Ansa-Ferrocene Derivatives as Potential Therapeutics.

It has been known since the 1990s that the introduction of a ferrocenyl-type substituent into compounds with proven biological activity can improve their properties. More recently, it was also shown that a carbon bridge connecting the two cyclopentadienyl rings in ferrocene derivatives could enhance the biological properties of the new compounds compared to those without them. However, the synthesis of ferrocenes with this additional linker, known as ansa-ferrocenes, is more difficult due to advanced synthetic protocols and the phenomenon of planar chirality in ring-substituted compounds. As a result, research into the formation of hybrids, conjugates and other ansa-ferrocene derivatives has not been widely conducted. This review discusses the potential biological properties of these units, covering scientific articles published between 1980 and 2024.

Fe(II)-Catalyzed Recrystallization Drives Phosphorus and Aluminum Release from Goethite.

Goethite often harbors impurities, such as phosphorus (P) and aluminum (Al), which are incorporated into its structure through direct substitution or coprecipitation with nanocrystalline phases. Understanding the processes that drive the release of P and Al from goethite is of paramount importance for the iron ore industry and for managing nutrient and pollutant behavior in the environment. This study investigates the impact of Fe(II)-catalyzed recrystallization on the release of P and Al from goethite. We evaluated the solubility and extractability of P and Al in suspensions of Al- and P-coprecipitated goethite, treated with 57Fe-enriched Fe(II)aq under oxygen-free conditions for 30 days at neutral pH and room temperatures. The addition of Fe(II)aq induced the recrystallization of goethite dominant initial synthetic phases (i.e., low P- and Al-containing phases) and the transformation of higher P- and/or Al-bearing starting material that was actually a mixture of goethite and minor amounts of lepidocrocite and feroxyhyte. Our results reveal that Fe(II)-catalyzed mineral and structural evolution led to the repartitioning of P and, to a lesser extent, Al throughout the crystal structure, mineral surface, and aqueous solution. Following a 30 day reaction with Fe(II)aq, we extracted approximately 80, 68.8, 73.9, and 83.2% of P from P-only, low, medium, and high P + Al goethite, respectively. Additionally, we observed total Al removals of approximately 17, 27, and 25% from low, medium, and high P + Al goethite, respectively. The results demonstrate that treating both P-only and P + Al goethite with Fe(II) at room temperature, followed by a 24 h extraction using 1 M NaOH, significantly enhances the overall extractability of P and Al, including both aqueous and surface-adsorbed fractions, compared to Fe(II)-free controls. These findings advance our understanding of the recrystallization process and impurity substitution in goethite, offering promising avenues for developing new environmentally friendly methods to extract P and other impurities from goethitic iron ores at lower temperatures.

A Novel Ferrocene-Linked Thionine as a Dual Redox Mediator for the Electrochemical Detection of Dopamine and Hydrogen Peroxide.

We introduce a novel dual redox mediator synthesized by covalently linking ferrocene dicarboxylic acid (FcDA) and thionine (TH) onto a pre-treated glassy carbon electrode. This unique structure significantly enhances the electro-oxidation of dopamine (DA) and the reduction of hydrogen peroxide (H2O2), offering a sensitive detection method for both analytes. The electrode exhibits exceptional sensitivity, selectivity, and stability, demonstrating potential for practical applications in biosensing. It facilitates rapid electron transfer between the analyte and the electrode surface, detecting H2O2 concentrations ranging from 1.5 to 60 µM with a limit of detection (LoD) of 0.49 µM and DA concentrations from 0.3 to 230 µM with an LoD of 0.07 µM. The electrode's performance was validated through real-sample analyses, yielding satisfactory results.

Ferrous sulfate remodels the properties of sodium alginate-based hydrogel and facilitates the healing of wound infection caused by MRSA.

