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Metallic nanoparticles and their medicinal potential. Part II: aluminosilicates, nanobiomagnets, quantum dots and cochleates Metallic miniaturization techniques have taken metals to nanoscale size where they can display fascinating properties and their potential applications in medicine. In recent years, metal nanoparticles such as aluminium, silicon, iron, cadmium, selenium, indium and calcium, which find their presence in aluminosilicates, nanobiomagnets, quantum dots (Q-dots) and cochleates, have caught attention of medical industries. The increasing impact of metallic nanoparticles in life sciences has significantly advanced the production techniques for these nanoparticles. In this Review, the various methods for the synthesis of nanoparticles are outlined, followed by their physicochemical properties, some recent applications in wound healing, diagnostic imaging, biosensing, assay labeling, antimicrobial activity, cancer therapy and drug delivery are listed, and finally their toxicological impacts are revised. The first half of this article describes the medicinal uses of two noble nanoparticles – gold and silver. This Review provides further information on the ability of aluminum, silicon, iron, selenium, indium, calcium and zinc to be used as nanoparticles in biomedical sciences. Aluminosilicates find their utility in wound healing and antibacterial growth. Iron-oxide nanoparticles enhance the properties of MRI contrast agents and are also used as biomagnets. Cadmium, selenium, tellurium and indium form the core nanostructures of tiny Q-dots used in cellular assay labeling, high-resolution cell imaging and biosensing. Cochleates have the bivalent nano ions calcium, magnesium or zinc imbedded in their structures and are considered to be highly effective agents for drug and gene delivery. The aluminosilicates, nanobiomagnets, Q-dots and cochleates are discussed in the light of their properties, synthesis and utility.

Nanostructured metallic films approximately 200–500 nm thick have been a part of ceramic decorations ‘luster’ since the medieval period. The homogeneous dispersion of silver and copper nanoparticles over glazed pottery results in a colored iridescence called luster, a technique very popular in the Middle East, Egypt, Persia and Spain. In 1685, Andreas Cassius invented a recipe of glass coloring pigment called Purple of Cassius. He made the purple precipitates by dissolving gold particles in aqua regia and then added a piece of tin to it. The pigment is famous for its use in high-quality porcelain ware. A Viennese chemist, Richard Zsigmondy was awarded the Nobel Prize in Chemistry in 1925 for discovering that colloidal gold adsorbed on stannous hydroxide base makes Purple of Cassius. Michael Faraday (1857) prepared gold sols, whose size was found out by JM Thomas in 1988 to be 3–30 nm in diameter, when he reproduced those gold nanoparticles. Industrial nanotechnology was initiated in 1930 with the manufacturing of silver coatings for photographic films. At around this time imaging techniques such as ultrasound, MRI, computed tomography, positron emission

tomography and surface enhanced raman spectroscopy were becoming popular for imaging various disease states and magnetic nanoparticles came to the rescue as contrast agent with unique physicochemical properties. The 1980s took nanomaterials to higher strata by introducing fullerenes and scanning tunnel microscopes. In the mid-1980s, when growth technologies such as molecular beam epitaxy tied nuptials with electron-beam lithography to confine electron motion in all three (x-y-z) directions, quantum dots (Q-dots) were produced. These metallic nanoparticles have been embraced by nanotechnology for more than four decades now. Today, with Q-dots as new nanoball bearings, aluminosilicates as nanowire gauges, cochleates as nanocrystalline delivery trucks and iron nanoparticles as new biomagnets, it is no wonder that nanoscience thinks about metals in terms of size control, spatial resolution, chemical reactivity and engineering their relationship at the cellular level in real time. Metal nanoparticles can be easily prepared to the nanometer scale, they possess fundamentals of light matter interaction and are highly suitable

Leena Loomba1 & Tiziano Scarabelli*2,3

10.4155/TDE.13.74 © 2013 Future Science Ltd

Ther. Deliv. (2013) 4(9), 1179–1196

ISSN 2041-5990

Punjab Agricultural University, Ludhiana, Punjab, India 2 Center for Heart & Vessel Preclinical Studies, St. John Hospital & Medical Center, Wayne State University School of Medicine, Detroit, MI, USA 3 Medical Center, Wayne State University School of Medicine, MI, USA *Author for correspondence: E-mail: [email protected] 1

