Diselenide Bond Research Articles

Improving Fmoc Solid Phase Synthesis of Human Beta Defensin 3.

Human β-defensin 3, HBD-3, is a 45-residue antimicrobial and immunomodulatory peptide that plays multiple roles in the host defense system. In addition to interacting with cell membranes, HBD-3 is also a ligand for melanocortin receptors, cytokine receptors and voltage-gated potassium channels. Structural and functional studies of HBD-3 have been hampered by inefficient synthetic and recombinant expression methods. Herein, we report an optimized Fmoc solid-phase synthesis of this peptide using an orthogonal disulfide bonds formation strategy. Our results suggest that utilization of an optimized resin, coupling reagents and pseudoproline dipeptide building blocks decrease chain aggregation and largely improve the amount of the target peptide in the final crude material, making the synthesis more efficient. We also present an alternative synthesis of HBD-3 in which a replacement of a native disulfide bridge with a diselenide bond improved the oxidative folding. Our work enables further biological and pharmacological characterization of HBD-3, hence advancing our understanding of its therapeutic potential.

Dynamic Fluorescent Patterning Based on Visible-Light-Responsive Diselenide Metathesis.

A diselenide bond, as a dynamic covalent bond, is a versatile tool to construct smart interfaces, which can respond to visible light. In this work, we used microcontact printing (μCP) to construct diselenide patterns on quartz substrates. Fluorescent patterns were obtained on the modified surfaces via the visible-light-induced diselenide metathesis reaction, which allowed the patterning process to be fast, dynamically erasable, and compatible with different fluorescent molecules including rhodamine B and boron-dipyrromethene (BODIPY) used in this work. A variety of analytical methods offered comprehensive evidence for the success of the printing of diselenides here. We further printed diselenide and disulfide intersecting stripes on one single quartz substrate layer by layer and introduced rhodamine B and BODIPY to obtain a multicolored pattern simultaneously. By taking advantage of their responsiveness to different wavelengths, the composite pattern of disulfides and diselenides could be erased by two stepwise stages. The fluorescent images of the modified substrate showed a good agreement with the pattern of the poly(dimethylsiloxane) (PDMS) stamp, indicating the methodology with a potential application for information storage.

Photothermal self-healing polyurethane/graphene oxide composites based on diselenide bond

The polymer PCL-MDI-SeSe-PU polyurethane was synthesized by the reaction of PCL, diisocyanate and a diselenide bond-containing chain extender, and a certain amount of diisocyanate-modified graphene oxide NCO-GO was doped into polyurethane to obtain the PCL-MDI-SeSe-PU/NCO-GO composite. Benefitting from the thermal stimulated dynamic properties of diselenide bond and the photothermal effects of NCO-GO, the composite exhibited efficient self-healing behaviors upon exposure to infrared irradiation. As a result, the polymer PCL-MDI-SeSe-PU has good self-healing properties with 95.4% self-healing efficiency at 80 °C for 3 h. After doping modified graphene oxide, the elongation at break of the polymer is greatly improved and reveals the excellent photothermal effect, the surface temperature can reach 148 °C and the maximum self-healing efficiency of 88.3% can be maintained under 60 s of infrared laser irradiation.

ROS-cleavable diselenide nanomedicine for NIR-controlled drug release and on-demand synergistic chemo-photodynamic therapy

