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The influence of polymer architecture of polycations on their ability to transfect mammalian cells is probed. Polymer bottle brushes with grafts made from partially hydrolysed poly(2-ethyl-2-oxazoline) are used while varying the length of the polymer backbone as well as the degree of hydrolysis (cationic charge content). Polyplex formation is investigated via gel electrophoresis, dye-displacement and dynamic light scattering. Bottle brushes show a superior ability to complex pDNA when compared to linear copolymers. Also, nucleic acid release was found to be improved by a graft architecture. Polyplexes based on bottle brush copolymers showed an elongated shape in transmission electron microscopy images. The cytotoxicity against mammalian cells is drastically reduced when a graft architecture is used instead of linear copolymers. Moreover, the best-performing bottle brush copolymer showed a transfection ability comparable with that of linear poly(ethylenimine), the gold standard of polymeric transfection agents, which is used as positive control. In combination with their markedly lowered cytotoxicity, cationic bottle brush copolymers are therefore shown to be a highly promising class of gene delivery vectors. [ABSTRACT FROM AUTHOR]

We have synthesized a series of novel substituted sulfonyl ethylenediamine (en) RuII arene complexes 1–8 of [(η6-arene)Ru(R1-SO2-EnBz)X], where the arene is benzene, HO(CH2)2O-phenyl or biphenyl (biph), X = Cl or I, and R1 is phenyl, 4-Me-phenyl, 4-NO2-phenyl or dansyl. The 'piano-stool' structure of complex 3, [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)I], was confirmed by X-ray crystallography. The values of their aqua adducts were determined to be high (9.1 to 9.7). Complexes 1–8 have antiproliferative activity against human A2780 ovarian, and A549 lung cancer cells with IC50 values ranging from 4.1 to >50 μM, although, remarkably, complex 7 [(η6-biph)Ru(phenyl-SO2-EnBz)Cl] was inactive towards A2780 cells, but as potent as the clinical drug cisplatin towards A549 cells. All these complexes also showed catalytic activity in transfer hydrogenation (TH) of NAD+ to NADH with sodium formate as hydride donor, with TOFs in the range of 2.5–9.7 h−1. The complexes reacted rapidly with the thiols glutathione (GSH) and N-acetyl- L -cysteine (NAC), forming dinuclear bridged complexes [(η6-biph)2Ru2(GS)3]2− or [(η6-biph)2Ru2(NAC-H)3]2−, with the liberation of the diamine ligand which was detected by LC-MS. In addition, the switching on of fluorescence for complex 8 in aqueous solution confirmed release of the chelated DsEnBz ligand in reactions with these thiols. Reactions with GSH hampered the catalytic TH of NAD+ to NADH due to the decomposition of the complexes. Co-administration to cells of complex 2 [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)Cl] with L -buthionine sulfoximine (L -BSO), an inhibitor of GSH synthesis, partially restored the anticancer activity towards A2780 ovarian cancer cells. Complex 2 caused a concentration-dependent G1 phase cell cycle arrest, and induced a significant level of reactive oxygen species (ROS) in A2780 human ovarian cancer cells. The amount of induced ROS decreased with increase in GSH concentration, perhaps due to the formation of the dinuclear Ru-SG complex. [ABSTRACT FROM AUTHOR]

Polymeric cylinders, a fascinating type of nanostructures with high surface area, internal volume and rigidity, have been exploited as novel drug delivery vehicles over the past decade. However, it's still an open challenge to afford cylindrical nanostructures using polymeric building blocks via traditional self‐assembly processes. Herein, we report a hierarchical self‐assembly strategy of preparing cylindrical aggregates (tubisomes) from an amphiphilic supramolecular bottlebrush polymer in which a cyclic peptide nanotube is employed as the noncovalent backbone. Additionally, an aggregation‐induced emission (AIE) effect was introduced into the tubisomes to endow them with excellent fluorescent properties. Intriguingly, by encapsulating with the anticancer drug doxorubicin (DOX), both the fluorescence of tubisome and DOX can be quenched due to the energy transfer relay (ETR) effect. The release of DOX can induce the interruption of the ETR effect and recover the silenced fluorescence, thereby permitting the in‐situ imaging of drug release. The AIE‐featured supramolecular tubisomes reported here provide an alternative approach for fabricating cylindrical polymeric nanostructures and holds great potential for imaging‐guided drug delivery. [ABSTRACT FROM AUTHOR]

Typically, the morphologies of the self‐assembled nanostructures from block copolymers are limited to spherical micelles, wormlike micelles and vesicles. Now, a new generation of materials with unique shape and structures, cylindrical soft matter particles (tubisomes), are obtained from the hierarchical self‐assembly of cyclic peptide‐bridged amphiphilic diblock copolymers. The capacity of obtained photo‐responsive tubisomes as potential drug carriers is evaluated. The supramolecular tubisomes pave an alternative way for fabricating polymeric tubular structures, and will expand the toolbox for the rational design of functional hierarchical nanostructures. [ABSTRACT FROM AUTHOR]

