📋 Browse Articles

Nanocarriers are fundamentally transforming targeted drug delivery (TDD) by addressing the major limitations of conventional therapies, such as systemic toxicity and poor drug localization. These nanoscopic vehicles, including liposomes and polymeric nanoparticles, typically sized between 1 and 100 nanometers, are engineered to encapsulate, protect, and escort therapeutic agents until they reach the precise site of action. The key to their success lies in targeted delivery mechanisms. Passive targeting utilizes the enhanced permeability and retention (EPR) effect, where nanocarriers accumulate preferentially in leaky tumor vasculature. Active targeting involves surface modification with specific ligands (e.g., functional chemical/group, antibodies, or peptides) that bind to overexpressed receptors on diseased cells, ensuring high local drug concentration. This precision significantly boosts therapeutic efficacy while minimally affecting healthy tissues, leading to fewer side effects. This review provides an in-depth examination of TDD, highlighting how nanocarriers are essential in achieving precision and improving therapeutic outcomes. It explores the diverse strategies and suitable materials utilized to guide therapeutic agents specifically to disease sites while minimizing systemic toxicity. Show less

Submarine hydrothermal vents harbor diverse microbial communities and have long intrigued researchers studying the origin of life. Transition metals in these environments can be reduced by serpentinization, potentially forming zeolite-supported transition metal nanoparticles capable of driving prebiotic chemistry. This inorganic structure could catalyze biochemical reactions, including converting metabolically crucial pyruvate before the emergence of biological processes. This study explores the catalytic interconversion of pyruvate and lactate, mediated by lactate dehydrogenase in biochemical systems, using inorganic zeolite Y-supported Ni nanoparticles (Ni/Y) under mild hydrothermal vent conditions. Our results demonstrate that Ni/Y effectively catalyzes the hydrogenation of pyruvate in an inert environment, facilitated by the in situ generation of H₂ through an autocatalytic reaction between Ni/Y and H₂O. Post-reaction analysis by X-ray absorption spectroscopy (XAS) revealed structural transformations in the catalyst, including the formation of unique nickel oxide and hydroxide species, along with extra-framework aluminum from zeolite dealumination, resulting in a thin amorphous nickel oxide/hydroxide layer. Notably, Ni/Y also enables the oxidative reconversion of lactate to pyruvate under atmospheric conditions-an essential reaction catalyzed by lactate dehydrogenase in biological systems. These findings underscore the potential prebiotic role of Ni/Y, suggesting they may have catalyzed the synthesis of key metabolic intermediates. Show less

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Since the identification of dihydroorotate dehydrogenase (DHODH) as a mitochondrial suppressor of ferroptosis in 2021, increasing evidence has highlighted its role in linking nucleotide metabolism, redox regulation, and tumor progression. We conducted a comprehensive review of publications on DHODH, ferroptosis, and cancer. Relevant studies were analyzed to synthesize mechanistic insights, translational implications, and therapeutic perspectives. DHODH, a flavin-dependent mitochondrial enzyme catalyzing the oxidation of dihydroorotate to orotate, integrates pyrimidine biosynthesis with electron transport chain activity. Beyond its canonical metabolic role, DHODH regenerates ubiquinol (CoQ10H2) to suppress mitochondrial lipid peroxidation and ferroptosis. Elevated DHODH expression in colorectal, hepatocellular, breast, renal, and brain cancers correlates with poor prognosis, therapy resistance, and immune evasion. Pharmacological inhibition of DHODH disrupts pyrimidine synthesis and redox defense, sensitizing GPX4-low tumors to ferroptosis. Preclinical studies demonstrate synergy between DHODH inhibitors and chemotherapy, radiotherapy, or immune checkpoint blockade. Nanoparticle-based delivery systems enhance therapeutic efficacy by simultaneously targeting multiple ferroptosis defense arms while reducing toxicity. DHODH serves as both a metabolic and redox checkpoint in cancer, linking ferroptosis suppression to proliferation and immune escape. Targeting DHODH offers a promising strategy to dismantle cancer resilience, particularly in combination with ferroptosis inducers and immunotherapies. Future research should focus on biomarker-guided stratification, nanomedicine platforms, and clinical translation of DHODH inhibitors. Show less

