Magnetic Responsive Release of Nitric Oxide from an MOF-Derived Fe3O4@PLGA Microsphere for the Treatment of Bacteria-Infected Cutaneous Wound.

Nitric oxide (NO) is an essential endogenous signaling molecule regulating multifaceted physiological functions in the (cardio)vascular, neuronal, and immune systems. Due to the short half-life and location-/concentration-dependent physiological function of NO, translational application of NO as a novel therapeutic approach, however, awaits a strategy for spatiotemporal control on the delivery of NO. Inspired by the magnetic hyperthermia and magneto-triggered drug release featured by Fe3O4 conjugates, in this study, we aim to develop a magnetic responsive NO-release material (MagNORM) featuring dual NO-release phases, namely, burst and steady release, for the selective activation of NO-related physiology and treatment of bacteria-infected cutaneous wound. After conjugation of NO-delivery [Fe(µ-S-thioglycerol)(NO)2]2 with a metal-organic framework (MOF)-derived porous Fe3O4@C, encapsulation of obtained conjugates within the thermo-responsive poly(lactic-co-glycolic acid) (PLGA) microsphere completes the assembly of MagNORM. Through continuous/pulsatile/no application of the alternating magnetic field (AMF) to MagNORM, moreover, burst/intermittent/slow release of NO from MagNORM demonstrates the AMF as an ON/OFF switch for temporal control on the delivery of NO. Under continuous application of the AMF, in particular, burst release of NO from MagNORM triggers an effective anti-bacterial activity against both Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli). In addition to the magneto-triggered bactericidal effect of MagNORM against E. coli-infected cutaneous wound in mice, of importance, steady release of NO from MagNORM without the AMF promotes the subsequent collagen formation and wound healing in mice.

Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies.

Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit.

Bioinorganic Chemistry of the Natural [Fe(NO)2] Motif: Evolution of a Functional Model for NO-Related Biomedical Application and Revolutionary Development of a Translational Model.

Identification of the distinctive electron paramagnetic resonance signal at g = 2.03 in the yeast cells and liver of mice treated with carcinogens opened the discovery and investigation of the natural [Fe(NO)2] motif in the form of dinitrosyliron complexes (DNICs). In this Viewpoint, a chronological collection of the benchmark for the study of DNIC demonstrates that the preceding study of its biological synthesis, storage, transport, transformation, and function related to NO physiology inspires the biomimetic study of structural and functional models supported by thiolate ligands to provide mechanistic insight at a molecular level. During the synthetic, spectroscopic, and theoretical investigations on the structure-to-reactivity relationship within DNICs, control of the Fe-NO bonding interaction and of the delivery of NO+/•NO/HNO/NO- by the supporting ligands and nuclearity evolves into the "redesign of the natural [Fe(NO)2] motif" as a strategy to develop DNICs for NO-related biomedical application and therapeutic approach. The revolutionary transformation of covalent a [Fe(NO)2] motif into a translational model for hydrogenase, triggered by the discovery of redox interconversion among [{Fe(NO)2}9-L•] ↔ {Fe(NO)2}9 ↔ {Fe(NO)2}10 ↔ [{Fe(NO)2}10-L•]-, echoes the preceding research journey on [Fe]/[NiFe]-hydrogenase and completes the development of an electrodeposited-film electrode for electrocatalytic water splitting. Through the 50-year journey, bioinorganic chemistry of DNIC containing the covalent [Fe(NO)2] motif and noninnocent/labile NO ligands highlights itself as a unique metallocofactor to join the longitudinal study between biology/chemistry/biomedical application and the lateral study toward multielectron (photo/electro)catalysis for industrial application. This Viewpoint discloses the potential [Fe(NO)2] motif awaiting continued contribution in order to emerge as a novel application in the next 50 years, whereas the parallel development of bioinorganic chemistry, guided by inspirational Nature, moves the science forward to the next stage in order to benefit the immediate needs for human activity.

Effects of curcumin on nitrosyl-iron complex-mediated DNA cleavage and cytotoxicity.