Many chemotherapeutic drugs and photosensitizers suffer from poor solubility, unspecific delivery and uncontrollable release, which severely impede their biomedical applications. Herein, we designed a type of ROS-cleavable hydrophilic diselenide nanoparticles through self-assembling of PEG-modified camptothecin (CPT, a hydrophobic drug) and meso‑tetra (4-carboxyphenyl) porphine (TCPP, a hydrophobic photosensitizer). The TCPP@SeSe-CPT nanomedicine (particle size: 116.5 ± 1.9 nm) has stability for long-time blood circulation. Near-infrared (NIR) laser-triggered generation of ROS from TCPP can efficiently break the ROS-sensitive diselenide bond, which induces the decomposition of TCPP@SeSe-CPT nanomedicine for concurrent release of CPT and TCPP. Moreover, the released amounts of CPT and TCPP can be regulated by adjusting the NIR laser irradiation time. Such NIR-controlled release of CPT and TCPP can give rise to on-demand synergistic chemo-/photodynamic therapeutic effects for maximized tumor growth suppression with minimized side effects. Statement of significanceIn this work, a ROS-cleavable diselenide nanoparticle was designed and successfully self-assembled with the hydrophobic drug camptothecin and photosensitizer TCPP into a hydrophilic TCPP@SeSe-CPT nanomedicine. Compared with traditional drug delivery systems, TCPP@SeSe-CPT nanomicelles could reduce premature drug release and co-deliver hydrophobic chemotherapeutic drugs/photosensitizers to tumors, which yielded a NIR-controlled synergistic chemo-/photodynamic therapeutic effect. Since diselenide bond is more sensitive than the traditional disulfide bond, under the 660 nm laser irradiation (300 mW/cm2), ROS generated from laser-excited TCPP in TCPP@SeSe-CPT nanomicelles could break the diselenium bonds to achieve the light-controlled release of CPT. In addition, the photosensitizer TCPP could also be imaged at the tumor site. Due to the photodynamic therapy from laser-excited TCPP and chemotherapy from photocontrolled release of CPT in TCPP@SeSe-CPT, our designed nanomicelles yielded potent antitumor effects both in vitro and in vivo.

Redox-Responsive Drug Delivery Systems: A Chemical Perspective.

With the widespread global impact of cancer on humans and the extensive side effects associated with current cancer treatments, a novel, effective, and safe treatment is needed. Redox-responsive drug delivery systems (DDSs) have emerged as a potential cancer treatment with minimal side effects and enhanced site-specific targeted delivery. This paper explores the physiological and biochemical nature of tumors that allow for redox-responsive drug delivery systems and reviews recent advances in the chemical composition and design of such systems. The five main redox-responsive chemical entities that are the focus of this paper are disulfide bonds, diselenide bonds, succinimide–thioether linkages, tetrasulfide bonds, and platin conjugates. Moreover, as disulfide bonds are the most commonly used entities, the review explored disulfide-containing liposomes, polymeric micelles, and nanogels. While various systems have been devised, further research is needed to advance redox-responsive drug delivery systems for cancer treatment clinical applications.

Stimuli-responsive conductive hydrogel touch sensor for electrochemical and fluorescence monitoring of acetylcholinesterase activity and inhibition

In this study, we produced a stimuli-responsive electrochemical and fluorescence biosensor using carbonized diselenide-crosslinked polymer dot-loaded polydopamine nanoparticles (PDA@dsPD) incorporated into polyvinyl alcohol/chitosan hydrogel, to examine the activity and inhibition of acetylcholinesterase (AChE). The PDA@dsPD inside the hydrogels (i.e., PDA@dsPD-Hydrogel) was sensitive to AChE in the presence of acetylthiocholine, which formed thiocholine that dissolved the diselenide bonds and simultaneously released polydopamine nanoparticles; this affected the optical and electronic performance of the hydrogel. The electronic response-based pressure and strain on the PDA@dsPD-Hydrogel shifted to 23 % when the AChE concentration was 300 U/L, while in the absence of AChE, this value shifted to 46 %. The PDA@dsPD-Hydrogels were able to visualize the AChE fluorescence signal expressed by PC-12 cells, in addition to an increase in electronic conductivity after the cleavage of the diselenide bond. In contrast, no change in the electrochemical or fluorescence signals was observed in the presence of neostigmine, an AChE inhibitor. The novel PDA@dsPD-Hydrogel can even be connected to a wireless electronic device to facilitate the detection of AChE via smartphones.

Exploring of the property of epoxy resins based on diselenide and disulfide dynamic linkers.

Over the last decade, there has been a lot of interest in incorporating dynamic covalent bonds (DCBs) into epoxy resins. Because diselenide and disulfide bonds have similar properties, they are frequently used as DCBs in self-healing epoxy networks. In this paper, we present diselenide and disulfide dynamic linkers containing epoxy networks by analyzing the effects of mechanical properties, thermal stability, activation energies, and self-healing properties. The glass transition temperature (T g) values, mechanical properties, crosslinking density (v e ), and thermal stability of disulfide linkers networks were higher than those of diselenide linkers networks, according to our research. The activation energies of disulfide linkers were higher than those of diselenide linkers (up to 14 kJ/mol), but their healing efficiency was lower than that of the diselenide network. These findings demonstrate the advantages of diselenide and disulfide dynamic linkers in epoxy networks systems, as well as a method for designing and preparing the appropriate diselenide dynamic linkers or disulfide dynamic linkers incorporated into epoxy networks for the appropriate application and processing technology.

