Phototriggered Cytotoxicity of Ferrocene-Based Micelles - A Nonconventional Approach to Phototherapy.

We report the design, synthesis, and in vitro evaluation of stimuli-responsive nanoscale micelles that can be activated by light to induce a cytotoxic effect. Micelles were assembled from amphiphilic units made of a photoactivatable ferrocenyl linker, connected on one side to a lipophilic chain, and on the other side to a hydrophilic pegylated chain. In vitro experiments indicated that pristine micelles ("off" state) were nontoxic to MCF-7 cancer cells, even at high concentrations, but became potent upon photoactivation ("on" state). The illumination process led to the dissociation of the micelles and the concomitant release of iron species, triggering cytotoxicity.

An ultra-sensitive uric acid second generation biosensor based on chemical immobilization of uricase on functionalized multiwall carbon nanotube grafted palm oil fiber in the presence of a ferrocene mediator.

In this work, palm oil fiber (POF) grafted functionalized multiwall carbon nanotube (FMWCNT) decorated ferrocene (Fc) has been drop coated on a platinum electrode (Pt), in which uricase (UOx) has been chemically immobilized for sensitive and selective biosensing of uric acid (UA). Through the use of EDC/NHS, a stable bioelectrode (UOx/Fc/FMWCNT-POF/Pt) was obtained and characterized by FTIR/ATRIR, XRD, Raman, EA/EDX, TGA, SEM, TEM, CV, EIS, CA, and DPV. Results from DPV showed the rapid response of the developed bioelectrode towards UA (0.185 V) with high sensitivity (41.14 µA mM-1) and good limit of detection (19 µM) in the linear range 10-1000 µM. The low value of Michaelis-Menten constant (km = 31.364 µM) shows high affinity of the UA towards the enzyme at the electrode surface. The developed biosensor demonstrates good reproducibility, repeatability, and stability with a deviation of less than 2.5%, and was successfully applied for human blood sample analysis. The CA study revealed a fast response time (2 s) of the sensor. The work has pioneered a new addition to the class of tailorable chemical species for biosensor development and proven to be a promising new tool for point of care testing (POCT) applications.

Redox ferrocenylseleno compounds modulate longitudinal and transverse relaxation times of FNPs-Gd MRI contrast agents for multimodal imaging and photo-Fenton therapy.

Developing a feasible way to feature longitudinal (T1) and transverse (T2) relaxation performance of contrast agents for magnetic resonance imaging (MRI) is important in cancer diagnosis and therapy. Improved accessibility to water molecule is essential for accelerating the relaxation rate of water protons around the contrast agents. Ferrocenyl compounds have reversible redox property for modulating the hydrophobicity/hydrophilicity of assemblies. Thus, they could be the candidates that can change water accessibility to the contrast agent surface. Herein, we incorporated ferrocenylseleno compound (FcSe) with Gd3+-based paramagnetic UCNPs, to obtain FNPs-Gd nanocomposites using T1-T2 MR/UCL trimodal imaging and simultaneous photo-Fenton therapy. When the surface of NaGdF4:Yb,Tm UNCPs was ligated by FcSe, the hydrogen bonding between hydrophilic selenium and surrounding water molecules accelerated their proton exchange to initially endow FNPs-Gd with high r1 relaxivity. Then, hydrogen nuclei from FcSe disrupted the homogeneity of the magnetic field around the water molecules. This facilitated T2 relaxation and resulted in enhanced r2 relaxivity. Notably, upon the near-infrared light-promoted Fenton-like reaction in the tumor microenvironment, hydrophobic ferrocene(II) of FcSe was oxidized into hydrophilic ferrocenium(III), which further increased the relaxation rate of water protons to obtain r1 = 1.90±0.12 mM-1 s-1 and r2 = 12.80±0.60 mM-1 s-1. With an ideal relaxivity ratio (r2/r1) of 6.74, FNPs-Gd exhibited high contrast potential of T1-T2 dual-mode MRI in vitro and in vivo. This work confirms that ferrocene and selenium are effective boosters that enhance the T1-T2 relaxivities of MRI contrast agents, which could provide a new strategy for multimodal imaging-guided photo-Fenton therapy of tumors. STATEMENT OF SIGNIFICANCE: T1-T2 dual-mode MRI nanoplatform with tumor-microenvironment-responsive features has been an attractive prospect. Herein, we designed redox ferrocenylseleno compound (FcSe) modified paramagnetic Gd3+-based UCNPs, to modulate T1-T2 relaxation time for multimodal imaging and H2O2-responsive photo-Fenton therapy. Selenium-hydrogen bond of FcSe with surrounding water molecules facilitated water accessibility for fast T1 relaxation. Hydrogen nucleus in FcSe perturbed the phase coherence of water molecules in an inhomogeneous magnetic field and thus accelerated T2 relaxation. In tumor microenvironment, FcSe was oxidized into hydrophilic ferrocenium via NIR light-promoted Fenton-like reaction which further increased both T1 and T2 relaxation rates; Meanwhile, the released toxic •OH performed on-demand cancer therapy. This work confirms that FcSe is an effective redox mediate for multimodal imaging-guided cancer therapy.

