Aristides Bakandritsos

Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies

Targeted delivery combined with controlled drug release has a pivotal role in the future of personalized medicine. This review covers the principles, advantages, and drawbacks of passive and active targeting based on various polymer and magnetic iron oxide nanoparticle carriers with drug attached by both covalent and noncovalent pathways. Attention is devoted to the tailored conjugation of targeting ligands (e.g., enzymes, antibodies, peptides) to drug carrier systems. Similarly, the approaches toward controlled drug release are discussed. Various polymer-drug conjugates based, for example, on polyethylene glycol (PEG), N-(2-hydroxypropyl)methacrylamide (HPMA), polymeric micelles, and nanoparticle carriers are explored with respect to absorption, distribution, metabolism, and excretion (ADME scheme) of administrated drug. Design and structure of superparamagnetic iron oxide nanoparticles (SPION) and condensed magnetic clusters are classified according to the mechanism of noncovalent drug loading involving hydrophobic and electrostatic interactions, coordination chemistry, and encapsulation in porous materials. Principles of covalent conjugation of drugs with SPIONs including thermo- and pH-degradable bonds, amide linkage, redox-cleavable bonds, and enzymatically-cleavable bonds are also thoroughly described. Finally, results of clinical trials obtained with polymeric and magnetic carriers are analyzed highlighting the potential advantages and future directions in targeted anticancer therapy.

Gd(III)-doped carbon dots as a dual fluorescent-MRI probe

We describe the synthesis of Gd(III)-doped carbon dots as dual fluorescence-MRI probes for biomedical applications. The derived Gd(III)-doped carbon dots show uniform particle size (3–4 nm) and gadolinium distribution and form stable dispersions in water. More importantly, they exhibit bright fluorescence, strong T1-weighted MRI contrast and low cytotoxicity.

Magnetic iron oxide/clay composites : effect of the layer silicate support on the microstructure and phase formation of magnetic nanoparticles

Magnetic iron oxide nanoparticles were synthesized on two different clay supports: natural montmorillonite and synthetic laponite. The nanocomposites obtained, characterized by inductively coupled plasma atomic emission spectroscopy (ICP-AES), x-ray diffraction (XRD), transmission electron microscopy (TEM), N2 adsorption, small-angle x-ray scattering (SAXS), vibrating sample magnetometry and M?ssbauer spectroscopy, were found to exhibit highly different physicochemical properties despite their similar iron content. The observed size effect of the layered silicate support, resulting in the high abundance of very small particles (diameter of 1?5?nm) on laponite, was explained in terms of the difference between the surface charge densities and the lamellar dimensions of the clay substrates. Moreover, it was revealed that the nature of the layered support greatly affected the nanostructure (fractal dimensions, surface area, porosity) of the formed hybrid solids as well as the phase formation of iron oxide crystals. The high surface area laponite composites, due to the dominance of very small iron oxide particles, exhibited more pronounced superparamagnetic behaviour as compared to the montmorillonite samples prepared under identical conditions. The observed higher saturation magnetization of the laponite composites, attributed to their lower content in the antiferromagnetic hematite and to the onset of superferromagnetism in the aggregated particles, shows their excellent utility for adsorption/magnetic separation.

Chemistry, properties, and applications of fluorographene

Graphical abstract

Merging high doxorubicin loading with pronounced magnetic response and bio-repellent properties in hybrid drug nanocarriers.

Hybrid magnetic drug nanocarriers are prepared via a self-assembly process of poly(methacrylic acid)-graft-poly(ethyleneglycol methacrylate) (p(MAA-g-EGMA)) on growing iron oxide nanocrystallites. The nanocarriers successfully merge together bio-repellent properties, pronounced magnetic response, and high loading capacity for the potent anticancer drug doxorubicin (adriamicin), in a manner not observed before in such hybrid colloids. High magnetic responses are accomplished by engineering the size of the magnetic nanocrystallites (∼13.5 nm) following an aqueous single-ferrous precursor route, and through adjustment of the number of cores in each colloidal assembly. Complementing conventional magnetometry, the magnetic response of the nanocarriers is evaluated by magnetophoretic experiments providing insight into their internal organization and on their response to magnetic manipulation. The structural organization of the graft-copolymer, locked on the surface of the nanocrystallites, is further probed by small-angle neutron scattering on single-core colloids. Analysis showed that the MAA segments selectively populate the area around the magnetic nanocrystallites, while the poly(ethylene glycol)-grafted chains are arranged as protrusions, pointing towards the aqueous environment. These nanocarriers are screened at various pHs and in highly salted media by light scattering and electrokinetic measurements. According to the results, their stability is dramatically enhanced, as compared to uncoated nanocrystallites, owing to the presence of the external protective PEG canopy. The nanocarriers are also endowed with bio-repellent properties, as evidenced by stability assays using human blood plasma as the medium.

