits promising anticancer effects, positioning it as a viable candidate for phytotherapy. PURPOSE: This article aims to review the existing research on BRB regarding its role in cancer prevention and treatment. It further analyzes the effective components of BRB, their metabolic pathways, and the potential mechanisms underlying the fruit's anticancer effects. METHODS: Ovid MEDLINE, EMBASE, Web of Science, and CENTRAL were searched through the terms of Black Raspberry, Raspberry, and Rubus Occidentali up to January 2023. Two reviewers performed the study selection by screening the title and abstract. Full texts of potentially eligible studies were retrieved to access the details. RESULTS: Out of the 767 articles assessed, 73 papers met the inclusion criteria. Among them, 63 papers investigated the anticancer mechanisms, while 10 conducted clinical trials focusing on cancer treatment or prevention. BRB was found to influence multiple cancer hallmarks by targeting various pathways. Decomposition of free radicals and regulation of estrogen metabolism, BRB can reduce DNA damage caused by reactive oxygen species. BRB can also enhance the function of nucleotide excision repair to repair DNA lesions. Through regulation of epigenetics, BRB can enhance the expression of tumor suppressor genes, inducing cell cycle arrest, and promoting apoptosis and pyroptosis. BRB can reduce the energy and nutrients supply to the cancer nest by inhibiting glycolysis and reducing angiogenesis. The immune and inflammatory microenvironment surrounding cancer cells can also be ameliorated by BRB, inhibiting cancer initiation and progression. However, the limited bioavailability of BRB diminishes its anticancer efficacy. Notably, topical applications of BRB, such as gels and suppositories, have demonstrated significant clinical benefits. CONCLUSION: BRB inhibits cancer initiation, progression, and metastasis through diverse anticancer mechanisms while exhibiting minimal side effects. Given its potential, BRB emerges as a promising phototherapeutic agent for cancer treatment.

Ultrathin 2D As2Se3 Nanosheets for Photothermal-Triggered Cancer Immunotherapy.

Arsenic trioxide (As2O3) has achieved groundbreaking success in the treatment of acute promyelocytic leukemia (APL). However, its toxic side effects seriously limit its therapeutic application in the treatment of solid tumors. To detoxify the severe side effects of arsenic, herein we synthesized innovative 2D ultrathin As2Se3 nanosheets (As2Se3 NSs) with synergistic photothermal-triggered immunotherapy effects. As2Se3 NSs are biocompatible and biodegradable under physiological conditions and can release As(III) and Se(0). Furthermore, selenium increases the immunomodulatory efficacy of arsenic treatments, facilitating reprogramming of the tumor microenvironment by As2Se3 NSs by enhancing the infiltration of natural killer cells and effector tumor-specific CD8+ T cells. The synergistic combination of photothermal therapy and immunotherapy driven by As2Se3 NSs via a simple but effective all-in-one strategy achieved efficient anticancer effects, addressing the key limitations of As2O3 for solid tumor treatment. This work demonstrates not only the great potential of selenium for detoxifying arsenic but also the application of 2D As2Se3 nanosheets for cancer therapy.

Single-atom engineering of hemicyanine and its amphiphilic derivative for optimized near infrared phototheranostics.

Near-infrared (NIR) dyes are widely used in the field of in vivo phototheranostics. Hemicyanine dyes (HDs) have recently received tremendous attention due to their easy synthesis and excellent NIR features. However, HDs can easily form non-fluorescent aggregates and their potential for phototherapy still needs further exploration due to their poor ability to generate reactive oxygen species (ROS). Herein, a series of hemicyanine dyes with different chalcogen atom (O, S, Se) substitutions were constructed to achieve optimized potential for phototheranostics. By replacing O with the heavy atom Se in the xanthene skeleton, CySe-NEt2 showed much more favourable features such as extended NIR absorption/emission wavelength, boosted 1O2 generation rate and higher photothermal effect. In addition, a poly(ethylene glycol) (PEG) group was introduced into the scaffold and yielded a nanotheranostic agent CySe-mPEG5K, which easily formed nanoparticles with appealing features such as excellent photostability, effective prevention of unpleasant H-aggregation, fast/selective tumor accumulation and minimum dark toxicity. Solid tumor growth was significantly suppressed through combined photodynamic therapy (PDT) and photothermal therapy (PTT) guided by NIR fluorescence (NIRF) and photoacoustic (PA) imaging. This study not only presents the first example of selenium-substituted hemicyanine dyes, but also offers a reliable design strategy for the development of potent NIR phototheranostic agents with multi-mode imaging-guided combination therapeutic ability.

An Optical/Photoacoustic Dual-Modality Probe: Ratiometric in/ex Vivo Imaging for Stimulated H2S Upregulation in Mice.

Tracking signaling H2S in live mice demands responsive imaging with fine tissue imaging depth and low interferences from tissue scattering/autofluorescence and probe concentration. With complementary advantages of fluorescence and photoacoustic (PA) imaging, optical/PA dual-modality imaging was suggested for in/ex vivo H2S imaging. Therefore, a meso-benzoyloxyltricarboheptamethine cyanine, HS-CyBz, was prepared as the first ratiometric optical/PA dual-modality probe for H2S, profiting from a keto-enol transition sensing mechanism. Tail intravenous injection of this probe leads to probe accumulation in the liver of mice, and the endogenous H2S upregulation triggered by S-adenosyl-l-methionine has been verified by ratiometric optical/PA imaging, suggesting the promising potential of this ratiometric dual-modality imaging.