A signal "on-off-on"-type electrochemiluminescence aptamer sensor for detection of sulfadimethoxine based on Ru@Zn-oxalate MOF composites.

An "on-off-on"-type electrochemiluminescence (ECL) aptamer sensor based on Ru@Zn-oxalate metal-organic framework (MOF) composites is constructed for sensitive detection of sulfadimethoxine (SDM). The prepared Ru@Zn-oxalate MOF composites with the three-dimensional structure provide good ECL performance for the "signal-on." The MOF structure with a large surface area enables the material to fix more Ru(bpy)32+. Moreover, the Zn-oxalate MOF with three-dimensional chromophore connectivity provides a medium which can accelerate excited-state energy transfer migration among Ru(bpy)32+ units, and greatly reduces the influence of solvent on chromophore, achieving a high-energy Ru emission efficiency. The aptamer chain modified with ferrocene at the end can hybridize with the capture chain DNA1 fixed on the surface of the modified electrode through base complementary pairing, which can significantly quench the ECL signal of Ru@Zn-oxalate MOF. SDM specifically binds to its aptamer to separate ferrocene from the electrode surface, resulting in a "signal-on" ECL signal. The use of the aptamer chain further improves the selectivity of the sensor. Thus, high-sensitivity detection of SDM specificity is realized through the specific affinity between SDM and its aptamer. This proposed ECL aptamer sensor has good analytical performance for SDM with low detection limit (27.3 fM) and wide detection range (100 fM-500 nM). The sensor also shows excellent stability, selectivity, and reproducibility, which proved its analytical performance. The relative standard deviation (RSD) of SDM detected by the sensor is between 2.39 and 5.32%, and the recovery is in the range 97.23 to 107.5%. The sensor shows satisfactory results in the analysis of actual seawater samples, which is expected to play a role in the exploration of marine environmental pollution.

Synthesis of magnetic nanocarbon using palm oil as the green precursor via microwave-assisted arc for wastewater treatment.

