Fine-tuning the side-chain length of iridium(III) complexes for enhanced Photophysical properties in Cancer Theranostics.

Cyclometalated iridium(III) complexes have emerged as versatile candidates for cancer theranostics, offering integrated diagnostic imaging and potent singlet oxygen (1O2) generation for photodynamic therapy (PDT). However, their application has been limited by subdued photoluminescence, primarily due to intramolecular motion-induced excited energy dissipation. In this study, we address these limitations through the design and synthesis of five novel iridium(III) complexes: IrC2, IrC4, IrC6, IrC8, and IrC12. Our approach employs meticulous side-chain extending strategy to modulate side-chain length, thereby reducing intramolecular motion and significantly enhancing both one- and three-photon emissions and 1O2 production in the aggregated state. Detailed photophysical investigations, supported by crystallographic insights, reveal that side-chain elongation substantially amplifies these properties. Among the synthesized complexes, IrC8 stands out as a superior candidate for image-guided photodynamic therapy in cellular and 3D tumor spheroid models. This investigation pioneers the simultaneous enhancement of dual-photon emissions and PDT efficacy through a novel side-chain extension strategy in iridium(III) complexes, paving the way for their translational application in clinical theranostics.

Advancing Two-Photon Photodynamic Therapy Over NIR-II Excitable Conjugated Microporous Polymer with NIR-I Emission.

The availability of second near-infrared (NIR-II) excitable two-photon photosensitizers with NIR-I emission for efficient photodynamic therapy (PDT) is limited by challenges in molecular design. In this study, a NIR-II light-excitable two-photon conjugated microporous polymer (Tph-Dbd) with emission in the NIR-I region is developed. The large conjugated system and delocalized electronic structures endow Tph-Dbd with a large two-photon absorption cross-section under NIR-II light excitation. Moreover, the efficient electron acceptor and donor units within the π-conjugated backbones result in NIR-I emission for high signal-to-background ratio imaging, as well as separated highest occupied molecular orbital and lowest unoccupied molecular orbital distributions for excellent singlet oxygen generation ability. The excellent NIR-II excitable two-photon absorption activity, NIR-I emission, good biocompatibility, and high photostability allow Tph-Dbd to be used for efficient in vitro fluorescence imaging guided PDT. Moreover, the impressive photothermal effect of Tph-Dbd can overcome the limitations of PDT in the treatment of hypoxic tumors. This study highlights a strategy for designing NIR-II excitable two-photon photosensitizers for advanced PDT.

Elevating Nonlinear Optical Response through d-electron Modulation in Metal-Organic Frameworks.

Electronic structure and excited state behavior is of pronounced influence on regulation of nonlinear optical (NLO) response. Herein, a serials of transition metal ions bearing different d-electron numbers were in situ coordinated within porphyrinic metal-organic frameworks (MOFs), creating NLO-responsive M-metal (metal = Fe, Co, Ni, Cu, and Zn) frameworks. It demonstrated that the NLO properties can be optimized with the increased occupancy of the d-shell, which enhances the degree of delocalization. Specifically, the full-filled (d10) electron configuration of Zn2+ stabilizes the electronic structure, combination with π-π* local excitation character of M-Zn, promoting charge transfer process and resulting in outstanding NLO properties. Moreover, parameters related to the nonlinear process (ß, n2, Imχ(3), Reχ(3) and χ(3)) of M-Zn are calculated to be higher than those of other materials, consistent with theoretical calculations. This work paves the way for NLO modulation based on electronic analysis and provides a promising approach for constructing high-performance NLO materials.

Dramatically Enhancing Multiphoton Harvesting Metal-Organic Frameworks for NIR-II Photocatalysis through Functional Regulation of Octupolar Molecules.