Here arsenohydrogels are introduced for the first time as functional, tuneable and responsive hydrogels. The distinctive redox reactivity of arsenic has been exploited to crosslink high molecular weight (Mw ＞ 300 kDa) polymeric arsenical scaffolds (PDMAmx-co-AsAmy) via reductive coupling of As(v) to As(i) which proceeds with the formation of As–As in the form of As(i)n homocycles. Soft arsenohydrogels (G′∼ 400–1700 Pa) that failed in compression tests at low compression and loading are formed when the polymer weight fraction is 2.5 wt%. When the polymer weight fraction is increased to 10 wt% the mechanical properties (stiffness and relaxation) of the arsenohydrogels are significantly improved and correlate with the mole fraction of arsenic (AsAm, y) present in the copolymer scaffolds. Furthermore, increasing the mole fraction of AsAm, reduces the degree of swelling and increases the stability of the gels against hydrolysis and oxidation of the As–As crosslinks. The functionality of the polymeric arsenical scaffolds has also been exploited to load arsenohydrogels with a model organic arsenical drug. The rate and degree of release of the loaded organic arsenical under simulated oxidative stress (H2O2) is inversely proportional to the mole fraction of arsenic in the original polymer scaffold. Finally, the polymeric arsenical scaffolds and the resulting arsenohydrogels have been shown to be non-toxic to NIH/3T3 (mouse fibroblast) and PC3 (human prostate cancer) cell lines. The properties and versitility of the arsenohydrogels alludes to their potential as a functional platform for biomaterials. [ABSTRACT FROM AUTHOR]

A series of neutral pseudo-octahedral RuII sulfonamidoethylenediamine complexes [(η6-p-cym)Ru(N,N′)Cl] where N,N′ is N-(2-(R1,R2-amino)ethyl)-4-toluenesulfonamide (TsEn(R1,R2)) R1,R2 = Me,H (1); Me,Me (2); Et,H (3); benzyl,H (Bz, 4); 4-fluorobenzyl,H (4-F-Bz, 5) or naphthalen-2-ylmethyl,H (Naph, 6), were synthesised and characterised including the X-ray crystal structure of 3. These complexes catalyse the reduction of NAD+ regioselectively to 1,4-NADH by using formate as the hydride source. The catalytic efficiency depends markedly on the steric and electronic effects of the N-substitutent, with turnover frequencies (TOFs) increasing in the order: 1 ＜ 2 ＜ 3, 6 ＜ 4, 5, achieving a TOF of 7.7 h−1 for 4 with a 95% yield of 1,4-NADH. The reduction rate was highest between pH* (deuterated solvent) 6 and 7.5 and improved with an increase in formate concentration (TOF of 18.8 h−1, 140 mM formate). The calculations suggested initial substitution of an aqua ligand by formate, followed by hydride transfer to RuII and then to NAD+, and indicated specific interactions between the aqua complex and both NAD+ and NADH, the former allowing a preorganisation involving interaction between the aqua ligand, formate anion and the pyridine ring of NAD+. The complexes exhibited antiproliferative activity towards A2780 human ovarian cancer cells with IC50 values ranging from 1 to 31 μM, the most potent complex, [(η6-p-cym)Ru(TsEn(Bz,H))Cl] (4, IC50 = 1.0 ± 0.1 μM), having a potency similar to the anticancer drug cisplatin. Co-administration with sodium formate (2 mM), increased the potency of all complexes towards A2780 cells by 20–36%, with the greatest effect seen for complex 6. [ABSTRACT FROM AUTHOR]

The development of catalytic metallodrugs is an emerging field that may offer new approaches to cancer chemotherapeutic design. By exploiting the unique properties of transition metal complexes, in‐cell catalysis can be applied to modulate the cellular redox balance as part of a multi‐targeting mechanism of action. We describe the synthesis and characterization of six coordinatively unsaturated iridium(III) diamine catalysts that are stable at physiological pH in aqueous solution. Reduction of the colorimetric substrate 2,6‐dichlorophenolindophenol by transfer hydrogenation under biologically compatible conditions achieved turnover frequencies up to 63 ± 2 h−1 and demonstrated that the source of hydride (sodium formate) is the limiting reagent, despite being in a 1000‐fold excess of the catalyst. The catalyst showed low in vivo acute toxicity in zebrafish embryos and modest in vitro potency towards cancer cells. When administered alone, the catalyst generated oxidative stress in cells (an effect that was conserved in vivo), but co‐treatment with a nontoxic dose of sodium formate negated this effect. Co‐treatment with sodium formate significantly enhanced catalyst potency in cancer cells (A2780 ovarian and MCF7 breast cancer cells) and drug‐resistant cells (A2780cis and MCF7‐TAMR1) but not in non‐tumorigenic cells (MRC5), demonstrating that a redox‐targeting mechanism may generate selectivity for cancer cells. [ABSTRACT FROM AUTHOR]