Copper is a necessary micronutrient for maintaining the well-being of the human body. The biological activity of organic ligands, especially their anticancer activity, is often enhanced when they coordinate with copper(I) and (II) ions. Copper and its compounds are capable of inducing tumor cell death through various mechanisms of action, including activation of apoptosis signaling pathways by reactive oxygen species (ROS), inhibition of angiogenesis, induction of cuproptosis, and paraptosis. Some of the copper complexes are currently being evaluated in clinical trials for their ability to map tumor hypoxia in various cancers, including locally advanced rectal cancer and bulky tumors. Several studies have shown that copper nanoparticles can be used as effective agents in chemodynamic therapy, phototherapy, hyperthermia, and immunotherapy. Despite the promising anticancer activity of copper-based compounds, their use in clinical trials is subject to certain limitations. Elevated copper concentrations may promote tumor growth, angiogenesis, and metastasis by affecting cellular processes. Show less

Cuproptosis, a newly identified copper (Cu)-dependent form of cell death, stands out due to its distinct mechanism that sets it apart from other known cell death pathways. The molecular underpinnings of cuproptosis involve the binding of Cu to lipoylated enzymes in the tricarboxylic acid cycle. This interaction triggers enzyme aggregation and proteotoxic stress, culminating in cell death. The specific mechanism of cuproptosis has yet to be fully elucidated. This newly recognized form of cell death has sparked numerous investigations into its role in tumorigenesis and cancer therapy. In this review, we summarized the current knowledge on Cu metabolism and its link to cancer. Furthermore, we delineated the molecular mechanisms of cuproptosis and summarized the roles of cuproptosis-related genes in cancer. Finally, we offered a comprehensive discussion of the most recent advancements in Cu ionophores and nanoparticle delivery systems that utilize cuproptosis as a cutting-edge strategy for cancer treatment. Show less

ConspectusThe study of the origin of life requires a multifaceted approach to understanding where and how life arose on Earth. One of the most compelling hypotheses is the chemosynthetic origin of life at hydrothermal vents, as this condition has been considered viable for early forms of life. The continuous production of H2 and heat by serpentinization generates reductive conditions at hydrothermal vents, in which CO2 can be used to build large biomolecules. Although this involves surface catalysis and an autocatalytic process, in which solid minerals act as catalysts in the conversion of CO2 to metabolically important organic molecules, the systematic investigation of heterogeneous catalysis to comprehend prebiotic chemistry at hydrothermal vents has not been undertaken.In this Account, we discuss geochemical CO2 fixation to metabolic intermediates by synthetic minerals at hydrothermal vents from the perspective of heterogeneous catalysis. Ni and Fe are the most abundant transition metals at hydrothermal vents and occur in the active site of the enzymes carbon monoxide dehydrogenases/acetyl coenzyme A synthases (CODH/ACS). Synthetic free-standing NiFe alloy nanoparticles can convert CO2 to acetyl coenzyme A pathway intermediates such as formate, acetate, and pyruvate. The same alloy can further convert pyruvate to citramalate, which is essential in the biological citramalate pathway. Thermal treatment of Ni3Fe nanoparticles under NH3, which can occur in hydrothermal vents, results in Ni3FeN/Ni3Fe heterostructures. This catalyst has been demonstrated to produce prebiotic formamide and acetamide from CO2 and H2O using Ni3FeN/Ni3Fe as both substrate and catalyst. In the process of serpentinization, Co can be reduced in the vicinity of olivine, a Mg-Fe silicate mineral. This produces CoFe and CoFe2 with serpentine in nature, representing SiO2-supported CoFe alloys. In mimicking these natural minerals, synthetic SiO2-supported CoFe alloys demonstrate the same liquid products as NiFe alloys, namely, formate, acetate, and pyruvate under mild hydrothermal vent conditions. In contrast to the NiFe system, hydrocarbons up to C6 were detected in the gas phase, which is also present in hydrothermal vents. The addition of alkali and alkaline-earth metals to the catalysts results in enhanced formate concentration, playing a promotional role in CO2 reduction. Finally, Co was loaded onto ordered mesoporous SiO2 after modification with cations to simulate the minerals found in hydrothermal vents. These catalysts were then investigated under diminished H2O concentration, revealing the conversion of CO2 to CO, CH4, methanol, and acetate. Notably, the selectivity to metabolically relevant methanol was enhanced in the presence of cations that could generate and stabilize the methoxy intermediate. Calculation using the machine learning approach revealed the possibility of predicting the selectivity of CO2 fixation when modifying mesoporous SiO2 supports with heterocations. Our research demonstrates that minerals at hydrothermal vents can convert CO2 into metabolites under a variety of prebiotic conditions, potentially paving the way for modern biological CO2 fixation processes. Show less