The development of effective multiphoton absorption (MPA) materials for near-infrared (NIR) light-driven photocatalysis holds great significance. In this study, we incorporated two multibranched cyclometallated iridium(III) modules with varying degrees of conjugation onto MPA-inert metal-organic frameworks (MOFs) to active MPA performance. Subsequently, the MOFs were further modified with Co(II) and hyaluronic acid (HA) to fabricate MINCH and MISCH, respectively. By introducing octupolar molecules and expanding the conjugation, MISCH exhibited a larger MPA cross section for efficient NIR light absorption and improved carrier transfer, leading to outstanding NIR light-driven multiphoton photocatalytic hydrogen production. Moreover, the HA modification enabled MISCH to achieve specific multiphoton photocatalytic hydrogen therapy for cancer cells. This study provides valuable insights into constructing highly active MPA materials for NIR light-driven photocatalysis, presenting a potential platform for hydrogen therapy in tumor treatment.

Harnessing Metal-Organic Frameworks for NIR-II Light-Driven Multiphoton Photocatalytic Water Splitting in Hydrogen Therapy.

The construction of near-infrared (NIR) light-activated hydrogen-producing materials that enable the controlled generation and high-concentration release of hydrogen molecules in deep tumor tissues and enhance the effects of hydrogen therapy holds significant scientific importance. To address the key technical challenge of low-efficiency oxidation-reduction reactions for narrow-bandgap photocatalytic materials, this work proposes an innovative approach for the controllable fabrication of multiphoton photocatalytic materials to overcome the limitations imposed by traditional near-infrared photocatalysts with "narrow-bandgap" constraints. Herein, an NIR-responsive multiphoton photocatalyst, ZrTc-Co, is developed by utilizing a post-synthetic coordination modification strategy to introduce hydrogenation active site CoII into a multiphoton responsive MOF (ZrTc). The results reveal that with the introduction of the CoII site, electron-hole recombination can be efficiently suppressed, thus promoting the efficiency of hydrogen evolution reaction. In addition, the integration of CoII can effectively enhance charge transfer and improve static hyperpolarizability, which endows ZrTc-Co with excellent multiphoton absorption. Moreover, hyaluronic acid modification endows ZrTc-Co with cancer cell-specific targeting characteristics, laying the foundation for tumor-specific elimination. Collectively, the proposed findings present a strategy for constructing NIR-II light-mediated hydrogen therapeutic agents for deep tumor elimination.

Advancing Central Nervous System Drug Delivery with Microtubule-Dependent Transcytosis of Novel Aqueous Compounds.

The challenge of delivering therapeutics to the central nervous system due to the restrictive nature of the blood-brain barrier (BBB) is a substantial hurdle in neuropharmacology. Our research introduces a breakthrough approach using microtubule-dependent transcytosis facilitated by novel aqueous compounds. We synthesized a series of red-emitting pyran nitrile derivatives. The molecular structure of compounds, photophysical properties, and water solubility were characterized. BBB permeability of BN1 was assessed in an in vitro BBB model. The transmembrane transport mechanism was next analyzed. The derivative was injected in the wild-type mouse for evaluation of brain penetration and biodistribution in the brain. We further investigated the potential of BN1-functionalized BBB-nonpenetrated silica nanoparticles for brain targeting. This compound demonstrated an ability to form endosomes within the phospholipid layer, thus enabling efficient penetration of the BBB via microtubule-mediated transcytosis, as evidenced in vitro model. This was further confirmed by in vivo experiments that BN1 displays the excellent BBB penetration and retained in brain parenchyma. Furthermore, BBB-impermeable mesoporous silica nanoparticle codelivery system markedly enhanced the transport efficiency to the brain in vivo by BN1-functionalized. These findings indicate that our designed aqueous molecules not only are capable of traversing the BBB but also serve as a viable new strategy for central-nervous-system-targeted drug delivery.

Correlative Super-resolution Optical and Electron Microscopic Imaging of Intracellular Ribosomal RNA by a Terpyridine Iridium(III) Complex.