Room temperature organic magnets derived from sp 3 functionalized graphene

Materials based on metallic elements that have d orbitals and exhibit room temperature magnetism have been known for centuries and applied in a huge range of technologies. Development of room temperature carbon magnets containing exclusively sp orbitals is viewed as great challenge in chemistry, physics, spintronics and materials science. Here we describe a series of room temperature organic magnets prepared by a simple and controllable route based on the substitution of fluorine atoms in fluorographene with hydroxyl groups. Depending on the chemical composition (an F/OH ratio) and sp3 coverage, these new graphene derivatives show room temperature antiferromagnetic ordering, which has never been observed for any sp-based materials. Such 2D magnets undergo a transition to a ferromagnetic state at low temperatures, showing an extraordinarily high magnetic moment. The developed theoretical model addresses the origin of the room temperature magnetism in terms of sp2-conjugated diradical motifs embedded in an sp3 matrix and superexchange interactions via –OH functionalization.

In vitro cytotoxicity analysis of doxorubicin-loaded/superparamagnetic iron oxide colloidal nanoassemblies on MCF7 and NIH3T3 cell lines.

One of the promising strategies for improvement of cancer treatment is based on magnetic drug delivery systems, thus avoiding side effects of standard chemotherapies. Superparamagnetic iron oxide (SPIO) nanoparticles have ideal properties to become a targeted magnetic drug delivery contrast probes, named theranostics. We worked with SPIO condensed colloidal nanocrystal clusters (MagAlg) prepared through a new soft biomineralization route in the presence of alginate as the polymeric shell and loaded with doxorubicin (DOX). The aim of this work was to study the in vitro cytotoxicity of these new MagAlg–DOX systems on mouse fibroblast and breast carcinoma cell lines. For proper analysis and understanding of cell behavior after administration of MagAlg–DOX compared with free DOX, a complex set of in vitro tests, including production of reactive oxygen species, comet assay, cell cycle determination, gene expression, and cellular uptake, were utilized. It was found that the cytotoxic effect of MagAlg–DOX system is delayed compared to free DOX in both cell lines. This was attributed to the different mechanism of internalization of DOX and MagAlg–DOX into the cells, together with the fact that the drug is strongly bound on the drug nanocarriers. We discovered that nanoparticles can attenuate or even inhibit the effect of DOX, particularly in the tumor MCF7 cell line. This is a first comprehensive study on the cytotoxic effect of DOX-loaded SPIO compared with free DOX on healthy and cancer cell lines, as well as on the induced changes in gene expression.

Nonlinear optical properties of colloidal carbon nanoparticles: nanodiamonds and carbon dots

Colloidal suspensions of nanometer quasi-spherical sized carbon dots and nanodiamonds have been prepared and their third-order nonlinear optical response was investigated by means of the Z-scan technique, employing 35 ps and 4 ns, 1064 and 532 nm laser excitation. Carbon dots were found to exhibit a significant nonlinear optical response only under visible excitation for both pulse durations, entirely due to nonlinear refraction. On the other hand, nanodiamonds were found to exhibit significant nonlinear optical responses at both excitation wavelengths under ns laser pulses, while in the case of ps excitation, they exhibited a sizeable nonlinear optical response only for visible laser pulses. Nevertheless, carbon dots were found to exhibit a significantly larger nonlinear optical response than that of nanodiamonds under all experimental conditions examined in the present study. Additionally, the optical limiting behavior of nanodiamonds was investigated in the ns regime, using both visible and infrared laser pulses. Nanodiamonds were found to exhibit important and broadband optical limiting efficiency making them possible candidates for photonic and/or optoelectronic applications.