Engineered Bacterial Outer Membrane Vesicles as Controllable Two-Way Adaptors to Activate Macrophage Phagocytosis for Improved Tumor Immunotherapy.

The most immune cells infiltrating tumor microenvironment (TME), tumor-associated macrophages (TAMs) closely resemble immunosuppressive M2-polarized macrophages. Moreover, tumor cells exhibit high expression of CD47 "don't eat me" signal, which obstructs macrophage phagocytosis. The precise and efficient activation of TAMs is a promising approach to tumor immunotherapy; however, re-education of macrophages remains a challenge. Bacteria-derived outer membrane vesicles (OMVs) are highly immunogenic nanovesicles that can robustly stimulate macrophages. Here, an OMV-based controllable two-way adaptor is reported, in which a CD47 nanobody (CD47nb) is fused onto OMV surface (OMV-CD47nb), with the outer surface coated with a polyethylene glycol (PEG) layer containing diselenide bonds (PEG/Se) to form PEG/Se@OMV-CD47nb. The PEG/Se layer modification not only mitigates the immunogenicity of OMV-CD47nb, thereby remarkedly increasing the dose that can be administered safely through intravenous injection, but also equips the formulation with radiation-triggered controlled release of OMV-CD47nb. Application of radiation to tumors in mice injected with the nanoformulation results in remodeling of TME. As two-way adaptors, OMV-CD47nb activates TAM phagocytosis of tumor cells via multiple pathways, including induction of M1 polarization and blockade of "don't eat me" signal. Moreover, this activation of TAMs results in the stimulation of T cell-mediated antitumor immunity through effective antigen presentation.

Sequentially Activatable Polypeptide Nanoparticles for Combinatory Photodynamic Chemotherapy of Breast Cancer.

Stimuli-activatable nanomaterials hold significant promise for tumor-specific drug delivery by recognizing the internal or external stimulus. Herein, we reported a dual-responsive and biodegradable polypeptide nanoparticle (PPTP@PTX2 NP) for combinatory chemotherapy and photodynamic therapy (PDT) of breast cancer. The NPs were engineered by encapsulating diselenide bond linked dimeric prodrug of paclitaxel (PTX2) in an intracellular acidity-activatable polypeptide micelle. Specifically, the acid-responsive polypeptide was synthesized by grafting a tetraphenyl porphyrin (TPP) photosensitizer and N,N-diisopropylethylenediamine (DPA) onto the poly(ethylene glycol)-block-poly(glutamic acid) diblock copolymer by the amidation reaction, which self-assembled into micellar NPs and was activated inside the acidic endocytic vesicles to perform PDT. The paclitaxel dimer can be stably loaded into the polypeptide NPs and be restored by PDT inside the tumor cells. The formed PPTP@PTX2 NPs remained inert during blood circulation and passively accumulated in the tumor foci, which could be activated within the endocytic vesicles via acid-triggered protonation of DPA groups to generate fluorescence signal and release PTX2 in 4T1 murine breast tumor cells. Upon 660 nm laser irradiation, the activated NPs carried out PDT via TPP and chemotherapy via PTX to induce apoptosis of 4T1 cells and thereby efficiently inhibited 4T1 tumor growth and prevented metastasis of tumor cells.

Near-infrared light and redox dual-activatable nanosystems for synergistically cascaded cancer phototherapy with reduced skin photosensitization