The presence of metal with microwave irradiation has always invited controversial arguments as the metal will catch on fire easily. But interestingly, researchers found that arc discharge phenomena provide a promising way for molecule cracking to synthesize nanomaterials. This study developed a single-step yet affordable synthesis approach that combines microwave heating and arcing in transforming crude palm oil into magnetic nanocarbon (MNC), which can be considered a new alternative for the palm oil sectors. It involves synthesizing the medium at a partial inert condition with constant coiled stainless steel metal wire (dielectric media) and ferrocene (catalyst). This approach successfully demonstrates heating at a temperature ranging from 190.9 to 472.0 °C with different synthesis times (10-20 min). The produced MNC shows formations of spheres with average sizes of 20.38-31.04 nm, mesoporous structure (SBET: 14.83-151.95 m2/g), and high content of fixed carbon (52.79-71.24wt%), and the ratio of the D and G bands (ID/IG) is 0.98-0.99. The formation of new peaks in the FTIR spectra (522.29-588.48 cm-1) supports the appearance of the FeO compounds from the ferrocene. The magnetometer shows high magnetization saturation (22.32-26.84 emu/g) in ferromagnetic materials. The application of the MNC in wastewater treatment has been demonstrated by evaluating their adsorbent capability with Methylene Blue (MB) adsorption test at a different concentrations varying between 5 and 20 ppm. The MNC produced at synthesis time (20 min) shows the highest adsorption efficiency (10.36 mg/g) compared to others, with 87.79% removal of MB dye. As a result, the value for Langmuir is not promising compared to Freundlich, with R2 being around 0.80, 0.98, and 0.99 for MNC synthesized at 10 min (MNC10), 15 min (MNC15), and 20 min (MNC20), respectively. Hence, the adsorption system is in a heterogeneous condition. The microwave-assisted arcing thereby presents a promising approach to transforming CPO into MNC that could remove the hazardous dye.

Electrochemical Detection of Femtomolar DNA via Boronate Affinity-Mediated Decoration of Polysaccharides with Electroactive Tags.

In view of their high efficiency and cost-effectiveness, polymers are of great promise as carriers for signal tags in amplified detection. Herein, we present a polysaccharide-amplified method for the electrochemical detection of a BRCA1 breast cancer gene-derived DNA target at the femtomolar levels. Briefly, peptide nucleic acid (PNA) with a complementary sequence was tethered as the capture probe for the DNA target, to which carboxyl group-containing polysaccharides were then attached via facile phosphate-Zr(IV)-carboxylate crosslinking, followed by the decoration of polysaccharide chains with electroactive ferrocene (Fc) signal tags via affinity coupling between a cis-diol site and phenylboronic acid (PBA) group. As the polysaccharide chain contains hundreds of cis-diol sites, boronate affinity can enable the site-specific decoration of each polysaccharide chain with hundreds of Fc signal tags, efficiently transducing each target capture event into the decoration of many Fc signal tags. As polysaccharides are cheap, renewable, ubiquitous, and biodegradable natural biopolymers, the use of polysaccharides for signal amplification offers the benefits of high efficiency, cost-effectiveness, excellent biocompatibility, and environmental friendliness. The linear range of the polysaccharide-amplified method for DNA detection was demonstrated to be from 10 fM to 10 nM (R2 = 0.996), with the detection limit as low as 2.9 fM. The results show that this method can also discriminate single base mismatch with satisfactory selectivity and can be applied to DNA detection in serum samples. In view of these merits, the polysaccharide-amplified PNA-based electrochemical method holds great promise in DNA detection with satisfactory sensitivity and selectivity.

Phototheranostic nanoparticles with aggregation-induced emission as a four-modal imaging platform for image-guided photothermal therapy and ferroptosis of tumor cells.

Due to the aggregation-caused quenching (ACQ) and weak photo-penetrating ability, the application of phototheranostic agents in drug delivery field is greatly limited. Ferroptosis, a newly discovered cell death mode, has not been extensively studied in the field of phototherapy up to now. Here, a new near-infrared II (NIR-II) molecule with aggregation-induced emission (AIE) property (named TSST) co-assembled with DHA-PEG and ferrocene as nanoparticles (DFT-NP), which was rationally designed and synthesized. The DFT-NP exhibited enhanced NIR-II fluorescence, photothermal, photoacoustic, magnetic resonance imaging, AIE and ferroptosis capacities. The NIR-II fluorescence intensity of obtained nanoparticles was improved, owing to the strong interaction between DHA and TSST, which limited the intramolecular rotation restriction and non-radiative attenuation of TSST to discourage energy dissipation in aggregation state. Inspiringly, the generated photothermal effect by DFT-NP can promote the Fenton reaction of ferrocene and H2O2, resulting in dissolution of the nanoparticles and cancer cells expedited ferroptosis via accumulation lipid free radicals of DHA. The released TSST enhanced the photothermal and photoacoustic imaging effects through removing the DHA restriction to restore the non-radiative attenuation. This work is the first example of nanoparticles that integrates four-mode imaging, photothermal and ferroptosis-induced therapy functions, which offers great advantages for potential clinical applications.

