Fullerene Epoxide Research Articles

A Simple Synthesis of Tetraamino-[60]Fullerene Epoxides as Potential Antitumor Drug Candidates

A Simple Synthesis of Tetraamino-[60]Fullerene Epoxides as Potential Antitumor Drug Candidates

A Two-Pronged Pulmonary Gene Delivery Strategy: A Surface-Modified Fullerene Nanoparticle and a Hypotonic Vehicle.

Inhaled gene therapy poses a unique potential of curing chronic lung diseases, which are currently managed primarily by symptomatic treatments. However, it has been challenging to achieve therapeutically relevant gene transfer efficacy in the lung due to the presence of numerous biological delivery barriers. Here, we introduce a simple approach that overcomes both extracellular and cellular barriers to enhance gene transfer efficacy in the lung in vivo. We endowed tetra(piperazino)fullerene epoxide (TPFE)‐based nanoparticles with non‐adhesive surface polyethylene glycol (PEG) coatings, thereby enabling the nanoparticles to cross the airway mucus gel layer and avoid phagocytic uptake by alveolar macrophages. In parallel, we utilized a hypotonic vehicle to facilitate endocytic uptake of the PEGylated nanoparticles by lung parenchymal cells via the osmotically driven regulatory volume decrease (RVD) mechanism. We demonstrate that this two‐pronged delivery strategy provides safe, wide‐spread and high‐level transgene expression in the lungs of both healthy mice and mice with chronic lung diseases characterized by reinforced delivery barriers.

A Two‐Pronged Pulmonary Gene Delivery Strategy: A Surface‐Modified Fullerene Nanoparticle and a Hypotonic Vehicle

AbstractInhaled gene therapy poses a unique potential of curing chronic lung diseases, which are currently managed primarily by symptomatic treatments. However, it has been challenging to achieve therapeutically relevant gene transfer efficacy in the lung due to the presence of numerous biological delivery barriers. Here, we introduce a simple approach that overcomes both extracellular and cellular barriers to enhance gene transfer efficacy in the lung in vivo. We endowed tetra(piperazino)fullerene epoxide (TPFE)‐based nanoparticles with non‐adhesive surface polyethylene glycol (PEG) coatings, thereby enabling the nanoparticles to cross the airway mucus gel layer and avoid phagocytic uptake by alveolar macrophages. In parallel, we utilized a hypotonic vehicle to facilitate endocytic uptake of the PEGylated nanoparticles by lung parenchymal cells via the osmotically driven regulatory volume decrease (RVD) mechanism. We demonstrate that this two‐pronged delivery strategy provides safe, wide‐spread and high‐level transgene expression in the lungs of both healthy mice and mice with chronic lung diseases characterized by reinforced delivery barriers.

Understanding phase-transfer catalytic synthesis of fullerenol and its interference from carbon dioxide and ozone

Phase-transfer catalytic reaction involving the use of tetrabutylammonium hydroxide (TBAH) as catalyst and sodium hydroxide (NaOH) solution as the source of hydroxide ions is among the popular choices for synthesis of fullerenol, the polyhydroxylated fullerene. To further understand the process, two experiments were conducted to preliminarily explore the influences of the amount of TBAH and NaOH, respectively, in terms of the achieved level of hydroxylation (i.e. number of hydroxyl groups per fullerenol molecule). The process responded to the variation of the amount of TBAH (over a twofold series of 3–192 drops, average volume 0.0223 ± 0.0004 ml per drop) in a nonlinear manner with a local maximum achieved from 24 drops TBAH (giving 13 OH groups) and a local minimum from 48 drops (giving 8 groups). To the variation of the amount of NaOH (over the range of 0.5–8.0 ml NaOH), the fitted function of the process response resembled Freundlich adsorption isotherm, with an initially increasing trend before levelling off at 4.0 ml NaOH (giving 15 OH groups). It is therefore suggested that fullerene hydroxylation could be explained by liquid–solid adsorption. In addition, it was found that ambient carbon dioxide led to the existence of sodium carbonate in the bulk of the collected product (although not chemically bound). It was also discovered that ambient ozone adversely affected fullerenol synthesis by converting C60 fullerene into fullerene epoxide (C60O). The affected syntheses thus produced epoxide-containing fullerenol instead.

Hierarchical Assembly of siRNA with Tetraamino Fullerene in Physiological Conditions for Efficient Internalization into Cells and Knockdown.

Delivery of siRNA is a key technique in alternative gene therapy, where the siRNA cargo must be effectively loaded onto a tailor-designed carrier molecule and smoothly unloaded precisely upon arrival at the target cells or organs. Any toxicity issues also need to be mitigated by suitable choice of the carrier molecule. A water-soluble cationic fullerene, tetra(piperazino)[60]fullerene epoxide (TPFE), was previously shown to be nontoxic and effective for lung-targeted in vivo siRNA delivery by way of agglutination-induced accumulation. We found in this in vitro study that hierarchical reversible assembly of micrometer-sized TPFE-siRNA-serum protein ternary complexes is the key element for effective loading and release, and stabilization of otherwise highly unstable siRNA under the physiological conditions. The amphiphilic TPFE molecule forms a sub-10 nm-sized stable micelle because of strong cohesion between fullerene molecules, and this fullerene aggregate protects siRNA and induces the hierarchical assembly. Unlike popularly used polyamine carriers, TPFE is not toxic at the dose used for the siRNA delivery.