Ribosomal RNA (rRNA) plays a vital role in binding amino acids together, which dictates the primary structure of a protein. Visualization of its intracellular distribution and dynamics during protein synthesis enables a better understanding of the correlated biological essence. However, appropriate tools targeting live cell rRNA that are capable of multimodal imaging at the nanoscale are still lacking. Here, we rationally designed a series of terpyridine ammonium iridium(III) complexes, one of which is capable of selectively labeling rRNA in living cells. Its metal core and photostable nature allow further super-resolution STED imaging of rRNA found on the rough endoplasmic reticulum at a ∼40 nm resolution that is well correlated under correlative light and electron microscopy (CLEM). Interestingly, the Ir(III) complex demonstrated rRNA dynamics in living cells while boosting protein synthesis at the nanoscale. Our work offers a versatile tool to visualize rRNA synchronously under optical and electron microscopy, which provides a better understanding of rRNA evolution in living systems.

Model-based closed-loop control of thalamic deep brain stimulation.

Introduction: Closed-loop control of deep brain stimulation (DBS) is beneficial for effective and automatic treatment of various neurological disorders like Parkinson's disease (PD) and essential tremor (ET). Manual (open-loop) DBS programming solely based on clinical observations relies on neurologists' expertise and patients' experience. Continuous stimulation in open-loop DBS may decrease battery life and cause side effects. On the contrary, a closed-loop DBS system uses a feedback biomarker/signal to track worsening (or improving) of patients' symptoms and offers several advantages compared to the open-loop DBS system. Existing closed-loop DBS control systems do not incorporate physiological mechanisms underlying DBS or symptoms, e.g., how DBS modulates dynamics of synaptic plasticity. Methods: In this work, we propose a computational framework for development of a model-based DBS controller where a neural model can describe the relationship between DBS and neural activity and a polynomial-based approximation can estimate the relationship between neural and behavioral activities. A controller is used in our model in a quasi-real-time manner to find DBS patterns that significantly reduce the worsening of symptoms. By using the proposed computational framework, these DBS patterns can be tested clinically by predicting the effect of DBS before delivering it to the patient. We applied this framework to the problem of finding optimal DBS frequencies for essential tremor given electromyography (EMG) recordings solely. Building on our recent network model of ventral intermediate nuclei (Vim), the main surgical target of the tremor, in response to DBS, we developed neural model simulation in which physiological mechanisms underlying Vim-DBS are linked to symptomatic changes in EMG signals. By using a proportional-integral-derivative (PID) controller, we showed that a closed-loop system can track EMG signals and adjust the stimulation frequency of Vim-DBS so that the power of EMG reaches a desired control target. Results and discussion: We demonstrated that the model-based DBS frequency aligns well with that used in clinical studies. Our model-based closed-loop system is adaptable to different control targets and can potentially be used for different diseases and personalized systems.

Nanoscale myelinogenesis image in developing brain via super-resolution nanoscopy by near-infrared emissive curcumin-BODIPY derivatives.

Understanding the intricate nanoscale architecture of neuronal myelin during central nervous system development is of utmost importance. However, current visualization methods heavily rely on electron microscopy or indirect fluorescent method, lacking direct and real-time imaging capabilities. Here, we introduce a breakthrough near-infrared emissive curcumin-BODIPY derivative (MyL-1) that enables direct visualization of myelin structure in brain tissues. The remarkable compatibility of MyL-1 with stimulated emission depletion nanoscopy allows for unprecedented super-resolution imaging of myelin ultrastructure. Through this innovative approach, we comprehensively characterize the nanoscale myelinogenesis in three dimensions over the course of brain development, spanning from infancy to adulthood in mouse models. Moreover, we investigate the correlation between myelin substances and Myelin Basic Protein (MBP), shedding light on the essential role of MBP in facilitating myelinogenesis during vertebral development. This novel material, MyL-1, opens up new avenues for studying and understanding the intricate process of myelinogenesis in a direct and non-invasive manner, paving the way for further advancements in the field of nanoscale neuroimaging.

Modeling Instantaneous Firing Rate of Deep Brain Stimulation Target Neuronal Ensembles in the Basal Ganglia and Thalamus.