Supramolecular erythrocytes-hitchhiking drug delivery system for specific therapy of acute pneumonia.

Acute pneumonia is an inflammatory syndrome often associated with severe multi-organ dysfunction and high mortality. The therapeutic efficacy of current anti-inflammatory medicines is greatly limited due to the short systemic circulation and poor specificity in the lungs. New drug delivery systems (DDS) are urgently needed to efficiently transport anti-inflammatory drugs to the lungs. Here, we report an inflammation-responsive supramolecular erythrocytes-hitchhiking DDS to extend systemic circulation of the nanomedicine via hitchhiking red blood cells (RBCs) and specifically "drop off" the payloads in the inflammatory lungs. ß-cyclodextrin (ß-CD) modified RBCs and ferrocene (Fc) modified liposomes (NP) were prepared and co-incubated to attach NP to RBCs via ß-CD/Fc host-guest interactions. RBCs extended the systemic circulation of the attached NP, meanwhile, the NP may get detached from RBCs due to the high ROS level in the inflammatory lungs. In acute pneumonia mice, this strategy delivered curcumin specifically to the lungs and effectively alleviated the inflammatory syndrome.

Ferrocene-based multifunctional nanoparticles for combined chemo/chemodynamic/photothermal therapy.

Ferrocene and its derivatives have great potential for biomedical applications, but few related studies have been reported. In this study, copper ions and ferrocene derivatives were used for the first time to construct the ferrocene-based nanoparticles (Cu-Fc) with a hydrated particle size of approximately 220 nm. Their good photothermal conversion properties were verified in vitro and in vivo for the first time, indicating that they could be used as a novel photothermal agent for tumor treatment. In addition, the nanoparticles exhibited efficient Fenton effect under weakly acidic conditions, indicating that they can generate hydroxyl radicals (OH) to kill tumors in the weakly acidic environment of the tumor-specific microenvironment. More importantly, the nanoparticles can deplete glutathione (GSH), thus further enhancing Fenton effect-mediated chemodynamic therapy (CDT). Multifunctional ferrocene-based nanoparticles (DOX@Cu-Fc) were obtained after loading the chemotherapeutic drug doxorubicin hydrochloride (DOX). The results of in vitro and in vivo experiments showed that DOX@Cu-Fc could enhance tumor treatment by the combination of chemo/CDT/photothermal therapy (PTT).

Ferrocene and glucose oxidase-installed multifunctional hydrogel reactors for local cancer therapy.

A hyaluronic acid (HA)-based one-pot hydrogel reactor with single syringe injection and immediate gelation was developed for starvation therapy (ST), chemodynamic therapy (CDT), ferroptosis, and photothermal therapy (PTT) against breast cancer. A rheologically tuned hydrogel network, composed of HA-phenylboronic acid (HP) and HA-dopamine (HD), was designed by introducing a boronate ester linkage (phenylboronic acid-dopamine interaction) and polydopamine bond (pH control). Ferrocene (Fc)-conjugated HP (Fc-HP) was synthesized to achieve ferroptosis, Fenton reaction-involved toxic hydroxyl radical (•OH) generation, and photothermal ablation in cancer therapy. Glucose oxidase (GOx) was entrapped in the pH-modulated Fc-HP (Fc-HP°)/HD hydrogel network for converting intracellular glucose to H2O2 to enable its own supply. The GOx/Fc combination-installed hydrogel reactor system can provide sustained ST/CDT/PTT functions along with ferroptosis. Injection of Fc-HP°/HD/GOx hydrogel with single-syringe injectability, shear-thinning feature, and self-healing capability offered a slow biodegradation rate and high safety profiles. Peritumorally injected Fc-HP°/HD/GOx hydrogel also efficiently suppressed the growth of breast cancer based on multifunctional therapeutic approaches with reduced dosing frequency. Hyperthermia induced by near-infrared (NIR) laser absorption may amplify the therapeutic effects of free radicals. It is expected that this Fc-HP°/HD/GOx hydrogel system can be applied to local cancer therapy with high efficacy and safety profiles.