Cyanographene and Graphene Acid: Emerging Derivatives Enabling High-Yield and Selective Functionalization of Graphene

Efficient and selective methods for covalent derivatization of graphene are needed because they enable tuning of graphene’s surface and electronic properties, thus expanding its application potential. However, existing approaches based mainly on chemistry of graphene and graphene oxide achieve only limited level of functionalization due to chemical inertness of the surface and nonselective simultaneous attachment of different functional groups, respectively. Here we present a conceptually different route based on synthesis of cyanographene via the controllable substitution and defluorination of fluorographene. The highly conductive and hydrophilic cyanographene allows exploiting the complex chemistry of −CN groups toward a broad scale of graphene derivatives with very high functionalization degree. The consequent hydrolysis of cyanographene results in graphene acid, a 2D carboxylic acid with pKa of 5.2, showing excellent biocompatibility, conductivity and dispersibility in water and 3D supramolecular assemblies after drying. Further, the carboxyl groups enable simple, tailored and widely accessible 2D chemistry onto graphene, as demonstrated via the covalent conjugation with a diamine, an aminothiol and an aminoalcohol. The developed methodology represents the most controllable, universal and easy to use approach toward a broad set of 2D materials through consequent chemistries on cyanographene and on the prepared carboxy-, amino-, sulphydryl-, and hydroxy- graphenes.

High-Yield Alkylation and Arylation of Graphene via Grignard Reaction with Fluorographene

C functionalization of graphene significantly broadens its application potential via tuning its electronic and surface properties. Therefore, a wide range of dry and wet chemistry approaches have been developed for graphene functionalization. Despite recent progress in this field, covalent modification of graphene is still hampered by its low reactivity. Moreover, the reactivity depends on the type of graphene support and number of graphene layers. Consequently, there is a need for new strategies that permit high yielding graphene functionalization under more controlled conditions. Very recently, fluorographene (FG), a stoichiometric (C1F1) and well-established graphene derivative, has been shown to be susceptible to reductive defluorination and nucleophilic attack. These findings suggest that FG may be a useful alternative material to graphene for the preparation of graphene derivatives. This idea is supported by recent achievements in the field employing nucleophilic substitution of fluorine atoms by other groups, such as sulfhydryl, amino, alkoxy, dichlorocarbene and urea. However, efficient reaction of FG with Grignard reagents to allow high yield alkylation and arylation of graphene has not yet been reported. The Grignard reaction is one of the most well-established methodologies for the formation of C−C bonds in organic chemistry. Grignard reagents bear a nucleophilic carbon atom owing to its bonding to magnesium, and the in situ formed hydrocarbon anion can attack electrophilic carbons, such as the carbons of FG. The Grignard reaction has been successfully applied to fluorinated carbon nanotubes, but to date, there is only one report regarding the covalent modification of chlorinated graphene with Grignard reagents. Very recently, the same group reported that Grignard reaction on fluorinated epitaxial graphene was not feasible. In the present work, we report the first successful covalent modification of FG based on the Grignard reaction, which yielded homogeneous and high-density (5.5−11.2%) functionalization of the graphene surface. Three different types of organometallic reagents, containing alkane (pentyl), alkene (allyl), and aryl (anisolyl or p-methoxyphenyl) moieties, reacted successfully, unlike the reaction with the ethynyl reagent. This behavior was rationalized in terms of the nucleophilicities of the reactive centers, assessed by computational chemistry (Figure 1). The new covalently functionalized graphene derivatives were characterized by complementary techniques: spectroscopic, thermogravimetric and microscopic. In addition, we used density functional theory (DFT) calculations to evaluate the thermodynamic stabilities of the chemically modified graphenes, and delineate the influence of the different covalently attached groups on the electronic properties of graphene. Initially, a FG suspension was prepared by sonication of graphite fluoride (GF) in dry tetrahydrofuran. Next, the Grignard reagent (Figure 1) was added dropwise to the suspension and the mixture was stirred under nitrogen for 5 h. Afterward, excess Grignard reagent was quenched with a saturated aqueous solution of ammonium chloride and the material was washed with a copious amount of water. To remove any residues of magnesium salts, the product was resuspended in aqueous 5% HCl solution and washed with water, ethanol and dichloromethane, consecutively. When ethynylmagnesium bromide was used as a precursor compound for the generation of the nucleophile (ethynyl group), the reaction with FG was unsuccessful, even after