Frequent occurrence of wound infection caused by multiple-resistant bacteria (MRB) has posed a serious challenge to the current healthcare system relying on antibiotics. The development of novel antimicrobial materials with high safety and efficacy to heal wound infection is of great importance in combating this crisis. Herein, we prepared a promising antibacterial hydrogel by cross-linking ferrous ions (Fe2+) with the deprotonated carboxyl anion in sodium alginate (Na-ALG) to cure wound infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Interestingly, ferrous-modified Na-ALG (Fe-ALG) hydrogel demonstrated better properties compared to the traditional Na-ALG-based hydrogels, including injectability, self-healing, appropriate fluidity, high-water retention, potent MRSA-killing efficacy, and excellent biocompatibility. Importantly, the addition of Fe2+ enhances the antibacterial efficacy of the Na-ALG hydrogel, enabling it to effectively eliminate MRSA and accelerate the healing of antibiotic-resistant bacterial-infected wounds in a remarkably short period (10 days). This modification not only facilitates wound closure and fur generation, but also mitigates systemic inflammation, thereby effectively impeding the spread of MRSA to the lungs. Taken together, Fe-ALG hydrogel is a promising therapeutic material for treating wound infections by Staphylococcus aureus, especially by antibiotic-resistant strains like MRSA.

Self-assembled ROS-triggered Bletilla striata polysaccharide-releasing hydrogel dressing for inflammation-regulation and enhanced tissue-healing.

The antimicrobial and pro-healing properties remain critical clinical objectives for skin wound management. However, the escalating problem of antibiotic overuse and the corresponding rise in bacterial resistance necessitates an urgent shift towards an antibiotic-free approach to antibacterial treatment. The quest for antimicrobial efficacy while accelerating wound healing without antibiotic treatment have emerged as innovative strategies in skin wound treatment. Here, a dual-function hydrogel with antimicrobial and enhanced tissue-healing properties was developed by utilizing cyclodextrin, ferrocene, polyethyleneimine (PEI), and Bletilla striata polysaccharide (BSP), through multiple non-covalent interactions, which can intelligently release BSP by recognizing the wound inflammatory microenvironment through the cyclodextrin-ferrocene unit. Moreover, the porosity (65 % - 85 %), Young's modulus (400 KPa - 140 KPa), and DPPH scavenge rate (18 % - 40 %) of the hydrogel are modulated by varying the BSP content. The hydrogel exhibits outstanding antibacterial properties (98.3 % reduction of Escherichia coli observed after exposure to HTFC@BSP-20 for 24 h) and favorable biocompatibility. Furthermore, in a rat full-thickness skin wound model, the dual-function hydrogel significantly accelerates wound healing, increased CD31 expression promotes vascular regeneration, reduced TNF-α express and inhibited the inflammation. This multifunctional ROS responsive hydrogel provides a new perspective for antibiotics-free treatment of skin injuries.

Transformable self-delivered supramolecular nanomaterials combined with anti-PD-1 antibodies alleviate tumor immunosuppression to treat breast cancer with bone metastasis.

Breast cancer is the most common malignant tumor that threatens women's life and health, and metastasis often occurs in the advanced stage of breast cancer, leading to pathological bone destruction and seriously reducing patient quality of life. In this study, we coupled chlorin e6 (Ce6) with mono-(6-amino-6-deoxy)-beta-cyclodextrin (ß-CD) to form Ce6-CD, and combined ferrocene with the FFVLG3C peptide and PEG chains to form the triblock molecule Fc-pep-PEG. In addition, the IDO-1 inhibitor NLG919 was loaded with Ce6-CD and Fc-pep-PEG to construct the supramolecular nanoparticle NLG919@Ce6-CD/Fc-pep-PEG (NLG919@CF). After laser irradiation, Ce6 produced robust reactive oxidative species to induce tumor cell apoptosis. Simultaneously, ferrocene became charged, and Fc-pep-PEG dissociated from the spherical nanoparticles, enabling their transformation into nanofibers, which increased both the retention effect and the induction of ferroptosis. The released NLG919 reduced the number of regulatory T cells (Tregs) and restored the function of cytotoxic T lymphocytes (CTLs) by inhibiting the activity of IDO-1. Moreover, combined administration with an anti-PD-1 antibody further relieved immune suppression in the tumor microenvironment. This article presents a new strategy for the clinical treatment of breast cancer with bone metastasis and osteolysis.

Protein-driven interaction enhanced electrochemiluminescence biosensor of hydrogen-bonded biohybrid organic frameworks for sensitive immunoassay of disease markers.