Covalent grafting diazotized black phosphorus with ferrocene oligomer towards smoke suppression and toxicity reduction.

In comparison with the thermal hazard of polymers, noxious smoke and gas produced by the combustion of polymers make the environment self-purification a huge challenge. As a new type of a highly effective flame retardant, black phosphorus (BP) can effectively decrease the thermal hazard of polymers, but its performances in smoke suppression and toxicity reduction are unsatisfactory. In this article, a method of covalently grafting diazotized BP with a ferrocene oligomer was applied to promote the smoke suppression and toxicity reduction efficiency of BP. In our work, the BP-NH nanomaterials with a mass of amino groups on the surface were acquired by diazotizing the BP. Then, the BP-Fe was obtained by covalently grafting the ferrocene chloride salt and nitrogen-containing heterocycles on the surface of BP. The smoke production rate (SPR) and total smoke production (TSP) values of the epoxy resin (EP) decreased by 49.8% and 52.5% with the addition of 2 wt% BP-Fe, respectively. In comparison with previous studies, this work was far more effective than the previous work in smoke suppression and flame retardant. The release of toxic gases (CO and HCN) and volatile organic compounds in the EP was also effectively inhibited at the same time. In addition, the storage modulus and tensile strength of nanocomposites increased by 35.1% and 27.2% with the addition of 1 wt% BP-Fe. This work also provides a new idea on how to simultaneously strengthen the toxic smoke suppression, mechanical properties, and flame retardant of polymer materials.

Borax exerts protective effect against ferrocene-induced neurotoxicity in Oncorhynchus mykiss.

BACKGROUND: In recent years, therapeutic targets and the development of new drugs have shifted research towards inflammatory and oxidative stress pathways. Ferrocene (FcH) is a stable, small molecule that exhibits immunostimulatory and anti-tumor properties by a different mechanism and is effective at low doses in oral administration. However, it was surprising that there has been no performed investigation using FcH on aquaculture. On the other hand, recent papers reveal the key biological functions and health benefits due to daily boron intake in animals and humans. Therefore, we investigated the neurotoxic damage potential of FcH and its related neurotoxicity action mechanism in aquatic environments. In addition, the protective potential of borax (BX, or sodium borate) were evaluated againt in vivo neurotoxicity by FcH. METHODS: Neurotoxicity assessment was performed in rainbow trout brain tissue, acutely under semi-static conditions via determining a vide range of parameters including catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD) activities as well as glutathione (GSH), myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA levels), DNA damage (8-OHdG), apoptosis (caspase 3), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), nuclear factor erythroid-2 (Nrf-2), acetylcholinesterase (AChE) and brain-derived neurotrophic factor (BDNF) levels. In addition, the LC50 96 h level of FcH was determined for the first time in rainbow trout in this study. RESULTS: In the obtained results, while FcH caused inhibition in enzyme activities, it showed an inducing effect on MDA, MPO, BDNF, Nrf2, TNF-α and IL-6 levels. It was determined that this oxidative damage related alterations were significantly different (p < 0.05) in comparison between FcH treated and controls. Again, the LC50 96 h value in rainbow trout was determined as 11.73 mg/L, which is approximately 5% less than the value given for freshwater fish (12.3 mg/L). On the contrary, it was observed that BX has a mitigating effect on FcH-induced neurotoxicity. CONCLUSION: The present study suggests that borax may be useful for preventing or alleviating neurotoxicity induced by environmental contaminants or toxic chemicals.