Currently, activatable photodynamic therapy (PDT) that is precisely regulated by endogenous or exogenous stimuli to selectively produce cytotoxic reactive oxygen species at the tumor site is urgently in demand. Herein, we fabricated a dual-activatable PDT nanosystem regulated by the redox tumor microenvironment and near-infrared (NIR) light-induced photothermal therapy (PTT). In this study, photosensitizer chlorin e6 (Ce6) was conjugated to hyaluronic acid (HA) via a diselenide bond to form an amphiphilic polymer (HSeC) for loading PTT agent IR780 to produce HSeC/IR nanoparticles (NPs). The photoactivity of Ce6 for PDT was “double-locked” by the aggregation-caused quenching (ACQ) effect and the fluorescence resonance energy transfer (FRET) from Ce6 to IR780 during blood circulation. After selective accumulation into tumors, HSeC/IR NPs were subsequently dissociated due to the “double-key”, which included diselenide bond dissociation under high redox conditions and IR780 degradation upon NIR laser irradiation, resulting in recovering Ce6. In vitro studies indicated that Ce6 photoactivity in HSeC/IR NPs was significantly suppressed when compared with free Ce6 or in HSeC NPs. Moreover, BALB/c mice treated with HSeC/IR NPs displayed distinctly alleviated skin damage during PDT. Synergetic cascaded PTT-PDT with superior tumor suppression was observed in SCC7 tumor-bearing mice. Therefore, the study findings could provide a promising treatment strategy for PTT-facilitated PDT with high antitumor efficacies and reduced skin phototoxicity levels.

A turn-on colorimetric dual-response fluorescent probe for rapid detecting and its application in bio-imaging and real water samples

A novel fluorescent probe (DSHN) was designed and synthesized. Two 4-hydrazino-N-hydroxyethyl-1, 8-naphthalimide blocks were used as the fluorophores, and the diselenide bond (-Se-Se-) and the amide bond (–CONH–) were used as the nucleophilic dual-response reaction sites of hydrogen sulfide (H2S). Large Stokes shift (111 nm) and good stability over a wide pH range of DSHN are obtained. The results of the experiments of fluorescence spectra show that DSHN can recognize H2S high selectively and sensitively. The turn-on effect is evident and the time response is rapid (60 s). The limit of detection (LOD) of DSHN fluorescence detection of H2S is low at 61.0 nM. Particularly, DSHN can not only be used as an ideal colorimetric tool for detecting H2S in real water samples, but also image H2S in living cells, indicating its potential utility for the fluorescence detection of H2S in environmental and biological samples.

Diselenide-crosslinked carboxymethyl chitosan nanoparticles for doxorubicin delivery: Preparation and in vivo evaluation

In this paper, we report a simple approach to fabricate diselenide-crosslinked carboxymethyl chitosan nanoparticles (DSe-CMC NPs) for doxorubicin (DOX) delivery, with disulfide analogs (DS-CMC NPs) as control. DS-CMC NPs and DSe-CMC NPs featured a spherical morphology and narrow size distribution with the average size about 200 nm. Carboxymethyl chitosan (CMC) as the starting material not only improved the biocompatibility of the nanocarriers but also enhanced physiological stability. Due to electrostatic interactions between DOX and CMC, the nanoparticles had high drug encapsulation efficiency (∼25 %). The nanoparticles disintegration and drug release were accelerated by the cleavage of diselenide bonds through oxidation by H2O2 or reduction by GSH. In vitro cell experiments revealed that DOX-loaded DSe-CMC NPs possessed the highest drug accumulation and cytotoxicity in tumor cells. Moreover, DOX-loaded DSe-CMC NPs performed the enhanced growth inhibition in vivo than that of DS-CMC NPs. Thus, the diselenide-crosslinked nanoparticles possess great potentials for DOX delivery.

Water-Enhanced and Remote Self-Healing Elastomers in Various Harsh Environments.

The development of underwater remote stimulus-responsive self-healing polymer materials for applications in inaccessible and urgent situations is very challenging because water can readily disturb traditional noncovalent bonds and absorb heat, UV light, IR light, and electromagnetic wave energy at the wave band of micrometers and millimeters. Herein, visible-light-responsive diselenide bonds are employed as the healing moieties to produce a water-enhanced and remote self-healing elastomer triggered by a blue laser, which possesses excellent underwater transmission capability. During healing, the strain at break reaches ∼200% in 5 min and its toughness almost fully recovers within 1 h, which is estimated to be the fastest reported to date for healing silicone elastomers with a healing efficiency above 90%. The remote underwater pipeline sealing is instantly accomplished with the diselenide-containing elastomers by a blue laser 3 m away, thereby providing a direction for future emergent healing applications.

Reactive Human Plasma Glutathione Peroxidase Mutant with Diselenide Bond Succeeds in Tetramer Formation.