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Review | Loomba & Scarabelli for conjugation with drugs, ligands, antibodies and genes, as well as functional groups of interest. Excitation and relaxation of conduction band electrons in metallic nanoparticles results in plasmon resonance – a unique phenomenon responsible for energy dissipation and optical effects. An effective cellular communication, the invincible ability of nanometals provides immense possibility for their growth and development in biomedicine. Nanoparticles have been synthesized, tested, used and modified over the years to function as agents for gene therapy, DNA sequencing, cancer detection, cellular tracking, targeted drug delivery and biomedical imaging. The versatile attitude of metallic nanoparticles attracts scientific research and clinical applications under the stream of nanotechnology (Table 1). Aluminosilicate nanoparticles „„Types, properties & synthesis of aluminosilicate nanoparticles Types

Aluminosilicates are broadly classified into the following categories (Figure 1): Orthosilicates with [AlO6]3- anions connected by isolated (SiO 4)4- clusters; for example, andalusite (Al 2 SiO5) and its polymorphs, kyanite and sillimanite;

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Phyllosilicates with tetrahedral and octahedral layers in two dimensions; for example, kaolinite, smectite and illite;

or connect outside the anionic framework, to form aluminosilicates. In nature, magma solidifies to form aluminosilicates such as feldspar (xAl[Al,Si]3O8, where x can be Na, K or Ca), mica, beryl or wollastonite. In feldspar the Al3+ ion replaces the Si4+ cation of (SiO4)4-, leaving behind a negative charge on the 3D framework. The positively charged ions neutralize this negative charge, for example, K+ in microcline (KAlSi 3O8) and Na+ in albite (NaAlSi 3O8), both K+ and Na+ in sanidine ([K,Na]AlSi3O8]4) and Ca 2+ in Anorthite (Ca[AlSi 2O8]). The weather plays its role to convert feldspar to clay kaolin (Al 2 Si 2O5[OH]4) or montmorillonite ([Na,Ca] 0.33 [Al,Mg] 2 [Si 4 O10][OH] 2 .nH 2 O). Naturally occurring aluminosilicate nanoparticles exist as nanotubes called imogolites, or hollow 3–5 nm spherical allophanes. Both these aluminosilicates have on identical chemical composition (Al 2SiO3[OH])4, but with different structures depending on the Al/Si ratio. Clay has negatively charged sites that can attract and hold positively charged particles and this is called ‘cation exchange capacity’; it is the measure of how many negatively charged sites are available on a nanoparticles surface. These exchange reactions are rapid, reversible and stoichiometric with respect to charge: 2{K+-Soil} + Ca 2+ → 2K+ + Ca 2+–(Soil)2

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Cyclosilicates with tetrahedral clusters of (Si3O7)6-, (Si4O12)8- or (Si6O18)12- arranged in a cyclic manner; for example, bentonite (BaTi[Si3O9]) and beryl (Be3Al2[Si6O18]).

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Properties

Aluminosilicates are minerals consisting of aluminium and silicon oxides. Silicates are tetrahedrally clustered polymers of (SiO4)4- anions. The positively charged ions of Al3+ can either substitute silica atoms in the silicate tetrahedra

Equation 1

Aluminosilicate nanoparticles undergo ion exchange readily, that is, adsorbed cations can be replaced by a large quantity of other competing ions, which superimpose their strength and resistance. The layered sheet-like structure of aluminosilicate nanoparticles provides additional surface area as well as the ability to hold substances for targeted delivery. Kaolinites are 1:1 aluminium phyllosilicates having the chemical formula Al 2Si 2O5(OH)4. Clays such as kaolinite, dichite, nacrite and halloysite fall under this category. They have SiO4 tetrahedrons and AlO4 octahedrons arranged in

Table 1. Examples of metallic nanoparticles used as drugs and diagnostic agents.