Synthesis and reactivity of tetraalkoxyl[60]fullerene epoxides, C60(O)(OR)4

Hexachloro[60]fullerene, C60Cl6, was reacted with a mixture of ROH/H2O (R = Me, Et, n-Pr, (CH2)2C≡CH) to form both C60Cl(OH)(OR)4 and C60Cl(OR)5. Only the C60Cl(OH)(OR)4 were isolated with bulky alcohols, ROH (R = (CH2)3C≡CH, (CH2)4C≡CH). Tetrahydro[60]fullerene epoxides, C60(O)(OR)4, were prepared by treating C60Cl(OH)(OR)4 with CuI. The epoxy moiety could be hydrolyzed to the vicinal diol derivatives, C60(OH)2(OR)4, and then oxidized to form dicarbonyl open-cage fullerenes, C60O2(OR)4. CuI was found to convert the terminal alkynyl addends into iodoalkynyl addends on the C60 cage.

Synthesis and chemical reactivity of tetrahydro[60]fullerene epoxides with both amino and aryl addends.

Tetrahydro[60]fullerene epoxides C60(O)Ar(n)(NR2)(4-n), n = 1, 2, have been prepared by treating 1,4-adducts C60(OH)Ph and C60(Tol)2 with cyclic secondary amines. The epoxy moieties in these mixed tetrahydro[60]fullerene epoxides were hydrolyzed into the corresponding diol derivatives, which were further oxidized into diketone open-cage fullerenes with a 10-membered orifice. A few other reactions also showed that the present tetrahydro[60]fullerene epoxides with both amino and aryl addends exhibit improved chemical reactivity over the tetraamino[60]fullerene epoxide without any aryl group.

Fullerene oxidation and clustering in solution induced by light

We investigate the environmental stability of fullerene solutions by static and dynamic light scattering, FTIR, NMR and mass spectroscopies, and quantum chemical calculations. We find that visible light exposure of fullerene solutions in toluene, a good solvent, under ambient laboratory conditions results in C60 oxidation to form fullerene epoxides, and subsequently causes fullerene clustering in solution. The clusters grow with time, even in absence of further illumination, and can reach dimensions from ≈100nm to the μm scale over ≈1day. Static light scattering suggests that resulting aggregates are fractal, with a characteristic power law (df) that increases from approximately 1.3 to 2.0 during light exposure. The clusters are bound by weak Coulombic interactions and are found to be reversible, disintegrating by mechanical agitation and thermal stress, and reforming over time. Our findings are relevant to the solution processing of composites and organic photovoltaics, whose reproducibility and performance requires control of fullerene solution stability under storage conditions.

Spiro-1,3-dioxolanofullerenes with Low-lying LUMO Level for Organic Solar Cells

Abstract A series of spiro-1,3-dioxolanofullerenes with 6-, 7-, 8-, and 12-membered ring were synthesized by the acid-catalyzed reaction of fullerene epoxide with cycloalkanones. The LUMO levels of these fullerenes are 0.07–0.08 eV lower than that of PCBM, due to the electron-withdrawing ester directly bonded to the C60 core. However, good power conversion efficiencies of 2.9 and 5.4% were obtained for the P3HT and PTB7 blend films, respectively. Characterization by solubility and morphology aided the understanding of the limiting factors behind the photovoltaic performance.

Pentafluorophenyl transfer reaction: preparation of pentafluorophenyl [60]fullerene adducts through opening of fullerene epoxide moiety with trispentafluorophenylborane.

Unlike the extensively studied perfluoroalkyl fullerene adducts, perfluorophenyl fullerene adducts are quite difficult to prepare by known methods. Trispentafluorophenylborane was found to react with fullerene epoxide to form the 1,2-perfluorophenylfullerenol. The method can be applied to both the simple epoxide C60(O) and fullerene multiadducts containing an epoxide moiety. Single crystal X-ray structure analysis confirmed the addition of the pentafluorophenyl group.

SiRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene.

The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications.

ChemInform Abstract: Chemistry of Fullerene Epoxides: Synthesis, Structure, and Nucleophilic Substitution—Addition Reactivity