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for movement disorders, including Parkinson disease and essential tremor. However, the underlying mechanisms of DBS remain elusive. Despite the capability of existing models in interpreting experimental data qualitatively, there are very few unified computational models that quantitatively capture the dynamics of the neuronal activity of varying stimulated nuclei-including subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and ventral intermediate nucleus (Vim)-across different DBS frequencies. MATERIALS AND METHODS: Both synthetic and experimental data were used in the model fitting; the synthetic data were generated by an established spiking neuron model that was reported in our previous work, and the experimental data were provided using single-unit microelectrode recordings (MERs) during DBS (microelectrode stimulation). Based on these data, we developed a novel mathematical model to represent the firing rate of neurons receiving DBS, including neurons in STN, SNr, and Vim-across different DBS frequencies. In our model, the DBS pulses were filtered through a synapse model and a nonlinear transfer function to formulate the firing rate variability. For each DBS-targeted nucleus, we fitted a single set of optimal model parameters consistent across varying DBS frequencies. RESULTS: Our model accurately reproduced the firing rates observed and calculated from both synthetic and experimental data. The optimal model parameters were consistent across different DBS frequencies. CONCLUSIONS: The result of our model fitting was in agreement with experimental single-unit MER data during DBS. Reproducing neuronal firing rates of different nuclei of the basal ganglia and thalamus during DBS can be helpful to further understand the mechanisms of DBS and to potentially optimize stimulation parameters based on their actual effects on neuronal activity.

Visualizing intracellular membrane interactions and cell type-specific differentiation in ferroptosis and apoptosis with Boranil-Carbazole derivative.

Intracellular lipid systems play essential roles in various physiological functions and cell growth processes. However, our understanding of the intricate interactions within this system, especially between mitochondria and lipid droplets, is limited, particularly in the context of cancer cells' altered lipid metabolism. To address this, our study introduces an N-B-O BODIPY-hexylcarbazole derivative, named Cz-Boranil, that sets a new benchmark in visualizing these critical interactions. Cz-Boranil's unique capability lies in its ability to display distinct intracellular distribution patterns in both normal and cancer cells, offering nuanced cell type-specific differentiation. More impressively, this probe tracks the coordinated interactions of lipid droplets and mitochondria during the critical processes of ferroptosis and apoptosis. We believe that the innovative capabilities of Cz-Boranil will revolutionize our understanding of intracellular lipid interactions and prove pivotal in identifying and studying cancerous cells.

Restriction of intramolecular rotation for functionalizing metal nanoclusters.

The restriction of intramolecular rotation has been extensively exploited to trigger the property enhancement of nanocluster-based materials. However, such a restriction is induced mainly by intermolecular aggregation. The direct restriction of intramolecular rotation of metal nanoclusters, which could boost their properties at the single molecular level, remains rarely explored. Here, ligand engineering was applied to activate intramolecular interactions at the interface between peripheral ligands and metallic kernels of metal nanoclusters. For the newly reported Au4Ag13(SPhCl2)9(DPPM)3 nanocluster, the molecule-level interactions between the Cl terminals on thiol ligands and the Ag atoms on the cluster kernel remarkably restricted the intramolecular rotation, endowing this robust nanocluster with superior thermal stability, emission intensity, and non-linear optical properties over its cluster analogue. This work presents a novel case of the restriction of intramolecular rotation (i.e., intramolecular interaction-induced property enhancement) for functionalizing metal clusters at the single molecular level.

Boosting activity of γ-alumina-supported vanadium catalyst for isobutane non-oxidative dehydrogenation via pure V3.

The vanadium-based dehydrogenation (DH) catalyst is becoming a promise alternative to the industrial used Pt- and Cr-based catalysts, due to lower cost and less environmental threat. However, the low DH activity hampered the industrial application of vanadium-based catalysts. Herein, for the first time, we introduce a method to prepare high-efficiency vanadium-based catalyst by constructing pure V3+ species on γ-Al2O3 through treatment of as-prepared thiovanadate. The V3+ species contributes to not only enhancing the DH activity, but also fabricating the V3+-O/S acid-base pair with ideal strength and stability. The isobutene yield can reach as high as 56.9 wt%. Only Lewis acid is recognized on V3+/Al2O3 catalyst, while no Brønsted acid remains. The side-reactions are consequently inhibited, and the selectivity to isobutene is improved. Besides, with the increase of vanadium loadings, the Lewis acid content increases at first and then decreases, and the content of acid sites in middle strength keeps decreasing. Though the deposited coke on V3+/Al2O3 was just 2.5 wt% during 8.5 h consecutive DH reaction, the valence state of vanadium was still influenced and the fraction of inert V4+ species increased steadily. This study will improve the potential for industrial application of vanadium-based DH catalyst, and offer theoretical guidance for optimization of ideal DH catalysts.