The oriented design of reticular materials as emitters can significantly enhance the sensitivity of electrochemiluminescence (ECL) sensing analysis for disease markers. However, due to the structural fragility of hydrogen bonds, relational research on hydrogen-bonded organic frameworks (HOFs) has not been thoroughly conducted. Additionally, the modulation of luminescence behavior through HOFs has been rarely reported. In view of this, hydrogen-bonded biohybrid organic frameworks (HBOFs) were synthesized and recruited for ECL immunoassay applications. HBOFs was easily prepared using 6,6',6″,6‴-(pyrene-1,3,6,8-tetrayl)tetrakis(2-naphthoic acid) as linkers via bovine serum albumin (BSA) activated hydrogen-bonded cross-linking. The material exhibited good fluorescence emission characteristics. And the highly ordered topological structure and molecular motion limitation mediated by BSA overcome aggregation-caused quenching and generate strong aggregation induced emission, expressing hydrogen-bond interaction enhanced ECL (HIE-ECL) activity with the participation of tri-n-propylamine. Furthermore, a sandwich immunosensor was constructed employing cobalt-based metal-phenolic network (CMPN) coated ferrocene nanoparticles (FNPs) as quenchers (CMPN@FNPs). Signal closure can be achieved by annihilating the excited state through electron transfer from both CMPN and FNPs. Using a universal disease marker, carcinoembryonic antigen, as the analysis model, the signal-off sensor obtained a detection limit of 0.47 pg/mL within the detection range of 1 pg/mL - 50 ng/mL. The synthesis and application of highly stable HBOFs triggered by proteins provide a reference for the development of new reticular ECL signal labels, and electron transfer model provides flexible solutions for more sensitive sensing analysis.

Mechano-triggered eradication of dentinal tubule biofilm via in situ generation of nanoscale sonosensitizer by the tailored irrigation formulation.

The efficient elimination of bacteria within the dentinal tubules has been hindered by the poor deposition and short residence of disinfecting agents. Meanwhile, the current irrigant (e.g., NaClO, 5.25 %) shows severe adverse effects on the surrounding soft tissues because of its inherent high irritancy. To address this issue, this work reports an in situ generated sonosensitizer to handle the biofilm in dentinal tubules with minimal adverse effects. The production of nanoscale sonosensitizer involves the concurrent delivery of H2O2 (0.01 %), ferrocene derivative (Fc), and indocyanine green (ICG). With ultrasound treatment, the reaction between H2O2 and Fc liberated Fe3+ that was further complexed with ICG to generate the nanoscale sonosensitizer in situ, followed by singlet oxygen production for potent disinfecting action. Because the above cascade reactions occur within the confined dentinal tubules, the generated ICG-Fe3+ nanosensitizer would show prolonged retention therein. The anti-bacterial potency of nanosensitizer was demonstrated in petrodish and ex vivo biofilm models. Meanwhile, the transmission electron microscope imaging of biofilm and cytotoxicity assay in L929 fibroblast cells proved the superiority of nanosensitizer against NaClO regarding adverse effects. The current work opens new avenues of biofilm elimination in dentinal tubules, showing a high translation potential.

Design and synthesis of ferrocenyl 1,4-dihydropyridines and their evaluation as kinesin-5 inhibitors.

Kinesin-5 inhibitors offer cancer cell-targeted approach, thus securing reduced systemic toxicity compared to other antimitotic agents. By modifying the 1,4-dihydropyridine-based kinesin-5 inhibitor CPUYL064 with a ferrocenyl moiety (Fc), we designed and prepared a series of organometallic hybrids that show high antiproliferative activity, with the best compounds exhibiting up to 19-fold increased activity. This enhanced activity can be attributed to the presence of the ferrocenyl moiety.

An electrochemical biosensor equipped with a logic circuit as a smart automaton for two-miRNA pattern detection.