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Metallic nanoparticles

Element

Use

Aluminosilicate nanoparticles Nano biomagnets Q-dots Cochleates

Al, Si Fe Cd, Se, In Ca, Zn, Mg

Faster blood clotting in open wounds Helps in targeted drug delivery Medical imaging Oral drug delivery of drugs encapsulated in a nanocrystalline structure

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Metallic nanoparticles & their medicinal potential

Aluminiosilicates

Orthosilicates

Examples: andalusite, kyanite, sillimanite (used in ceramics, boiler furnaces and kiln linings).

Phyllosilicates

Examples: kaolinite, smectite, illite (used in wound healing, burns, sepsis and inflammation)

Cyclosilicates

Examples: bentonite, beryl (used as a laxative and anti-inflammatory agents)

| Review

Figure 1. Various types of aluminosilicates and their uses.

a 2D hexagonal array. This arrangement twists the tetrahedral sheet, flattens the octahedral sheet and compels the hexagonal arrangement to distort in a ditrigonal manner. Smectites and illites are 2:1 bonded sheets of aluminium phyllosilicates with an octahedral sheet sandwiched between two tetrahedral sheets (TOT). The space between two TOT sheets is occupied by cations and/or water molecules. The arrangement can be designated as TOT (H2O/ cations) TOT. Smectites have the chemical formula: Na0.3 Al2(Si3.7Al0.3)O10(OH)2 and examples include montmonrillonite, nantronite, saponite and hectorite. They have high cation exchange capacity, a very large chemically active surface area and an unusual tendency to hold water molecules in the interlamellar surface. Illites have the chemical formula K0.7Al2(Si3.3Al0.7)O10(OH)2. The cation exchange capacity of the illite group is midway between that of kaolinite and smectite, but their hydration capacity is low due to the replacement of Na+ ions by K+ ions. Synthesis

Mesoporous aluminosilicate nanoparticles with narrow size distribution (30–50 nm) are synthesized by a hydrothermal method using cetyltrimethylammonium bromide as a template and polyethylene glycol as a means to tailor the nanoparticles [1]. The aluminium salt, aluminum nitrate nonahydrate, catalyzes the hydrolysis of the silica precursor tetraethyl orthosilicate. The hydrolyzed species can be rapidly assembled into mesostructured nanocomposites under the direction of cationic micelles with the addition of basic ammonia water. The nonionic polyethylene glycol shields the formed nanoparticles through hydrogen-bonding interactions, thereby tuning the grain size distribution of mesoporous future science group

nanoparticles. A sol–gel route has been used to synthesize aluminosilicates, with varying alumina–silica ratios. The process uses boehmite and tetraethyl orthosilicate as alumina and silica precursors, respectively [2]. „„Aluminosilicate

nanoparticles in medicine Clay has been popular since the prehistoric era in bath spas to preserve complexion; in ochres to cure wounds caused by serpents, to reduce the flow from the lachrymal ducts; against hemorrhage, inflammation, gastrointestinal infections and kidney diseases; and even to make mummies. Modern physicians use the same clay particles at a nanoscale level in bandages, antibacterial ointments and pharmaceutical carriers. Kaolinites are known for wound healing

Kaolin clay has long been used for curing injuries, festering inflammations and healing wounds. From the 1950s kaolin has been an activating agent for a clotting test that doctors perform routinely. The clay is predominantly rich in aluminosilicate nanoparticles that have the ability to reduce staunch bleeding by absorbing water; resulting in quick blood clotting [101]. The surgical dressings, impregnated with kaolin, are sold under the tradename ‘QuickClot®’ and are used to combat life-threatening hemorrhage on the battlefield. The presence of kaolin on the surface of nonwoven rayon gauge leads to enhanced transformation of factor XII, factor XI and prekallikrein to their activated forms; this activation further initiates the coagulation cascade of hemostasis. Chemists at the University of California (Santa Barbara, CA, USA), realized that the aluminosilicate nanoparticles could be used to halt severe nose bleeds. The inorganic specks, which are derived from kaolin clay, when infused with a bandage, www.future-science.com

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Review | Loomba & Scarabelli trigger the body’s natural clotting process. The bandage stops the bleeding immediately, when rolled up and inserted in the nose [102]. Smectites & illites possess antibacterial ability