Abstract Ferroptosis is a new form of regulated cell death featuring iron‐dependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosis‐based cancer therapy in eradicating refractory malignancies that are resistant to apoptosis‐based conventional therapies. In recent years, studies have reported a number of ferroptosis inducers that can increase the vulnerability of tumor cells to ferroptosis by regulating ferroptosis‐related signaling pathways. Encouraged by the rapid development of ferroptosis‐driven cancer therapies, interdisciplinary fields that combine ferroptosis, pharmaceutical chemistry, and nanotechnology are focused. First, the prerequisites and metabolic pathways for ferroptosis are briefly introduced. Then, in detail emerging ferroptosis inducers designed to boost ferroptosis‐induced tumor therapy, including metal complexes, metal‐based nanoparticles, and metal‐free nanoparticles are summarized. Subsequently, the application of synergistic strategies that combine ferroptosis with apoptosis and other regulated cell death for cancer therapy, with emphasis on the use of both cuproptosis and ferroptosis to induce redox dysregulation in tumor and intracellular bimetallic copper/iron metabolism disorders during tumor treatment is discussed. Finally, challenges associated with clinical translation and potential future directions for potentiating cancer ferroptosis therapies are highlighted. Show less

We describe the synthesis of a triazolyl-pyridine-based aminophosphine, N-(diphenylphosphaneyl)-6-(1-phenyl)-1H-(1,2,3-triazol-4-yl)pyridine-2-amine [2,6-{(PPh2)-N(H)(C5H3N)(C2HN3C6H5)}] [1, PN(H)N hereafter], and its palladium and platinum complexes and their catalytic application. The reaction of 1 with [M(COD)Cl2] (M = Pd or Pt) afforded the cationic complex [(MCl){PN(H)N}-κ3-P,N,N]Cl [M = Pd (2) or Pt (3)]. Alternatively, compounds 2 and 3 were also synthesized by treating [2,6-{H2N(C5H3N)(C2HN3C6H5)}] (A) with [M(COD)Cl2] (M = Pd or Pt), followed by the addition of stoichiometric amounts of PPh2Cl and Et3N. The neutral, dearomatized complexes [(MCl){PNN}-κ3-P,N,N] [M = Pd (4) or Pt (5)] were prepared by the deprotonation of the NH of 2 and 3 with 1 equiv of tBuOK. Compounds 4 and 5 were also synthesized stepwise by treating [2,6-{H2N(C5H3N)(C2HN3C6H5)}] (A) with [M(COD)Cl2] (M = Pd or Pt) to give intermediate complexes [{MCl2}2,6-{NH2(C5H3N)(C2HN3C6H5)-κ2-N,N}] [M = Pd (B) or Pt (C)], which were subsequently phosphinated. The in situ-generated PNN ligand-stabilized Pd nanoparticles from compound 2 catalyzed the annulation of o-bromobenzaldehyde with alkynes to yield indenone derivatives. Mechanistic investigations suggested that the reaction was catalyzed by Pd nanoparticles (Pd@2) generated from compound 2 and proceeded through sequential oxidative addition, alkyne insertion, and reductive elimination steps to produce indanone products. Show less