Detecting multiple targets in complex cellular and biological environments yields more reliable results than single-label assays. Here, we introduced an electrochemical biosensor equipped with computing functions, acting as a smart automaton to enable computing-based detection. By defining the logic combinations of miR-21 and miR-122 as detection patterns, we proposed the corresponding AND and OR detection automata. In both logic gate modes, miR-21 and miR-122 could be replaced with single-stranded FO or FA, modified with Fc, binding to the S chain on the electrode surface. This process led to a significant decrease in the square wave voltammetry (SWV) of Fc on the same sensing platform, as numerous ferrocene (Fc)-tagged DNA fragments escaped from the electrode surface. Experimental results indicated that both automata efficiently and sensitively detected the presence of the two targets. This strategy highlighted how a small amount of target could generate a large current signal decrease in the logic automata, significantly reducing the detection limit for monitoring low-abundance targets. Moreover, the short-stranded DNA components of the detection automata exhibited a simple composition and easy programmability of probe sequences, offering an innovative detection mode. This simplified the complex process of detection, data collection, computation, and evaluation. The direct detection result ("0" or "1") was exported according to the embedded computation code. This approach could be expanded into a detection system for identifying other sets of biomarkers, enhancing its potential for clinical applications.

GalNAc-modified FeS nanoparticles for specific chemodynamic and gas therapy against orthotopic hepatocellular carcinoma.

GalNAc-modified ferrous sulfide nanoparticles have been developed to conduct chemodynamic and gas therapy for fighting against orthotopic hepatocellular carcinoma. This nanomedicine owns good liver targeting ability, which takes full advantage of the tumor microenvironment to ensure the therapy effect and improve the safety.

Spectroscopic definition of ferrous active sites in non-heme iron enzymes.

Non-heme iron enzymes play key roles in antibiotic, neurotransmitter, and natural product biosynthesis, DNA repair, hypoxia regulation, and disease states. These enzymes had been refractory to traditional bioinorganic spectroscopic methods. Thus, we developed variable-temperature variable-field magnetic circular dichroism (VTVH MCD) spectroscopy to experimentally define the excited and ground ligand field states of non-heme ferrous enzymes (Solomon et al., 1995). This method provides detailed geometric and electronic structure insight and thus enables a molecular level understanding of catalytic mechanisms. Application of this method across the five classes of non-heme ferrous enzymes has defined that a general mechanistic strategy is utilized where O2 activation is controlled to occur only in the presence of all cosubstrates.

ROS-Responsive and Self-Catalytic Nanocarriers for a Combination of Chemotherapy and Reinforced Ferroptosis against Breast Cancer.

Ferroptosis is an appealing cancer therapy strategy based on the H2O2-involved Fenton reaction to produce toxic •OH for lipid peroxidation. However, intracellular H2O2 is easily consumed and results in a deficient Fenton reaction. This obstacle can be overcome by traditional chemotherapeutic drugs for H2O2 supplements. Moreover, a recent work illustrated that dihydroartemisinin (DHA) could promote ferroptosis against tumoral cells, particularly in the presence of ferrous compounds. To achieve combined chemotherapy and ferroptosis, a nanocarrier (TKNPDHA-Fc) was constructed by using thioketal (TK)-bridged paclitaxel prodrug (PEG-TK-PTX) and ferrocene (Fc)-conjugated PEG-Fc, where DHA was encapsulated by a hydrophobic-hydrophobic interaction. Upon cellular uptake, TKNPDHA-Fc could facilitate PTX release through TK breakage under an excess H2O2 microenvironment. Owing to the loss of the hydrophobic PTX component, TKNPDHA-Fc underwent a rapid dissociation for improving DHA to act as a ferroptotic inducer along with Fe supplied from Fc. Moreover, both the chemotherapy-induced reactive oxygen species and the •OH produced from reinforced ferroptosis further stimulated the TK cleavage. The "self-catalytic" loop of TKNPDHA-Fc remarkably improved the antitumor performance in vivo via combined mechanisms, and its tumor inhibition rate reached 78.3%. This work highlights the contribution of ROS-responsive and self-catalytic nanoplatforms for enhancing the potential of combined chemotherapy and ferroptosis for cancer therapy in the future.

Manipulating Fe(II) spin states to achieve higher anti-tumor cell activities in multinuclear complexes.

Exploring the different spin states of central metals in the complex to regulate the anti-tumor activity of cancer cells is of great significance in drug design and clinical use. However, it is a challenge to build a strong coupling between spin states and anti-tumor activities in one system. Herein, we present two complexes {FeII2L2[PdII(CN)4]2}·2H2O (L = Bztpen (1), Bztppn (2); Bztpen = N-benzyl-N,N',N'-tris(2-pyridylmethyl)ethylenediamine, Bztppn = N-benzyl-N,N',N'-tris(2-pyridylmethyl)propylenediamine) showing different cytotoxic activities actuated by fine-tuning the structure with different spin states of Fe(II). Magnetic susceptibility measurements and X-ray diffraction revealed that the Fe(II) ion in complexes 1 and 2 remains in the LS and HS state, respectively, at room temperature. Cytotoxicity tests indicate that complex 1 is more biologically effective than complex 2. In complex 2, however, the high-spin Fe(II) played a key role in regulating its in vitro antitumor effects and seems to be associated with ROS-mediated apoptosis. These findings offer a new avenue for developing anti-cancer drugs by designing complexes with different spin states.