Plasma glutathione peroxidase (GPx3) belongs to the GPx superfamily, and it is the only known secreted selenocysteine (Sec)−containing GPx in humans. It exists as a glycosylated homotetramer and catalyzes the reduction of hydrogen peroxide and lipid peroxides, depending on the Sec in its active center. In this study, a previously reported chimeric tRNAUTuT6 was used for the incorporation of Sec at the UAG amber codon, and the mature form of human GPx3 (hGPx3) without the signal peptide was expressed in amber−less E. coli C321.ΔA.exp. Reactive Sec−hGPx3, able to reduce H2O2 and tert−butyl hydroperoxide (t−BuOOH), was produced with high purity and yield. Study of the quaternary structure suggested that the recombinant Sec−hGPx3 contained an intra−molecular disulfide bridge but failed to form tetramer. Mutational and structural analysis of the mutants with three Cys residues, individually or jointly replaced with Ser, indicated that the formation of intra−molecular disulfide bridges involved structure conformational changes. The secondary structure containing Cys77 and Cys132 was flexible and could form a disulfide bond, or form a sulfhydryl–selenyl bond with Sec49 in relative mutants. Mutation of Cys8 and Cys132 to Sec8 and Sec132 could fix the oligomerization loop through the formation of diselenide bond, which, in turn, facilitated tetramer formation and noticeably improved the GPx activity. This research provides an important foundation for the further catalysis and functional study of hGPx3.

Diselenide as a Dual Functional Mechanophore Capable of Stress Self-Reporting and Self-Strengthening in Polyurethane Elastomers

Diselenide as a Dual Functional Mechanophore Capable of Stress Self-Reporting and Self-Strengthening in Polyurethane Elastomers

Redox-responsive properties of core-cross-linked micelles of poly(ethylene oxide)-b-poly(furfuryl methacrylate) for anticancer drug delivery application

The design and fabrication of smart delivery systems that can efficiently deliver a payload to a targeted site in a controlled manner are immensely desirable in chemotherapy. We report the redox-responsive drug delivery property of core-cross-linked (CCL) micelles of poly(ethylene oxide)5k-b-poly(furfuryl methacrylate)2k (PEO5k-b-PFMA2k). The PEO5k-b-PFMA2k was prepared by using single electron transfer-living radical polymerization of furfuryl methacrylate (FMA) with a PEO-Br macro-initiator. Doxorubicin (DOX) was loaded into hydrophobic PFMA cores of the polymeric micelles, which were subsequently cross-linked with a diselenide-containing cross-linker, bis(maleimidoethyl) 3,3′-diselanediyldipropionoate via Diels-Alder reaction. Under physiological conditions, CCL micelles displayed increased structural stability, whereas the micelles showed a redox-responsive behavior when treated with 100 mM hydrogen peroxide (H2O2) and 10 mM glutathione (GSH). The CCL micelles were de-cross-linked due to the breaking of diselenide bonds present in the core-cross-linkages. DOX-loaded CCL micelles were stable at pH 7.4, while a higher DOX release was achieved at acidic pH 5.0 owing to the protonation of DOX. The DOX release was significantly enhanced in presence of 10 mM GSH or 100 mM H2O2 at pH 5.0 (which is a similar environment in tumor cells). The non-CCL and CCL micelles were found non-toxic to HFF-1 normal cells. However, DOX encapsulated CCL micelles showed remarkable cytotoxicity in HeLa cells. The confocal images showed that the DOX-loaded CCL micelles can quickly be internalized and efficiently deliver DOX into the HeLa cells.

When Dynamic Diselenide Bonds Meet Dynamic Imine Bonds in Polymeric Materials.

In both natural and artificial functional systems, the cooperation between different dynamic interactions is of vital importance for realizing complicated functions. Dynamic covalent bonds are one kind of relatively stable dynamic interactions and have shown synergistic effect in natural systems such as functional proteins. However, synergistic interactions between different dynamic covalent bonds in polymeric materials are still unclear. Herein, polymeric materials containing diselenide and imine bonds are prepared, and then the synergistic effect between the two dynamic covalent bonds is quantitatively evaluated in typical processes of dynamic materials. The results reveal that dynamic covalent bonds show weak synergistic effect in the degradation process and have strong synergistic effect in stress relaxation process. Therefore, introducing multiple dynamic covalent bonds in polymeric materials can extensively enhance their dynamic properties.