Formation of Oxidation- and Acid-Sensitive Assemblies from Sterols and a Quaternary Ammonium Ferrocene Derivative: Quatsome- and Onion-like Vesicles and Extended Nanoribbons.

Quatsomes are a class of nonphospholipid vesicles in which bilayers are formed from mixtures of quaternary ammonium (QA) amphiphiles and sterols. We describe the formation of oxidation and acid-sensitive quatsome-like vesicles and other bilayer assemblies from mixtures of a ferrocenylated QA amphiphile (FTDMA) and several cholesterol derivatives. The influence of the sterol and the preparation method (extrusion or probe sonication) on the stability and morphology of the resulting vesicles is explored; a variety of structures can be obtained from small (ca. 30 nm) spherical unilamellar and oligolamellar quatsome-like vesicles to large (ca. 200 nm) multilamellar onion-like vesicles to extended nanoribbons many micrometers long. FTDMA-sterol vesicles undergo drastic shifts in vesicle and membrane structure when treated with a chemical oxidant (Frémy's salt), a feature previously observed in liposomes containing FTDMA and now confirmed in nonphospholipid vesicles. Size distributions of spherical quatsome-like vesicles obtained from cryo-TEM are examined to estimate the membrane bending rigidity, and a hypothesis is presented to explain the underlying mechanism of the profound membrane alterations observed as a consequence of ferrocene oxidation.

FC-BBR/IND-induced glucose oxidase nanodrugs for targeted combination therapy.

Targeted therapy from cells to mitochondria can improve the bioavailability and therapeutic effects of drugs. Combination therapy by combining two or more therapeutic methods comes to be seen a hopeful strategy to overcome the emergence of resistance. Ferrocene (FC) derivatives of the sandwich structure can not only directly inhibit the proliferation of cancer cells but also catalyze the Fenton reaction to enhance chemodynamic therapy. Berberine (BBR) is a Chinese herbal extract with mitochondria-targeted anticancer activity. In our work, glucose oxidase (GOD) was induced to self-assemble by ferrocene-berberine conjugate (FC-BBR) and indomethacin (IND), which was then encapsulated by hyaluronic acid (HA) and formed nanodrugs (FC-BBR/IND@GOD@HA NPs). Molecular simulation results showed that the drugs could be bound to multiple sites of GOD and induce its self-assembly. The prepared nanoassembly could inhibit the proliferation and induce the apoptosis of HepG2 cells, which might be the result of targeted chemodynamic therapy and starvation therapy. Moreover, the FC-BBR/IND@GOD@HA NPs could also promote the production of reactive oxygen species and the loss of mitochondrial membrane potential and block the cells in S phase. More importantly, it could inhibit the movement and migration of cancer cells, which gave it the potential to prevent tumor metastasis.

Hypoxia responsive nano-drug delivery system based on angelica polysaccharide for liver cancer therapy.

Based on the tumor hypoxic microenvironment and the new programmed cell death mode of combined ferroptosis, an angelica polysaccharide-based nanocarrier material was synthesized. The polymer contains hydrophilic angelica polysaccharide (ASP) that is linked by azobenzene (AZO) linker with ferrocene (Fc), and then the side chain was covalently modified with arachidonic acid (AA). It was postulated that the polymer micelles could work as an instinctive liver targeting drug delivery carrier, owing to the existence of ASP with liver targeting. Moreover, the aim was to engineer hypoxia-responsive polymer micelles which was modified by AA, for selective enhancement of ferroptosis in solid tumor, via diminishing glutathione (GSH) under hypoxia. Finally, we synthesized the amphiphilic polymer micelles AA/ASP-AZO-Fc (AAAF) by self-assembling. The structure of AAAF was confirmed by 1H-NMR and FT-IR. Then, we exemplified the hydrophobic medication curcumin into polymer micelles AAAF@Cur, which has smooth and regular spheres. In vitro release test affirmed that AAAF@Cur can achieve hypoxia response to drug release. In addition, a series of cell experiments confirmed that hypoxia could enhance cell uptake and effectively improve the proliferation inhibitory activity of HepG2 cells. In conclusion, AAAF, as an effective cell carrier, is expected to develop in sensitizing ferroptosis and anti-tumor.