Revealing the amyloid ß-protein with zinc finger protein of micronucleus during Alzheimer's disease progress by a quaternary ammonium terpyridine probe.

Micronucleus (MN) is regarded as an abnormal structure in eukaryotic cells which can be used as a biomarker for genetic instability. However, direct observation of MN in living cells is rarely achieved due to the lack of probes that are capable of distinguishing nuclear- and MN-DNA. Herein, a water-soluble terpyridine organic small molecule (ABT) was designed and employed to recognize Zinc-finger protein (ZF) for imaging intracellular MN. The in vitro experiments suggested ABT has a high affinity towards ZF. Further live cell staining showed that ABT could selectively target MN in HeLa and NSC34 cells when combined with ZF. Importantly, we use ABT to uncover the correlation between neurotoxic amyloid ß-protein (Aß) and MN during Alzheimer's disease (AD) progression. Thus, this study provides profound insight into the relationship between Aß and genomic disorders, offering a deeper understanding for the diagnosis and treatment of AD.

Lighting up RNA-specific multi-photon and super-resolution imaging using a novel zinc complex.

Ribonucleic acid (RNA) probes are critical for understanding the role of RNA dynamics in cellular function but are in short supply due to the lack of optimized imaging systems and excellent fluorescence emission performance. Here, the terpyridine Zn(II) complex (Zn-T) with D-π-A configuration and bright aggregation-induced fluorescence emission (AIE) has been fabricated for the selective detection and real-time monitoring of RNA. Impressively, Zn-T exhibits a large Stokes shift and three-photon absorption (3PA) activity and responds specifically through hydrophobic interactions with an RNA pocket. The combination of AIE-assisted two-photon fluorescence and stimulated emission depletion (STED) microscopy of Zn-T for imaging nuclear RNA has higher spatial resolution and brightness, thus providing an imaging platform for studying RNA-related physiological or pathological processes.

Four-Photon Absorption Iron Complex for Magnetic Resonance/Photoacoustic Dual-Model Imaging and an Enhanced Ferroptosis Process.

Four-photon absorption (4PA) multimodal therapeutic agent applied to tumor ferroptosis process tracking is rarely reported. In this paper, two functionalized terpyridine iron complexes (TD-FeCl3, TD-Fe-TD) with four-photon absorption properties were designed and synthesized. The four-photon absorption cross sections of TD-FeCl3 reached 6.87 × 10-74cm8·s3·photon-3. Due to its strong near-infrared absorption, TD-FeCl3 has excellent photoacoustic imaging (PAI) capability for accurate PA imaging. TD-FeCl3 has an efficient longitudinal electron relaxation rate (r1 = 2.26 mM-1 s-1) and high spatial resolution, which can be applied as T1-weighted magnetic resonance imaging (MRI) contrast agent for tumor imaging in vivo. In addition, Fe3+ as a natural ferroptosis tracer, TD-FeCl3, is able to deplete glutathione (GSH) effectively, which can further enhance the ferroptosis process. We found that the series of cheap transition metal complexes has four-photon absorption activity and can be used as multimodal (MRI/PAI) diagnostic agents for tumor tracing processes.

A tumor microenvironment-activated metal-organic framework-based nanoplatform for amplified oxidative stress-induced enhanced chemotherapy.