Biomimetic Redox-Responsive Mesoporous Organosilica Nanoparticles Enhance Cisplatin-Based Chemotherapy.

Cisplatin-based chemotherapy is dominated in several cancers; however, insufficient therapeutic outcomes and systemic toxicity hamper their clinical applications. Controlled release of cisplatin and reducing inactivation remains an urgent challenge to overcome. Herein, diselenide-bridged mesoporous organosilica nanoparticles (MON) coated with biomimetic cancer cell membrane were tailored for coordination responsive controlled cisplatin delivery and GSH depletion to strengthen Pt-based chemotherapy. Cisplatin-loaded MON (MON-Pt) showed high loading capacity due to robust coordination between selenium and platinum atoms and preventing premature leakage in normal tissue. MON-Pt exhibited a controlled release of activated cisplatin in response to the redox tumor microenvironment. Meanwhile, MON-Pt containing redox-responsive diselenide bonds could efficiently scavenge intracellular inactivation agents, such as GSH, to enhance Pt-based chemotherapy. 4T1 breast cancer cell membranes cloaked MON-Pt (MON-Pt@CM) performed efficient anticancer performance and low in vivo system toxicity due to long blood circulation time and high tumor accumulation benefiting from the tumor targeting and immune-invasion properties of the homologic cancer cell membrane. These results suggest a biomimetic nanocarrier to control release and reduce the inactivation of cisplatin for efficient and safe Pt-based chemotherapy by responding and regulating the tumor microenvironment.

Hyaluronic acid-modified redox-sensitive hybrid nanocomplex loading with siRNA for non-small-cell lung carcinoma therapy

A novel hyaluronic acid (HA)-modified hybrid nanocomplex HA-SeSe-COOH/siR-93C@PAMAM, which could efficiently deliver siRNA into tumor cells via a redox-mediated intracellular disassembly, was constructed for enhanced antitumor efficacy. Thereinto, siR-93C (siRNA) and positive PAMAM were firstly mixed into the electrostatic nano-intermediate, and then diselenide bond (-SeSe-)-modified HA was coved to shield excessive positive charges. This hybrid nanocomplex displayed uniform dynamic sizes, high stability, controlled zeta potential and narrow PDI distribution. Moreover, the -SeSe- linkage displayed GSH/ROS dual responsive properties, improving intracellular trafficking of siRNA. In vitro assays in A549 cell line presented that HA-SeSe-COOH/siR-93C@PAMAM has low cytotoxicity, rapid lysosomal escape and significant transfection efficiency; besides, an efficient proliferation inhibition ability and enhanced apoptosis. Furthermore, in animal studies, this negative-surfaced hybrid nanocomplex showed a prolonged circulation in blood and improved inhibition of tumor growth. All these results verified our hypothesis in this study that diselenide bonds-modified HA could promote not only stability and safety of nanoparticles in vivo but also intracellular behavior of siRNA via redox-dual sensitive properties; furthermore, this hybrid nanocomplex provided a visible potential approach for siRNA delivery in the antitumor field.

Epoxy resin with exchangeable diselenide crosslinks to obtain reprocessable, repairable and recyclable fiber-reinforced thermoset composites

The cross-linked structure of thermosetting carbon fiber composites makes it difficult to degrade and recycle, especially the non-destructive recovery and recycling of high value-added carbon fiber is a major challenge for the sustainable development of carbon fiber composites. The high-efficiency degradation of chemical health and the high performance of materials are mutually restricted and difficult to balance. We report a epoxy resin networks, prepared through ring-opening reaction of epoxy resin with diselenide-labeled diaromatic amine, that can be turned into catalyst-free vitrimer material by exchange of diselenide bonds. When the diselenide bonds are introduced, specific relaxation times and activation energy of the vitrimer have been measured. Based on the dynamic diselenide bonds, this new vitrimer materials can be reprocessed and repaired upon heating via swift metathesis reactions. In addition, the diselenide crosslinks thermoset materials, which have high modulus and high glass transition temperature, exhibit considerable reprocessability, recyclability and reparability. Furthermore, recyclable carbon fiber reinforced composites (CFRC) are prepared using dynamic diselenide covalent network materials as binders.