Diastereoselective Double C-H Functionalization of Chiral Ferrocenes with Heteroaromatics.

Diastereoselective double C-H heteroarylation of chiral ferrocenes provides valuable compounds with multiple functionalities using mild reaction conditions and simple reagents. Pd-Complexes with chiral mono-protected amino acids afforded corresponding heteroarylated ferrocenyl amines in good yields and high diastereomeric purities. In this way, a variety of indole, thiophene, pyrrole, or furan substituents were introduced to the ferrocene moiety. Furthermore, a range of relevant functional groups, for example ketone, ester, chloro, nitro, or silyl, are tolerated by this method. An alternative combination of amino acid and ferrocenyl amine configurations was leveraged to provide the complementary diastereomeric products. The products of C-H heteroarylation can be transformed into corresponding phosphines. Absolute configurations of CH-activation products were confirmed by the combination of X-ray crystallographic analysis and CD spectroscopy. 19 F NMR kinetic study and DFT calculations provided insights into the reaction mechanism and reasons governing stereoinduction.

Conjugated Polymer-Ferrocence Nanoparticle as an NIR-II Light Powered Nanoamplifier to Enhance Chemodynamic Therapy.

Chemodynamic therapy (CDT) is a promising therapeutic modality with transition metal ions and endogenous H2O2 as reagents, but its efficiency is impaired by low endogenous H2O2 levels and nonregeneration of metal ions. Most intracellular H2O2 supplement strategies use oxidases and are intensively dependent on oxygen participation. The hypoxia microenvironments of solid tumors weaken their performance. Here, we develop a near-infrared II light powered nanoamplifier to improve the local oxygen level and to enhance CDT. The nanoamplifier CPNP-Fc/Pt consists of ferrocene (Fc)- and cisplatin prodrug (Pt(IV))-modified conjugated polymer nanoparticles (CPNPs). CPNP has a donor-acceptor structure and demonstrates a good photothermal effect under 1064 nm light irradiation, which accelerates blood flow and efficiently elevates the local oxygen content. In response to intracellular glutathione, Pt(II) is released from CPNP-Fc/Pt and triggers enzymatic cascade reactions with nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and superoxide dismutase to convert oxygen into H2O2. The enhanced oxygen level results in efficient intracellular H2O2 supply. Fc is reacted with H2O2 and converted to Fc+ via the Fenton reaction, with the generation of hydroxyl radicals for CDT. Unlike free metal ions, the Fe(III) in Fc+ is reduced to Fe(II) by intracellular NAD(P)H, which achieves the regeneration of Fc. The sufficient intracellular H2O2 supply and efficient Fc regeneration effectively enhance the Fenton reaction and demonstrate good in vivo CDT results with tumor growth suppression. This design offers a promising strategy to enhance CDT efficiency in the hypoxia microenvironment of solid tumors.

Self-Assembled Herbal Medicine Encapsulated by an Oxidation-Sensitive Supramolecular Hydrogel for Chronic Wound Treatment.