The Keap1-Nrf2 system is the master regulator of the cellular response against oxidative and xenobiotic stresses. Constitutive activation of Nrf2 is frequently observed in various types of cancers. Nrf2 hyperactivation induces metabolic reprogramming in cancer cells, which supports the increased energy demand required for rapid proliferation and confers high-level resistance against anticancer radio/chemotherapy. Hence, Nrf2 inhibition has emerged as an attractive therapeutic strategy to counter such acquired resistance in Nrf2-activated tumors. We previously identified Halofuginone (HF) as a promising Nrf2 inhibitor. In this study, we pursued preclinical characterization of HF and found that while HF markedly reduced the viability of cancer cells, it also caused severe hematopoietic and immune cell suppression in a dose-dependent manner. Hence, to overcome this toxicity, we decided to employ a nanomedicine approach to HF. We found that encapsulation of HF into a polymeric micelle (HF micelle; HFm) largely relieved the systemic toxicity exhibited by free HF while maintaining the tumor-suppressive properties of HF. LC-MS/MS analysis revealed that the reduction in the magnitude of adverse effects was the result of the ability to release HF from the HFm core in a slow and sustained manner. These results thus support the contention that HFm will potentially counteract Nrf2-activated cancers in the clinical settings. Show less

Abstract As a kind of multifunctional materials with high porosity, tunable pore structure and easy functionalization, coordination complexes have been widely used in various fields. Here, three complexes were prepared by self‐assembly with Co(II) ions using tetrazolylacetic acids as ligands, 2,2′,2′′‐(benzene‐1,3,5‐triyltris(2 H ‐tetrazole‐5,2‐diyl)) triacetic acid (H 3 tzpha), 2‐(5‐(pyrazin‐2‐yl)‐2 H ‐tetrazol‐2‐yl) propanoic acid (Hpztzma) and 2‐(5‐(pyridin‐2‐yl)‐2 H ‐tetrazol‐2‐yl) acetic acid (Hpytza), and were characterized by X‐ray crystallography. These complexes can also self‐assemble into nanoparticles (NPs) in aqueous solution by nanocoprecipitation. In vitro CCK‐8 assay on three kind of human cancer cells (HeLa, HepG2 and Huh7) cells showed these Co(II) complexes have the best cytotoxicity against HeLa cells. And complex 1 had a half maximal inhibitory concentration (IC 50 value) of 14.8 μg mL −1 , which was superior to 16.5 μg mL −1 and 15.2 μg mL −1 of complex 2 and 3 . In addition, the effect of different ligands on cancer cell ablation was explored. The results showed the three NPs can effectively inhibit the proliferation of cancer cells in vitro and provided a strategy on designing highly efficient anticancer materials based on coordination complexes. Show less

Transition metal coordination complexes have provided cancer treatment with new insights to overcome the limitations of current chemotherapeutic agents. Utilization of bifunctional tetrazole–carboxylate ligands with Zn(II) obtained two self-assembled complexes [Zn(HL1)(bipy)3/2(H2O)]·CH3OH·4(H2O) (1) (H3L1 = 1,3,5-tri(2-carboxymethyltetrazol-5-yl) benzene) and [Zn(L2)2(H2O)2]2·2H2O (2) (HL2 = (5-pyridin-3-yl-tetrazol-2-yl)-acetic acid). The X-ray diffraction results showed that the two complexes displayed a two-dimensional (2D) layer structure and a one-dimensional (1D) layer structure. Nanocoprecipitation with DSPE-PEG-2000 resulted in the formation of complex nanoparticles (NPS) with excellent water dispersion. In vitro CCK-8 assay indicated the two NPs exert high cytotoxicity and sensitivity and a low half-maximum inhibitory concentration (IC50) towards HeLa than HepG2 cells. In addition, the cytotoxicity was also confirmed by live/dead co-stained experiments. The presented experimental results showed the 1 and 2 NPs were capable of inhibiting cell proliferation in vitro and may help design coordination complex-based anticancer candidates for cancer cells. Show less

Transition metal luminophores are emerging as important tools for intracellular imaging and sensing. Their putative suitability for such applications has long been recognised but poor membrane permeability and cytotoxicity were significant barriers that impeded early progress. In recent years, numerous effective routes to overcoming these issues have been reported, inspired in part, by advances and insights from the pharmaceutical and drug delivery domains. In particular, the conjugation of biomolecules but also other less natural synthetic species, from a repertoire of functional motifs have granted membrane permeability and cellular targeting. Such motifs can also reduce cytotoxicity of transition metal complexes and offer a valuable avenue to circumvent such problems leading to promising metal complex candidates for application in bioimaging, sensing and diagnostics. The advances in metal complex probes permeability/targeting are timely, as, in parallel, over the past two decades significant technological advances in luminescence imaging have occurred. In particular, super-resolution imaging is enormously powerful but makes substantial demands of its imaging contrast agents and metal complex luminophores frequently possess the photophysical characteristics to meet these demands. Here, we review some of the key vectors that have been conjugated to transition metal complex luminophores to promote their use in intra-cellular imaging applications. We evaluate some of the most effective strategies in terms of membrane permeability, intracellular targeting and what impact these approaches have on toxicity and phototoxicity which are important considerations in a luminescent contrast or sensing agent. Show less