Combination therapy aims to improve the pharmaceutical efficacy of different drugs, thus lowering the dosages used and reducing the side effects. However, interactions between individual drugs may also occur and lead to uncertain consequences. This study demonstrated that curcumin, a natural phenolic compound found in the rhizomes of turmeric, could either inhibit or enhance DNA cleavage caused by the synthetic nitrosyl-iron complex NC10 ([Fe2(C2H5OS)2(NO)4]). Without UV irradiation, higher concentrations of curcumin protected DNA from being cleaved by NC10. Conversely, in the presence of lower concentrations of curcumin (< 5 µM), cleaved DNA increased by raising curcumin concentrations. After UV irradiation, the DNA protective effect of curcumin decreased while the enhancing DNA cleavage effect of curcumin remained. UV/visible spectroscopy analysis showed that curcumin is associated with the iron of NC10, suggesting the formation of curcumin-Fe complexes. Furthermore, a cytotoxicity assay revealed that cotreatment of NC10 and curcumin had synergetic effects on the growth inhibition of mouse melanoma B16-F10 cells. To our knowledge, this is the first study of the cotreatment of curcumin with inorganic compounds that showed synergistic cytotoxicity.

Dinuclear [{Fe(NO)2}(10)-{Fe(NO)2}(10)] dinitrosyl iron complex with thiolate-CO-bridged ligands.

Air-sensitive complexes {Fe(NO)(2)}(9)-{Fe(NO)(2)}(9) [Fe(mu-SC(6)H(4)-o-N(CH(3))(2))(NO)(2)](2) (1), {Fe(NO)(2)}(9)-{Fe(NO)(2)}(10) [Fe(mu-SC(6)H(4)-o-N(CH(3))(2))(NO)(2)](2)(-) (2), the anionic {Fe(NO)(2)}(10) [(SC(6)H(4)-o-N(CH(3))(2))Fe(NO)(2)](-) (3), and the anionic {Fe(NO)(2)}(10)-{Fe(NO)(2)}(10) [Fe(NO)(2)(mu-SC(6)H(4)-o-N(CH(3))(2))(mu-CO)Fe(NO)(2)](-) (4) with mixed CO-thiolate-bridged ligands were synthesized. All complexes were characterized by IR, UV-vis, electron paramagnetic resonance, and single-crystal X-ray diffraction. The interconversions among these complexes were demonstrated. The interconversion between complexes 1 and 2 is accomplished by reduction and oxidation. Complex 3 adapts a {Fe(NO)(2)}(10) electronic structure with a N/S ligation mode and serves as a donor reagent of the {Fe(NO)(2)}(10) moiety. {Fe(NO)(2)}(10)-{Fe(NO)(2)}(10) complex 4 possesses the butterfly-like [Fe(mu-S)(mu-C)Fe] core with a shorter Fe...Fe distance of 2.5907(5) A attributed to the shorter Fe-S and Fe-C bond distances.

The water-soluble Roussin's red ester acting as a potential photochemical NO-delivery agent: photolysis reactions, DNA cleavage and anticancer activity.

The water-soluble Roussin's red ester [(NO)(2)Fe(mu-SCH(2)CH(2)P(O)(CH(2)OH)(2))(2)Fe(NO)(2)] (1), a potential photochemical prodrug of an NO precursor, was synthesized from the reaction of HSCH(2)CH(2)P(O)(CH(2)OH)(2) (F) and [Fe(CO)(2)(NO)(2)]. The IR v(NO) stretching frequencies of complex 1 appear at 1759 (s), 1784 (s) and 1816 (w) cm(-1) in buffer (pH = 7.4). NO was released with a stoichiometry ratio Delta[NO]/Delta[1] = 3.6 +/- 0.2 when complex 1 was exposed to UV in deaerated aqueous phosphate buffer solution. Here light acts as an On/Off switch for NO release. Incubation of pBR322 supercoiled DNA with complex 1, followed by irradiation, produced DNA strand breakage. In contrast to the addition of carboxy-PTIO (NO radical scavenger), DNA strand breakage was not inhibited when the scavengers of hydroxyl radical and singlet oxygen were added. Complex 1 irradiated under a N(2) atmosphere exhibited the same cleavage efficiency as complex 1 irradiated under air. The results show that DNA strand cleavage efficiency depends on the concentration of complex 1, the pH value of the buffer, and the duration of the photolysis of complex 1. The conversion rate from supercoiled (SC form) to nicked circular (NC form) of complex 1 was 2.96 x 10(-2) s(-1). The results of a T4 ligase enzymatic assay reveals the nonhydrolytic DNA breakage mechanism. The NO-release ability of complexes 1, 2, and 3 follows the order 1 > 2 > 3. Upon UV-irradiation, complex 1 exhibits cytotoxicity against B16-F10 mouse melanoma cells.