We have synthesized a series of novel substituted sulfonyl ethylenediamine (en) Ru II arene complexes 1-8 of [(η 6 -arene)Ru(R 1 -SO 2 -EnBz)X], where the arene is benzene, HO(CH 2 ) 2 O-phenyl or biphenyl (biph), X = Cl or I, and R 1 is phenyl, 4-Me-phenyl, 4-NO 2 -phenyl or dansyl. The 'piano-stool' structure of complex 3, [(η 6 -biph)Ru(4-Me-phenyl-SO 2 -EnBz)I], was confirmed by X-ray crystallography. The values of their aqua adducts were determined to be high (9.1 to 9.7). Complexes 1-8 have antiproliferative activity against human A2780 ovarian, and A549 lung cancer cells with IC 50 values ranging from 4.1 to >50 μM, although, remarkably, complex 7 [(η 6 -biph)Ru(phenyl-SO 2 -EnBz)Cl] was inactive towards A2780 cells, but as potent as the clinical drug cisplatin towards A549 cells. All these complexes also showed catalytic activity in transfer hydrogenation (TH) of NAD + to NADH with sodium formate as hydride donor, with TOFs in the range of 2.5-9.7 h -1 . The complexes reacted rapidly with the thiols glutathione (GSH) and N -acetyl-L-cysteine (NAC), forming dinuclear bridged complexes [(η 6 -biph) 2 Ru 2 (GS) 3 ] 2- or [(η 6 -biph) 2 Ru 2 (NAC-H) 3 ] 2- , with the liberation of the diamine ligand which was detected by LC-MS. In addition, the switching on of fluorescence for complex 8 in aqueous solution confirmed release of the chelated DsEnBz ligand in reactions with these thiols. Reactions with GSH hampered the catalytic TH of NAD + to NADH due to the decomposition of the complexes. Co-administration to cells of complex 2 [(η 6 -biph)Ru(4-Me-phenyl-SO 2 -EnBz)Cl] with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, partially restored the anticancer activity towards A2780 ovarian cancer cells. Complex 2 caused a concentration-dependent G1 phase cell cycle arrest, and induced a significant level of reactive oxygen species (ROS) in A2780 human ovarian cancer cells. The amount of induced ROS decreased with increase in GSH concentration, perhaps due to the formation of the dinuclear Ru-SG complex.

Polymeric cylinders, a fascinating type of nanostructures with high surface area, internal volume and rigidity, have been exploited as novel drug delivery vehicles over the past decade. However, it's still an open challenge to afford cylindrical nanostructures using polymeric building blocks via traditional self-assembly processes. Herein, we report a hierarchical self-assembly strategy of preparing cylindrical aggregates (tubisomes) from an amphiphilic supramolecular bottlebrush polymer in which a cyclic peptide nanotube is employed as the noncovalent backbone. Additionally, an aggregation-induced emission (AIE) effect was introduced into the tubisomes to endow them with excellent fluorescent properties. Intriguingly, by encapsulating with the anticancer drug doxorubicin (DOX), both the fluorescence of tubisome and DOX can be quenched due to the energy transfer relay (ETR) effect. The release of DOX can induce the interruption of the ETR effect and recover the silenced fluorescence, thereby permitting the in-situ imaging of drug release. The AIE-featured supramolecular tubisomes reported here provide an alternative approach for fabricating cylindrical polymeric nanostructures and holds great potential for imaging-guided drug delivery., (© 2021 Wiley-VCH GmbH.)

A series of neutral pseudo-octahedral RuII sulfonamidoethylenediamine complexes [(η6-p-cym)Ru(N,N')Cl] where N,N' is N-(2-(R1,R2-amino)ethyl)-4-toluenesulfonamide (TsEn(R1,R2)) R1,R2 = Me,H (1); Me,Me (2); Et,H (3); benzyl,H (Bz, 4); 4-fluorobenzyl,H (4-F-Bz, 5) or naphthalen-2-ylmethyl,H (Naph, 6), were synthesised and characterised including the X-ray crystal structure of 3. These complexes catalyse the reduction of NAD+ regioselectively to 1,4-NADH by using formate as the hydride source. The catalytic efficiency depends markedly on the steric and electronic effects of the N-substitutent, with turnover frequencies (TOFs) increasing in the order: 1 < 2 < 3, 6 < 4, 5, achieving a TOF of 7.7 h-1 for 4 with a 95% yield of 1,4-NADH. The reduction rate was highest between pH* (deuterated solvent) 6 and 7.5 and improved with an increase in formate concentration (TOF of 18.8 h-1, 140 mM formate). The calculations suggested initial substitution of an aqua ligand by formate, followed by hydride transfer to RuII and then to NAD+, and indicated specific interactions between the aqua complex and both NAD+ and NADH, the former allowing a preorganisation involving interaction between the aqua ligand, formate anion and the pyridine ring of NAD+. The complexes exhibited antiproliferative activity towards A2780 human ovarian cancer cells with IC50 values ranging from 1 to 31 μM, the most potent complex, [(η6-p-cym)Ru(TsEn(Bz,H))Cl] (4, IC50 = 1.0 ± 0.1 μM), having a potency similar to the anticancer drug cisplatin. Co-administration with sodium formate (2 mM), increased the potency of all complexes towards A2780 cells by 20-36%, with the greatest effect seen for complex 6.