Clusters of solvated ferrous ion in water-ammonia mixture: Structures and noncovalent interactions.

The behavior of metal ions is commonly studied in pure solvent although, in our daily life, these metals are involved in mixtures of solvents. In the present study, we investigated structures, relative stabilities and temperature dependance of solvated ferrous ion in water-ammonia mixture solvent at 0K and at various temperatures ranging from 25K to 400K. All the calculations are performed at the MN15 level of theory associated with the aug-cc-pVDZ basis set. For deep understanding of binding patterns in solvated ferrous ion in water-ammonia mixture solvent, noncovalent interactions are presented based on the QTAIM analysis using AIMAll. Our results prove that the ferrous ion is more stable when it is solvated by ammonia instead of water. In addition, hydrogen bonds are weakened by the presence of ammonia molecules. The temperature dependence of the different obtained geometries indicates that from s=6 (s is the sum of water and ammonia molecules around the ferrous ion), when the number of water molecules is almost equal to that of ammonia, the structures with coordination number 5 are dominant. However, the coordination number is six when there are a maximum water molecules (rich water solution) or maximum ammonia molecules (rich ammonia solution) around the ferrous ion (for s≥6). The QTAIM analysis shows that there are two coordination bondings and four hydrogen bondings. Furthermore, it is found that the Fe2+⋯N coordination bondings are stronger than the Fe2+⋯O confirming that the ferrous ion prefers to be solvated by ammonia instead of water.

The electro-responsive nanoliposome as an on-demand drug delivery platform for epilepsy treatment.

Nano-based drug delivery systems are regarded as a promising tool for efficient epilepsy treatment and seizure medication with the least general side effects and socioeconomic challenges. In the current study, we have designed a smart nanoscale drug delivery platform and applied it in the kindling model of epilepsy that is triggered rapidly by epileptic discharges and releases anticonvulsant drugs in situ, such as carbamazepine (CBZ). The CBZ-loaded electroactive ferrocene nanoliposomes had an average diameter of 100.6 nm, a surface charge of -7.08 mV, and high drug encapsulation efficiency (85.4 %). A significant increase in liposome size was observed in response to direct current (50-500 µA) application. This liposome-based drug delivery system can release CBZ at a fast rate in response to both direct current and pulsatile electrical stimulation in vitro. The CBZ-liposome can release the anticonvulsant drug upon epileptiform activity in the kindled rat model and can decline electrographic and behavioral seizure activity in response to electrical stimulation of the hippocampus with an initially subconvulsive current. With satisfactory biosafety results, this "smart" nanocarrier has promising potential as an effective and safe drug delivery system to improve the therapeutic index of antiepileptic drugs.

Ferrocene-Conjugated Paclitaxel Prodrug for Combined Chemo-Ferroptosis Therapy of Cancer.

Herein, we developed a paclitaxel prodrug (PSFc) through the conjugation of paclitaxel (PTX) and ferrocene via a redox-responsive disulfide bond. PSFc displays acid-enhanced catalytic activity of Fenton reaction and is capable of forming stable nanoparticles (PSFc NPs) through the assembly with distearoyl phosphoethanolamine-PEG2000. After being endocytosed, PSFc NPs could release PTX to promote cell apoptosis in response to overexpressed redox-active species of tumor cells. Meanwhile, the ferrocene-mediated Fenton reaction promotes intracellular accumulation of hydroxyl radicals and depletion of glutathione, thus leading to ferroptosis. Compared with the clinically used Taxol, PSFc NPs exhibited more potent in vivo antitumor outcomes through the combined effect of chemotherapy and ferroptosis. This study may offer insight into a facile design of a prodrug integrating different tumor treatment methods for combating malignant tumors.