Background Known as the main site of ATP production and intrinsic apoptosis regulator, mitochondria play vital roles in physiological functions and pathological progression. Evidences have shown that mitochondrial dysfunction correlated with a variety of diseases, especially with cancer. Mitochondria are emerged as an attractive target for diseases treatment. Area covered This review introduces efficient mitochondrial targeting strategies, and summarizes application of multiple drug delivery systems targeted to mitochondria for antitumor treatment, including anti-drug resistance, anti-metastasis and immunotherapy. Furthermore, we discuss the application and perspectives of mitochondrial targeting in treatment of other mitochondrial-related diseases. Expert opinion A number of chemotherapeutics exert their efficacy in specific sub-organelles. Targeting drugs to one certain organelle would exhibit their maximum therapeutic effects. The mitochondria in tumor cells are closely related to the development of tumor. Also, the main cause of clinical failure in antitumor treatment, including multidrug resistance (MDR) and metastasis, are associated with mitochondrial dysfunction. In addition, mitochondria disorders also lead to some other diseases. Therefore, constructing mitochondrial targeted drug delivery systems to regulate mitochondrial functions is necessarily desired. Show less

It is well known that the pH of tumor tissue is lower than that of the corresponding normal adjacent tissue. Here, the authors report a clinical trial of a pH activatable nanoparticle for imaging tumours. Show less

Fluorescence imaging is a powerful tool in biomedical research. It has been frequently used to uncover or better understand physiological mechanisms in disease-related processes such as cancer. The majority of chromophores used for imaging are based on a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) scaffold. However, their applications are limited due to their poor water solubility as well as poor cancer cell selectivity. To circumvent these drawbacks, we present herein the use of bis(dipyrrinato)zinc(II) complexes. As this class of compounds is associated with a quenching effect of the excited state in water, the lead compound of this study (3) was encapsulated in a polymer matrix with biotin as a targeting moiety (3-NP). This encapsulation improved the water solubility, overcame the quenching effects in water, as well as allowed selective accumulation in the lysosomes with a bright fluorescence signal in monolayer cells as well as 3D multicellular tumor spheroids (MCTS). As a benefit from the biotin targeting moiety, the nanoparticles were majorly taken up by the sodium dependent multivitamin transporter (SMVT) which is overexpressed in various cancers cells and selectively accumulated in cancerous cells over noncancerous cells. Show less

AbstractAnticancer therapies, which can induce cell death and elevate antitumor immune response in the meantime, are considered as effective treatments for many types of cancers. Immunogenic cell death (ICD) induced by chemodrugs is a promising and typical strategy to achieve cell cytotoxicity and immunological enhancement together. However, due to the low level of ICD induction and less tumor‐targeting accumulation, application of traditional ICD inducers is limited. Here, tumor‐targeting core–shell magnetic nanoparticles (ETP‐PtFeNP:α‐enolase targeting peptide modified Pt‐prodrug loaded Fe3O4 nanoparticles) are developed to reinforce ICD induction of loaded‐oxaliplatin (IV) prodrug. After tumor‐targeting accumulation and endocytosis, platinum (IV) complexes are activated by intracellular reductive elimination to yield and release the Pt (II) congener, oxaliplatin, leading to DNA lesions and reactive oxygen species (ROS) generation. Simultaneously, in‐progress‐released ferric ions elicit highly toxic ROS (·OH or ·OOH) burst and interfere with the intracytoplasmic redox balance (like endoplasmic reticulum stress), leading to ICD‐associated immunogenicity enhancement and specific antitumor immune responses to kill the tumor cells synergistically. Meanwhile, the transverse relaxation rate R 2 of ETP‐PtFeNP is remarkably increased by more than three times while triggered by reductant, suggesting ETP‐PtFeNP a high‐sensitivity T 2 contrast agent for magnetic resonance imaging. Show less