We report the synthesis and characterization of four neutral organometallic tethered complexes, [Ru(η 6 -Ph(CH 2 ) 3 -ethylenediamine- N -R)Cl], where R = methanesulfonyl (Ms, 1 ), toluenesulfonyl (Ts, 2 ), 4-trifluoromethylbenzenesulfonyl (Tf, 3 ), and 4-nitrobenzenesulfonyl (Nb, 4 ), including their X-ray crystal structures. These complexes exhibit moderate antiproliferative activity toward human ovarian, lung, hepatocellular, and breast cancer cell lines. Complex 2 in particular exhibits a low cross-resistance with cisplatin. The complexes show potent catalytic activity in the transfer hydrogenation of NAD + to NADH with formate as hydride donor in aqueous solution (310 K, pH 7). Substituents on the chelated ligand decreased the turnover frequency in the order Nb > Tf > Ts > Ms. An enhancement of antiproliferative activity (up to 22%) was observed on coadministration with nontoxic concentrations of sodium formate (0.5-2 mM). Complex 2 binds to nucleobase guanine (9-EtG), but DNA appears not to be the target, as little binding to calf thymus DNA or bacterial plasmid DNA was observed. In addition, complex 2 reacts rapidly with glutathione (GSH), which might hamper transfer hydrogenation reactions in cells. Complex 2 induced a dose-dependent G 1 cell cycle arrest after 24 h exposure in A2780 human ovarian cancer cells while promoting an increase in reactive oxygen species (ROS), which is likely to contribute to its antiproliferative activity., Competing Interests: The authors declare no competing financial interest.

We report the synthesis, characterization, and antiproliferative activity of organo-osmium(II) and organo-ruthenium(II) half-sandwich complexes [(η 6 - p -cym)Os(L)Cl]Cl ( 1 and 2 ) and [(η 6 - p -cym)Ru(L)Cl]Cl ( 3 and 4 ), where L = N -(2-hydroxy)-3-methoxybenzylidenethiosemicarbazide ( L1 ) or N -(2,3-dihydroxybenzylidene)-3-phenylthiosemicarbazide ( L2 ), respectively. X-ray crystallography showed that all four complexes possess half-sandwich pseudo-octahedral "three-legged piano-stool" structures, with a neutral N,S-chelating thiosemicarbazone ligand and a terminal chloride occupying three coordination positions. In methanol, E / Z isomerization of the coordinated thiosemicarbazone ligand was observed, while in an aprotic solvent like acetone, partial dissociation of the ligand occurs, reaching complete displacement in a more coordinating solvent like DMSO. In general, the complexes exhibited good activity toward A2780 ovarian, A2780Cis cisplatin-resistant ovarian, A549 lung, HCT116 colon, and PC3 prostate cancer cells. In particular, ruthenium complex 3 does not present cross-resistance with the clinical drug cisplatin in the A2780 human ovarian cancer cell line. The complexes were more active than the free thiosemicarbazone ligands, especially in A549 and HCT116 cells with potency improvements of up to 20-fold between organic ligand L1 and ruthenium complex 1 ., Competing Interests: The authors declare no competing financial interest.

Functional drug carrier systems have potential for increasing solubility and potency of drugs while reducing side effects. Complex polymeric materials, particularly anisotropic structures, are especially attractive due to their long circulation times. Here, we have conjugated cyclic peptides to the biocompatible polymer poly(2-hydroxypropyl methacrylamide) (pHPMA). The resulting conjugates were functionalized with organoiridium anticancer complexes. Small angle neutron scattering and static light scattering confirmed their self-assembly and elongated cylindrical shape. Drug-loaded nanotubes exhibited more potent antiproliferative activity toward human cancer cells than either free drug or the drug-loaded polymers, while the nanotubes themselves were nontoxic. Cellular accumulation studies revealed that the increased potency of the conjugate appears to be related to a more efficient mode of action rather than a higher cellular accumulation of iridium.