Phytic acid inhibits Cr(VI) reduction on Fe(II)-bearing clay minerals: Changing reduction sites and electron transfer pathways.

The presence of organic phosphorus may influence the characteristics of Cr(VI) reduction and immobilization on Fe(II)-bearing clay minerals under anoxic conditions, as the organic phosphorus tends to bind strongly to clay minerals in soil. Herein, reduced nontronite (rNAu-2) was used to reduction of Cr(VI) in the presence of phytic acid (IHP) at neutral pH. With IHP concentration from 0 to 500 µM, Cr(VI) reduction decreased obviously (17.8%) within first 5 min, and then preferred to stagnate during 4-12 h (≥50 µM). After that, Cr(VI) was reduced continuously at a slightly faster rate. Density functional theory (DFT) calculations revealed that IHP primarily absorbed at the edge sites of rNAu-2 to form Fe-IHP complexes. X-ray diffraction (XRD), scanning transmission electron microscopy (STEM), and Fourier transform infrared spectroscopy (FTIR) results demonstrated that IHP hindered the ingress of CrO42- into the interlayer space of rNAu-2 and impeded their reduction by trioctahedral Fe(II) and Al-Fe(II) at basal plane sites in the initial stage. Additionally, Fe(II) extraction results showed that IHP promoted the electron from interior transfer to near-edge, but hindered it further transfer to surface, resulting in the inhibition on Cr(VI) reduction at edge sites during the later stage. Consequently, IHP inhibits the reduction and immobilization of Cr(VI) by rNAu-2. Our study offers novel insights into electron transfer pathways during the Cr(VI) reduction by rNAu-2 with coexisting IHP, thereby improve the understanding of the geochemical processes of chromium within the iron cycle in soil.

Electrochemical aptasensor based on a dual signal amplification strategy of 1-AP-CNHs and ROP for highly sensitive detection of ERα.

Estrogen receptor alpha (ERα) serves as a crucial biomarker for early breast cancer diagnosis. In this study, we proposed an electrochemical aptasensor with nanomaterial carbon nanohorns/gold nanoparticle composites (1-AP-CNHs/AuNPs) as the substrate, and the primary amine groups on the antibody initiated the ring-opening polymerization (ROP) of monomer amino acid-ferrocene (NCA-Fc) on the electrode surface for ultrasensitive detection of ERα. The composite of 1-AP-CNHs/AuNPs not only possessed more active sites, but also increased the specific surface area of the electrode and allowed a large amount of ferrocene polymer long chains to be grafted onto the electrode surface to achieve signal amplification. Under optimal conditions, the detection limit of the method was 11.995 fg mL-1 with a detection range of 100 fg mL-1-100 ng mL-1. In addition, the biotin-streptavidin system was used to further improve the sensitivity of the sensor. Importantly, this approach could be applied for the practical detection of ERα in real samples.

Self-assembled hyaluronic acid nanomicelle for enhanced cascade cancer chemotherapy via self-sensitized ferroptosis.

The clinical utility of chemotherapy is often compromised by its limited efficacy and significant side effects. Addressing these concerns, we have developed a self-assembled nanomicelle, namely SANTA FE OXA, which consists of hyaluronic acid (HA) conjugated with ferrocene methanol (FC), oxaliplatin prodrug (OXA(IV)) and ethylene glycol-coupled linoleic acid (EG-LA). Targeted delivery is achieved by HA binding to the CD44 receptors that are overexpressed on tumor cells, facilitating drug uptake. Once internalized, hyaluronidase (HAase) catalyzes the digestion of the SANTA FE OXA, releasing FC and reducing OXA(IV) into an active form. The active oxaliplatin (OXA) induces DNA damage and increases intracellular hydrogen peroxide (H2O2) levels via cascade reactions. Simultaneously, FC disrupts the redox balance within tumor cells, inducing ferroptosis. Both in vivo and in vitro experiments confirmed that SANTA FE OXA inhibited tumor growth by combining cascade chemotherapy and self-sensitized ferroptosis, achieving a tumor inhibition rate of up to 76.61 %. Moreover, this SANTA FE OXA significantly mitigates the systemic toxicity commonly associated with platinum-based chemotherapeutics. Our findings represent a compelling advancement in nanomedicine for enhanced cascade cancer therapy.