Iron is critical for virtually all organisms, yet major questions remain regarding the systems-level understanding of iron in whole cells. Here, we obtained Mössbauer and EPR spectra of Escherichia coli cells prepared under different nutrient iron concentrations, carbon sources, growth phases, and O2 concentrations to better understand their global iron content. We investigated WT cells and those lacking Fur, FtnA, Bfr, and Dps proteins. The coarse-grain iron content of exponentially growing cells consisted of iron-sulfur clusters, variable amounts of nonheme high-spin FeII species, and an unassigned residual quadrupole doublet. The iron in stationary-phase cells was dominated by magnetically ordered FeIII ions due to oxyhydroxide nanoparticles. Analysis of cytosolic extracts by size-exclusion chromatography detected by an online inductively coupled plasma mass spectrometer revealed a low-molecular-mass (LMM) FeII pool consisting of two iron complexes with masses of ∼500 (major) and ∼1300 (minor) Da. They appeared to be high-spin FeII species with mostly oxygen donor ligands, perhaps a few nitrogen donors, and probably no sulfur donors. Surprisingly, the iron content of E. coli and its reactivity with O2 were remarkably similar to those of mitochondria. In both cases, a "respiratory shield" composed of membrane-bound iron-rich respiratory complexes may protect the LMM FeII pool from reacting with O2 When exponentially growing cells transition to stationary phase, the shield deactivates as metabolic activity declines. Given the universality of oxidative phosphorylation in aerobic biology, the iron content and respiratory shield in other aerobic prokaryotes might be similar to those of E. coli and mitochondria. Show less

Purpose The effect of existing anti-cancer therapies is based mainly on the stimulation of apoptosis in cancer cells. Here, we have demonstrated the ability of a catalytically-reactive nanoparticle-based complex of cytochrome c with cardiolipin (Cyt-CL) to induce the apoptosis and killing of cancer cells in a monolayer cell culture. Methods Cyt-CL nanoparticles were prepared by complexing CytC with different molar excesses of CL. Following characterization, cytotoxicity and apoptosis inducing effects of nanoparticles were investigated. In an attempt to identify the anticancer activity mechanism of Cyt-CL, pseudo-lipoxygenase and lipoperoxidase reaction kinetics were measured by chemiluminescence. Results Using chemiluminescence, we have demonstrated that the Cyt-CL complex produces lipoperoxide radicals in two reactions: by decomposition of lipid hydroperoxides, and by lipid peroxidation under the action of H2O2. Antioxidants inhibited the formation of lipid radicals. Cyt-CL nanoparticles, but not the CytC alone, dramatically enhanced the level of apoptosis and cell death in two cell lines: drug-sensitive (A2780) and doxorubicin-resistant (A2780-Adr). The proposed mechanism of the cytotoxic action of Cyt-CL involves either penetration through the cytoplasm and outer mitochondrial membrane and catalysis of lipid peroxidation reactions at the inner mitochondrial membrane, or/and activation of lipid peroxidation within the cytoplasmic membrane. Conclusions Here we propose a new type of anticancer nano-formulation, with an action based on the catalytic action of Cyt-CL nanoparticles on the cell membrane and and/or mitochondrial membranes that results in lipid peroxidation reactions, which give rise to activation of apoptosis in cancer cells, including multidrug resistant cells. Show less

AbstractWith the extensive use of two‐photon fluorescence microscopy (2PFM) in the biomedical field, the need for development of fluorescent probes with improved two‐photon fluorescence (2PF) properties has triggered extensive studies in the synthesis of new probes that undergo efficient two‐photon absorption (2PA). In order to provide a more comprehensive comparison of fluorophores for 2PF bioimaging, a figure of merit (FM) was developed by normalizing the 2PA action cross‐section, a commonly used parameter for characterizing bioimaging 2PF probes, by the photodecomposition quantum yield. Another important aspect of developing 2PA fluorophores is hydrophilicity. Although hydrophilic fluorophores are generally preferred in 2PFM bioimaging, hydrophobic fluorophores are typically easier to synthesize and purify, and have been used successfully in 2PFM bioimaging. The methodologies of dispersing hydrophobic fluorophores into aqueous media, such as in a DMSO/water mixture, micelles, silica nanoparticles, or forming polymer nanoparticles, are reviewed. The design and synthesis of hydrophilic 2PA fluorophores, achieved by introducing polyethylene glycol (PEG), anionic acid groups, cationic ammonium salt, and PAMAM dendrimers, is presented. Introduction of specificity to target certain biomarkers via labeling of antibodies, DNA, smallbioactive molecules, and peptides, and for the sensing of sepcific cations and pH, is also reviewed. Show less