Inflammation has been assumed to affect the pathology of wound healing and is associated with many nonhealing chronic wounds. Naturally derived herbal medicines with anti-inflammatory properties are of interest because of their effectiveness and affordability in clinical treatment. Herein, we report a supramolecular hydrogel comprising self-assembled natural herb rhein and an oxidative responsive cross-linked network based on ferrocene and ß-cyclodextrin host-guest recognitions. Rhein can directly self-assemble into fibrils, exerting better anti-inflammation efficiency than its free drug form. The adaption of the supramolecular network can greatly improve the stability and retain the structural integrity of encapsulated self-assembled rhein. In addition, host-guest recognition confers dissolution of the hydrogel under oxidative stress, thereby delivering self-assembled rhein to the wound site and exerting better therapeutic efficiency. Evaluations in diabetic mice indicate that the resultant hydrogel promoted chronic wound healing by suppressing excess reactive oxygen species, facilitating the transition of the wound healing process, and restoring the normal wound-repair process. Therefore, the proposed hydrogel has a potential value as an herbal-based dressing for future clinical chronic wound management.

4-Aminoquinoline-ferrocene Hybrids as Potential Antimalarials.

BACKGROUND: Malaria is a deadly disease. It is mostly treated using 4- aminoquinoline derivatives such as chloroquine etc. because it is well-tolerated, displays low toxicity, and after administration, it is rapidly absorbed. The combination of 4-aminoquinoline with other classes of antimalarial drugs has been reported to be an effective approach for the treatment of malaria. Furthermore, some patents reported hybrids 4-aminoquinolines containing ferrocene moiety with potent antimalarial activity. OBJECTIVE: The objective of the current study is to prepare 4-aminoquinoline-ferrocene hybrids via esterification and amidation reactions. The compounds were characterized via FTIR, LC-MS and NMR spectroscopy. In vitro screening against chloroquine-sensitive P. falciparum parasite (NF54) at concentrations (1 µM and 5 µM) and an inhibitory concentration (full dose-response) was studied. METHODS: The compounds were prepared via known reactions and monitored by Thin Layer Chromatography. The compounds were purified by column chromatography and characterized using FTIR, NMR and MS. In vitro antiplasmodial evaluation was performed against asexual parasite and chloroquine was used as a reference drug. RESULTS: The percentage inhibition effects of the hybrid compounds were in a range of 97.9-102% at 5 µM and 36-96% at 1 µM. Furthermore, the IC50 values of the compounds were in the range of 0.7-1.6 µM when compared to the parent drug, 4-ferrocenylketobutanoic acid. CONCLUSION: The hybrid compounds displayed significant antimalarial activity when compared to the parent drug. However, they were not as effective as chloroquine on the drug-sensitive parasite. The findings revealed that 4-aminoquinolines and ferrocene are potential scaffolds for developing potent antimalarials.

One Stone Two Birds: Zr-Fc Metal-Organic Framework Nanosheet for Synergistic Photothermal and Chemodynamic Cancer Therapy.

Metal-organic frameworks (MOFs) have been identified as promising materials for the delivery of therapeutics to cure cancer owing to their intrinsic porous structure. However, in a majority of cases, MOFs act as only a delivery cargo for anticancer drugs while little attention has been focused on the utilization of their intriguing physical and chemical properties for potential anticancer purposes. Herein for the first time, an ultrathin (16.4 nm thick) ferrocene-based MOF (Zr-Fc MOF) nanosheet has been synthesized for synergistic photothermal therapy (PTT) and Fenton reaction-based chemodynamic (CDT) therapy to cure cancer without additional drugs. The Zr-Fc MOF nanosheet acts not only as an excellent photothermal agent with a prominent photothermal conversion efficiency of 53% at 808 nm but also as an efficient Fenton catalyst to promote the conversion of H2O2 into hydroxyl radical (•OH). As a consequence, an excellent therapeutic performance has been achieved in vitro as well as in vivo through this combinational effect. This work aims to construct an "all-in-one" MOF nanoplatform for PTT and CDT treatments without incorporating any additional therapeutics, which may launch a new era in the investigation of MOF-based synergistic therapy platforms for cancer therapy.