ChemInformVolume 43, Issue 36 Reviews ChemInform Abstract: Chemistry of Fullerene Epoxides: Synthesis, Structure, and Nucleophilic Substitution—Addition Reactivity Yusuke Tajima, Yusuke Tajima Lab. Org. Optoelectron., RIKEN, Saitama 351-01, JapanSearch for more papers by this authorKazumasa Takeshi, Kazumasa Takeshi Lab. Org. Optoelectron., RIKEN, Saitama 351-01, JapanSearch for more papers by this authorYasuo Shigemitsu, Yasuo Shigemitsu Lab. Org. Optoelectron., RIKEN, Saitama 351-01, JapanSearch for more papers by this authorYouhei Numata, Youhei Numata Lab. Org. Optoelectron., RIKEN, Saitama 351-01, JapanSearch for more papers by this author Yusuke Tajima, Yusuke Tajima Lab. Org. Optoelectron., RIKEN, Saitama 351-01, JapanSearch for more papers by this authorKazumasa Takeshi, Kazumasa Takeshi Lab. Org. Optoelectron., RIKEN, Saitama 351-01, JapanSearch for more papers by this authorYasuo Shigemitsu, Yasuo Shigemitsu Lab. Org. Optoelectron., RIKEN, Saitama 351-01, JapanSearch for more papers by this authorYouhei Numata, Youhei Numata Lab. Org. Optoelectron., RIKEN, Saitama 351-01, JapanSearch for more papers by this author First published: 09 August 2012 https://doi.org/10.1002/chin.201236231AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume43, Issue36September 4, 2012 RelatedInformation

Chemistry of Fullerene Epoxides: Synthesis, Structure, and Nucleophilic Substitution-Addition Reactivity

Fullerene epoxides, C60On, having epoxide groups directly attached to the fullerene cage, constitute an interesting class of fullerene derivatives. In particular, the chemical transformations of fullerene epoxides are expected to play an important role in the development of functionalized fullerenes. This is because such transformations can readily afford a variety of mono- or polyfunctionalized fullerene derivatives while conserving the epoxy ring arrangement on the fullerene surface, as seen in representative regioisomeric fullerene polyepoxides. The first part of this review addresses the synthesis and structural characterization of fullerene epoxides. The formation of fullerene epoxides through different oxidation reactions is then explored. Adequate characterization of the isolated fullerene epoxides was achieved by concerted use of NMR and LC-MS techniques. The second part of this review addresses the substitution of fullerene epoxides in the presence of a Lewis acid catalyst. Most major substitution products have been isolated as pure compounds and their structures established through spectroscopic methods. The correlation between the structure of the substitution product and the oxygenation pattern of the starting materials allows elucidation of the mechanistic features of this transformation. This approach promises to lead to rigorous regioselective production of various fullerene derivatives for a wide range of applications.

Oxygen Atom Transfer from Peroxide Intermediates to Fullerenes

Abstract Photoreaction of C60 and C70 with adamantylideneadamantane or sulfide under oxygen flow gives fullerene epoxide together with adamantylideneadamantane epoxide or sulfoxide via peroxide intermediates.

ChemInform Abstract: Synthesis of Fullerene Epoxide (C60O) by Oxidation of Fullerene C60 with Oxygen Catalyzed by Mn(III), Ni(II), and Co(II) Acetylacetonates.

A procedure has been developed for the synthesis of fullerene monoepoxide C60O via liquid-phase oxidation of fullerene C60 in the presence of accessible catalysts [(Mn(acac)3, Ni(acac)2, and Co(acac)2].

Synthesis of fullerene epoxide (C60O) by oxidation of fullerene C60 with oxygen catalyzed by Mn(III), Ni(II), and Co(II) acetylacetonates

A procedure has been developed for the synthesis of fullerene monoepoxide C60O via liquid-phase oxidation of fullerene C60 in the presence of accessible catalysts [(Mn(acac)3, Ni(acac)2, and Co(acac)2].

ChemInform Abstract: Synthesis and Characterization of C60O, the First Fullerene Epoxide.

ChemInform Abstract: Synthesis and Characterization of C60O, the First Fullerene Epoxide.

In vivo gene delivery by cationic tetraamino fullerene

Application of nanotechnology to medical biology has brought remarkable success. Water-soluble fullerenes are molecules with great potential for biological use because they can endow unique characteristics of amphipathic property and form a self-assembled structure by chemical modification. Effective gene delivery in vitro with tetra(piperazino)fullerene epoxide (TPFE) and its superiority to Lipofectin have been described in a previous report. For this study, we evaluated the efficacy of in vivo gene delivery by TPFE. Delivery of enhanced green fluorescent protein gene (EGFP) by TPFE on pregnant female ICR mice showed distinct organ selectivity compared with Lipofectin; moreover, higher gene expression by TPFE was found in liver and spleen, but not in the lung. No acute toxicity of TPFE was found for the liver and kidney, although Lipofectin significantly increased liver enzymes and blood urea nitrogen. In fetal tissues, neither TPFE nor Lipofectin induced EGFP gene expression. Delivery of insulin 2 gene to female C57/BL6 mice increased plasma insulin levels and reduced blood glucose concentrations, indicating the potential of TPFE-based gene delivery for clinical application. In conclusion, this study demonstrated effective gene delivery in vivo for the first time using a water-soluble fullerene.

Tetra(piperazino)fullerene epoxide (TPFE)-based gene delivery

Tetra(piperazino)fullerene epoxide (TPFE)-based gene delivery

ChemInform Abstract: One‐Pot Synthesis of Indolino[2′,3′:1,2][60]fullerenes from Fullerene Epoxide: Lewis Acid‐Assisted Nucleophilic Addition Followed by Intramolecular Cyclization.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.