The speciation of iron in intact human Jurkat leukemic cells and their isolated mitochondria was assessed using biophysical methods. Large-scale cultures were grown in medium enriched with (57)Fe citrate. Mitochondria were isolated anaerobically to prevent oxidation of iron centers. 5 K Mössbauer spectra of cells were dominated by a sextet due to ferritin. They also exhibited an intense central quadrupole doublet due to S = 0 [Fe(4)S(4)](2+) clusters and low-spin (LS) Fe(II) heme centers. Spectra of isolated mitochondria were largely devoid of ferritin but contained the central doublet and features arising from what appear to be Fe(III) oxyhydroxide (phosphate) nanoparticles. Spectra from both cells and mitochondria contained a low-intensity doublet from non-heme high-spin (NHHS) Fe(II) species. A portion of these species may constitute the "labile iron pool" (LIP) proposed in cellular Fe trafficking. Such species might engage in Fenton chemistry to generate reactive oxygen species. Electron paramagnetic resonance spectra of cells and mitochondria exhibited signals from reduced Fe/S clusters, and HS Fe(III) heme and non-heme species. The basal heme redox state of mitochondria within cells was reduced; this redox poise was unaltered during the anaerobic isolation of the organelle. Contributions from heme a, b, and c centers were quantified using electronic absorption spectroscopy. Metal concentrations in cells and mitochondria were measured using inductively coupled plasma mass spectrometry. Results were collectively assessed to estimate the concentrations of various Fe-containing species in mitochondria and whole cells - the first "ironome" profile of a human cell. Show less

The condensation of DNA is essential for biological processes such as DNA transcription and replication, and its study receives additional impetus from an interest in gene therapy. Although many efficacious condensing agents have been discovered and investigated, little is known about the conversation of condensation-release under suitable conditions. A novel class of DNA condensing agents based on small azaheterocyclic metal-binding molecules has been discovered and described. Both linear and plasmid DNA can be condensed to nanoparticles by the title compounds with 50 °C incubation, especially in the presence of divalent metal ions. Importantly, this condensation may be released to original forms with little or no damage to the DNA under incubation at physiological temperatures. These changes in DNA morphology over time have been analyzed by gel electrophoresis, circular dichroism (CD), and atomic force microscopy (AFM). The present work might help to develop strategies for the design and synthesis of controllable condensing agents, which may also be applied to control gene expression and delivery. Show less

Readily synthesised and functionalised di-1,2,3-triazole “click” ligands are shown to self-assemble into coordinatively saturated, quadruply stranded helical [Pd2L4](BF4)4 cages with Pd(II) ions. The cages have been fully characterised by elemental analysis, HR-ESMS, IR, 1H, 13C and DOSY NMR, DFT calculations, and in one case by X-ray crystallography. By exploiting the CuAAC “click” reaction we were able to rapidly generate a small family of di-1,2,3-triazole ligands with different core spacer units and peripheral substituents and examine how these structural modifications affected the formation of the [Pd2L4](BF4)4 cages. The use of both flexible (1,3-propyl) and rigid (1,3-phenyl) core spacer units led to the formation of discrete [Pd2L4](BF4)4 cage complexes. However, when the spacer unit of the di-1,2,3-triazole ligand was a 1,4-substituted-phenyl group steric interactions led to the formation of an oligomeric/polymeric species. By keeping the 1,3-phenyl core spacer constant the effect of altering the “click” ligands’ peripheral substituents was also examined. It was shown that ligands with alkyl, phenyl, electron-rich and electron-poor benzyl substituents all quantitatively formed [Pd2L4](BF4)4 cage complexes. The results suggest that a wide range of functionalised palladium(II) “click” cages could be rapidly generated. These novel molecules may potentially find uses in catalysis, molecular recognition and drug delivery. Show less