trans-Bis(µ-2-hydroxy-ethanethiol-ato-κS:S)bis-[dinitro-syliron(II)](Fe-Fe).

The title complex, [Fe(2)(C(2)H(5)OS)(2)(NO)(4)], lies on a crystallographic inversion center. The Fe-Fe distance is characteristic of a metal-metal bond. In the crystal structure, inter-molecular O-H⋯O hydrogen bonds link complex mol-ecules into a two-dimensional network.

Mononitrosyl tris(thiolate) iron complex [Fe(NO)(SPh)3]- and dinitrosyl iron complex [(EtS)2Fe(NO)2]-: formation pathway of dinitrosyl iron complexes (DNICs) from nitrosylation of biomimetic rubredoxin [Fe(SR)4]2-/1- (R = Ph, Et).

Nitrosylation of the biomimetic reduced- and oxidized-form rubredoxin [Fe(SR)4]2-/1- (R = Ph, Et) in a 1:1 stoichiometry led to the formation of the extremely air- and light-sensitive mononitrosyl tris(thiolate) iron complexes (MNICs) [Fe(NO)(SR)3]- along with byproducts [SR]- or (RS)2. Transformation of [Fe(NO)(SR)3]- into dinitrosyl iron complexes (DNICs) [(RS)2Fe(NO)2]- and Roussin's red ester [Fe2(mu-SR)2(NO)4] occurs rapidly under addition of 1 equiv of NO(g) and [NO]+, respectively. Obviously, the mononitrosyl tris(thiolate) complex [Fe(NO)(SR)3]- acts as an intermediate when the biomimetic oxidized- and reduced-form rubredoxin [Fe(SR)4]2-/1- exposed to NO(g) were modified to form dinitrosyl iron complexes [(RS)2Fe(NO)2]-. Presumably, NO binding to the electron-deficient [Fe(III)(SR)4]- and [Fe(III)(NO)(SR)3]- complexes triggers reductive elimination of dialkyl/diphenyl disulfide, while binding of NO radical to the reduced-form [Fe(II)(SR)4]2- induces the thiolate-ligand elimination. Protonation of [Fe(NO)(SEt)3]- yielding [Fe(NO)(SPh)3]- by adding 3 equiv of thiophenol and transformation of [Fe(NO)(SPh)3]- to [Fe(NO)(SEt)3]- in the presence of 3 equiv of [SEt]-, respectively, demonstrated that complexes [Fe(NO)(SPh)3]- and [Fe(NO)(SEt)3]- are chemically interconvertible. Mononitrosyl tris(thiolate) iron complex [Fe(NO)(SPh)3]- and dinitrosyl iron complex [(EtS)2Fe(NO)2]- were isolated and characterized by X-ray diffraction. The mean NO bond distances of 1.181(7) A (or 1.191(7) A) in complex [(EtS)2Fe(NO)2]- are nearly at the upper end of the 1.178(3)-1.160(6) A for the anionic {Fe(NO)2}9 DNICs, while the mean FeN(O) distances of 1.674(6) A (or 1.679(6) A) exactly fall in the range of 1.695(3)-1.661(4) A for the anionic {Fe(NO)2}9 DNICs.