Engineering a highly tumor microenvironment-responsive nanoplatform toward effective chemotherapy has always been a challenge in targeted cancer treatment. Metal-organic frameworks are a promising delivery system to reformulate previously approved drugs for enhanced chemotherapy, such as disulfiram (DSF). Herein, a tumor microenvironment-activated metal-organic framework-based nanoplatform DSF@MOF-199@FA has been fabricated to realize amplified oxidative stress-induced enhanced chemotherapy. Our results unveil that the copper ions and DSF released by DSF@MOF-199@FA in an acidic environment can be converted into toxic bis(N, N-diethyl dithiocarbamate) copper and then induce cell apoptosis. Simultaneously, we determined that the apoptosis outcome is further promoted by amplified oxidative stress through effective generation of reactive oxygen species and GSH elimination. In conclusion, this work provides a promising platform for effective anticancer treatment.

Nanoscopic evaluation on mitochondrial ultrastructures by regulating reactive oxygen species productivity within terpyridyl Zn(II) complexes with different alkyl chain lengths.

Mitochondria targeting complexes are widely utilized as photosensitizers in photodynamic therapy. However, the mechanisms by which they regulate reactive oxygen species (ROS) production at the molecular level and their influence on intracellular mitochondrial signaling and ultrastructures remain rarely studied. Herein, we present two terpyridyl Zn(II) complexes with different side alkyl chain lengths (Zn-2C and Zn-6C) that lead to low and high ROS productivities in vitro, respectively. Both complexes could enter live cells effectively with minimal dark toxicity and accumulate preferably in the mitochondria. We also demonstrated that Zn-6C, with more efficient ROS productivity, could significantly downregulate the caspase signaling pathway but showed no evident influence on mitochondrial membrane proteins. We also highlighted and compared the mitochondrial ultrastructural variations during such a process by stimulated emission depletion (STED) super-resolution nanoscopy.

Novel two-photon absorption compounds with different organic cations: facile synthesis, photophysical properties, detection of viscosity, and selective imaging of the endoplasmic reticulum in living cells.

Three novel imidazole-based two-photon absorption compounds bearing different organic cations (1PIPy, 2PIQu, and 3PIIm) were facilely synthesized and fully characterized by 1H NMR, 13C NMR, FT-IR, and HRMS. The linear and nonlinear photophysical properties of the target compounds were systematically investigated in various solvents, supplemented with the density functional theory calculations to shed light on their structure-property relationships. The maximum two-photon action cross-sections (Φ × Î´max) were determined to be 22.4-98.2 (CH2Cl2), 9.6-41.3 (DMF), and 3.9-11.8 (H2O) GM. It is found that 3PIIm shows significant viscosity sensitivity with a sharp 27-fold increase in fluorescence intensity. Its fluorescence intensity also exhibits a linear relationship with the viscosity of the media in a logarithmic plot. The Φ × Î´max value of 3PIIm in highly viscous glycerol was found to be 107.5 GM. Cytotoxicity tests indicate that these compounds have relatively low cytotoxicity. All the target compounds were successfully characterized by one- and two-photon fluorescence imaging in living cells. The colocalization experiments reveal that 1PIPy and 3PIIm are specially located in the endoplasmic reticulum (ER) with the Pearson's coefficients above 0.90. 3PIIm can also monitor the fluctuation of ER viscosity during etoposide-induced apoptosis.

In Situ Coordination and Confinement of Two-Photon Active Unit Within Metal-Organic Frameworks for High-Order Multiphoton-Excited Fluorescent Performance.

Exploration of high-order multiphoton-excited fluorescent (H-MPEF) material for bioimaging with deeper tissue penetration and higher spatial resolution has attracted great interest but remains a challenge. Herein, a H-MPEF-responsive metal-organic framework-based material, ZLPH, was rationally fabricated by the pore confinement of a two-photon active unit (ZL) using the "ship-in-bottle" strategy. It demonstrated that the judicious selection effectively avoided the annoying weakened/quenched H-MPEF behavior due to the instability of ZL in the molecular state. Moreover, the obtained material, ZLPH, exhibited bright four-photon-excited fluorescence (4PEF) under the excitation of a 1550 nm femtosecond laser. In view of deep-tissue biological applications, it is envisioned that this work provides a promising platform for bright H-MPEF imaging.