Modulating Conformation of Aß-Peptide: An Effective Way to Prevent Protein-Misfolding Disease.

Alzheimer's disease (AD) is a typical protein-misfolding disease. Aggregation of amyloid ß-peptide (Aß) plays a key role in the etiology of AD. The misfolding of Aß results in the formation of ß-sheet-rich aggregates and damages the function of neurons. A modified polyoxometalate (POM), [CoL(H2O)]2[CoL]2[HAsVMoV6MoVI6O40] [CAM, L = 2-(1 H-pyrazol-3-yl)pyridine], was designed to disaggregate the Aß aggregates, where L acts as an Aß-targeting group and POM as a conformational modulator. X-ray crystallography shows that CAM is composed of a ε-Keggin unit and four coordination units. CAM can disaggregate the ß-sheet-rich fibrils and metal-induced or self-aggregated Aß aggregates, and it further inhibits the production of ROS; as a result, it can protect the neurons from synaptic toxicity induced by Zn2+- or Cu2+-Aß aggregates or Aß self-aggregation. The mechanism of disaggregation involves a transformation of Aß conformation from ß-sheet to other conformers. The nature of the process is an interference of the ß-sheet conformation by CAM via hydrogen bonding. CAM specifically interacts with Aß aggregates but does not disturb the cerebral metal homeostasis and enzymatic systems. Molecular simulation suggests that the appropriate size of CAM and the cavity of ß-sheets facilitate the interaction between CAM and Aß aggregates; additionally, the H-bonding-favored amino acid residues in the cavity provide a precondition for the interaction. Moreover, CAM is lipophilic and capable of penetrating the blood-brain barrier, and it is metabolizable without causing an untoward effect to mice at high dosages. In view of the significant inhibitory effect on the Aß aggregation and related neurotoxicity, CAM represents a new type of leading compounds with a distinctive mechanism of action for the treatment of Alzheimer' disease. The conception of this study may be applied to other protein-misfolding diseases caused by conformational changes.

Metal-based anticancer chemotherapeutic agents.

Since the discovery of the cisplatin antitumor activity, great efforts have focused on the rational design of metal-based anticancer agents that can be potentially used in cancer chemotherapy. Over the last four decades, a large number of metal complexes have been extensively investigated and evaluated in vitro and in vivo, and some of them were at different stages of clinical studies. Amongst these complexes, platinum (Pt(II) and Pt(IV)), ruthenium (Ru(II) and Ru(III)), gold (Au(I) and Au(III)) and titanium (Ti(IV)) complexes are the most studied metals. We describe here some most recent progresses on Pt(IV) prodrugs which can be activated once enter tumor cells, polynuclear Pt(II) complexes which have unique DNA binding ability and mode, anti-metastatic Ru(II)/Ru(III) complexes, and Au(I)/Au(III) and Ti(IV) antitumor active complexes. The key focuses of these studies lie in finding novel metal complexes which could potentially overcome the hurdles of current clinical drugs including toxicity, resistance and other pharmacological deficiencies.

Fast cleavage of a diselenide induced by a platinum(II)-methionine complex and its biological implications.

Platinum-based anticancer drugs such as cisplatin induce increased oxidative stress and oxidative damage of DNA and other cellular components, while selenium plays an important role in the antioxidant defense system. In this study, the interaction between a platinum(II) methionine (Met) complex [Pt(Met)Cl(2)] and a diselenide compound selenocystine [(Sec)(2)] was studied by electrospray ionization mass spectrometry, high performance liquid chromatography mass spectrometry, and (1)H NMR spectroscopy. The results demonstrate that the diselenide bond in (Sec)(2) can readily and quickly be cleaved by the platinum complex. Formation of the selenocysteine (Sec) bridged dinuclear complex [Pt(2)(Met-S,N)(2)(µ-Sec-Se,Cl)](3+) and Sec chelated species [Pt(Met-S,N)(Sec-Se,N)](2+) was identified at neutral and acidic media, which seems to result from the intermediate [Pt(Met-S,N)(Sec-Se)Cl](+). An accelerated formation of S-Se and S-S bonds was also observed when (Sec)(2) reacted with excessive glutathione in the presence of [Pt(Met)Cl(2)]. These results imply that the mechanism of activity and toxicity of platinum drugs may be related to their fast reaction with seleno-containing biomolecules, and the chemoprotective property of selenium agents against cisplatin-induced toxicity could also be connected with such reactions.

Copper in medicine: homeostasis, chelation therapy and antitumor drug design.

As one of the most important essential transition metals, copper is involved in a variety of biological processes such as embryo development, connective tissue formation, temperature control and nerve cell function. It is also related to severe diseases such as Wilson's and Menkes diseases and some neurological disorders. Novel components of copper homeostasis include copper-transporting P-type ATPases, Menkes and Wilson proteins, and copper chaperones in humans have been identified and characterized at the molecular level. These findings have paved the way towards better understanding of the role of copper deficiency or copper toxicity in physiological and pathological conditions. Therefore, organic compounds that can interfere with copper homeostasis may find therapeutic application in copper-dependent diseases. The antitumor activity of copper complexes was reported several decades ago, and many new complexes have demonstrated great antitumor potential. Copper complexes may have relatively lower side effects than platinum-based drugs, and are suggested to be able to overcome inherited or acquired resistance of cisplatin. In this overview, the most recent advances in copper homeostasis, copper-related chelation therapy and design of copper-based antitumor complexes will be summarized.