Dinitrosyl iron complexes (DNICs) [L(2)Fe(NO)2]- (L = thiolate): interconversion among {Fe(NO)2}9 DNICs, {Fe(NO)2}10 DNICs, and [2Fe-2S] clusters, and the critical role of the thiolate ligands in regulating NO release of DNICs.

Dinitrosyl iron complex [(-SC(7)H(4)SN)(2)Fe(NO)(2)](-) (1) was prepared by reaction of [S(5)Fe(NO)(2)](-) and bis(2-benzothiozolyl) disulfide. In synthesis of the analogous dinitrosyl iron compounds (DNICs), the stronger electron-donating thiolates [RS](-) (R = C(6)H(4)-o-NHCOCH(3), C(4)H(3)S, C(6)H(4)NH(2), Ph), compared to [-SC(7)H(4)SN](-) of complex 1, trigger thiolate-ligand substitution to yield [(-SC(6)H(4)-o-NHCOCH(3))(2)Fe(NO)(2)](-) (2), [(-SC(4)H(3)S)(2)Fe(NO)(2)](-) (3), and [(SPh)(2)Fe(NO)(2)](-) (4), respectively. At 298 K, complexes 2 and 3 exhibit a well-resolved five-line EPR signal at g = 2.038 and 2.027, respectively, the characteristic g value of DNICs. The magnetic susceptibility fit indicates that the resonance hybrid of {Fe(+)((*)NO)(2)}(9) and {Fe(-)((+)NO)(2)}(9) in 2 is dynamic by temperature. The IR nu(NO) stretching frequencies (ranging from (1766, 1716) to (1737, 1693) cm(-)(1) (THF)) of complexes 1-4 signal the entire window of possible electronic configurations for such stable and isolable {Fe(NO)(2)}(9) [(RS)(2)Fe(NO)(2)](-). The NO-releasing ability of {Fe(NO)(2)}(9) [(RS)(2)Fe(NO)(2)](-) is finely tuned by the coordinated thiolate ligands. The less electron-donating thiolate ligands coordinated to {Fe(NO)(2)}(9) motif act as better NO-donor DNICs in the presence of NO-trapping agent [Fe(S,S-C(6)H(4))(2)](2)(2-). Interconversion between {Fe(NO)(2)}(9) [(RS)(2)Fe(NO)(2)](-) and {Fe(NO)(2)}(10) [(Ph(3)P)(2)Fe(NO)(2)] was verified in the reaction of (a) [(RS)(2)Fe(NO)(2)](-), 10 equiv of PPh(3) and sodium-biphenyl, and (b) 2 equiv of thiol, [RS](-), and [(Ph(3)P)(2)Fe(NO)(2)], respectively. The biomimetic reaction cycle, transformation between {Fe(NO)(2)}(9) [(RS)(2)Fe(NO)(2)](-) and {Fe(NO)(2)}(9) [(R'S)(2)Fe(NO)(2)](-), reversible interconversion of {Fe(NO)(2)}(9) and {Fe(NO)(2)}(10) DNICs, and degradation/reassembly of [2Fe-2S] clusters may decipher and predict the biological cycle of interconversion of {Fe(NO)(2)}(9) DNICs, {Fe(NO)(2)}(10) DNICs, and the [Fe-S] clusters in proteins.

Synthetic modeling of zinc thiolates: quantitative assessment of hydrogen bonding in modulating sulfur alkylation rates.

A series of mononuclear zinc thiolate complexes have been prepared and fully characterized. The reactions of the complexes with alkyl halides, leading to zinc halides and the corresponding thioethers, have been examined by kinetic methods. In toluene, the reactions obey a second-order rate law displaying activation parameters consistent with a S(N)2 attack of the zinc-bound thiolate on the carbon electrophile. Intramolecular hydrogen bonding of an amide NH to the thiolate sulfur reduces the nucleophilicity and consequently, the rate of alkylation more than 30-fold at 25 degrees C. The H-bonding shows an inverse HD isotope effect of 0.33 (60 degrees C) ascribed to differential H-bonding for the two isotopomers due to zero point energy differences. These model studies provide quantitative evaluation of H-bonding on reaction rates relevant to zinc thiol-activating proteins.