Smectites are famous for their tendency to absorb the carcinogenic metabolite aflatoxin B1, produced by the fungi Aspergillus flavus in animal diet [3]. The nanoparticles of smectites– illites and reduced iron present in natural clay have the potential to eliminate Escherichia coli and even antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus. The hydrated clay leaches into the bacterial cell membrane to increase bacterial iron and phosphorous levels and metabolic activity of the membrane. The regulatory proteins subsequently come into action to oxidize Fe2+ to Fe3+ and even produce hydroxyl radicals, which enter the cytoplasm and cause cell death [4]. The in vitro antibacterial activity of clay minerals has proven effective against Buruli ulcer and b-lactamase E. coli. The mineral surfaces of aluminosilicates in clay alter pH and oxidation states in bacterial membranes to control redox reactions, resulting in cell lysis [5]. The layered metal hydroxides of clay behave as excellent pharmaceutical carriers. The lamellar surfaces of various layers can easily hybridize nanomedicines in their 2D structure. For example, methotrextate – a folate antagonist anticancer drug – is unstable and also has a short plasma half-life. The drug, when layered in Mg and Al hydroxides of clay, specifically suppresses growth of human osteosarcoma cancer cells [6]. Bentonite: a versatile aluminisilicate

Bentonite is a chemically inert, absorbent aluminium phyllosilicate consisting of montmorillonite. Bentonite supports good digestion and acts as a laxative. In the gastrointestinal tract of animals bentonite reduces bacterial mucolysis and inflammation. The granular form of bentonite is used under the commercial name ‘WoundStat™’, in battlefields for wound dressings. It reduces pain associated with stings, burns and cuts, promotes detoxification and also shields against urushiol – the oil found in poison ivy. Nanobiomagnets „„Types, properties & synthesis of nanobiomagnets Types

The nanosized, biocompatible, paramagnetic iron oxides that serve as biomagnets are 1182

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magnetite (Fe3O4), maghemite (g-Fe2O3) and haematite (a-Fe 2O3); of which magnetite, because of its biocompatibility, is very promising. Iron oxide nanoparticles (IONps) are available in various dimensions and shapes such as nanorods, nanotubes, hollow fibers, rings and snowflakes. The iron oxide nanorods demonstrate higher incident photon-to-current conversion compared with nanospheres, which is further improved by surface modification and doping with Zn. The nanoparticle size imposes a huge impact on superparamagnetism and, in turn, their usage. Generally, iron oxide nanoparticles ranging from 1 to 25 nm are highly efficient models. Superparamagnetic iron oxide nanoparticles are of particular interest in MRI; examples include: AMI-227 (Sinerem, Combidex®) and SHU55C – a 20 nm sized iron oxide nanoparticle coated with carbodextran. It demonstrates excellent T2 relaxivities of 151.0 mmol/sec and has been used for lymph node and bone marrow imaging.

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OMP (Abdoscan®) and AMI-121 (Lumirem®, GastroMARK®) are 300 nm sized iron oxide nanoparticles (IONps) coated with silica. Their oral administration finds utility as a gastrointestinal contrast.

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Properties

In magnetite, Fe3+ ions are placed at all tetrahedral sites, whereas both ferrous and ferric ions occupy octahedral sites of inverse spinel structure. Maghemite is the oxidized form of magnetite having 56 ions in each unit cell, of which 32 are O2- ions, eight Fe3+ ions in tetrahedral sites and 16 Fe3+ in octahedral sites. Magnetite is a spin-polarized black crystal containing both Fe (II), Fe (III) and absorbs throughout the UV–vis–IR spectrum, while maghemite is an insulator. Both phases are ferrimagnetic. Haematite, a-Fe2O3, has a 3D framework built up of trigonally distorted octahedra FeO6, with oxygens in hexagonal closest-packing. The trivalent iron ions are closely packed between two oxygen layers. This arrangement makes the structure neutral with no excess charge. Haematite has antiferromagnetic properties and an absorption spectrum in the visible range between 295 and 600 nm. The magnetic behavior of these oxides is due to their stereochemistry that triggers internal superexchange competition between tetrahedral and octahedral future science group

Metallic nanoparticles & their medicinal potential sites. At room temperature both magnetite and maghemite are superpara­magnetic, which means an external magnetic field can easily magnetize the nanoparticles. The IONps need to be superparamagnetic, biocompatible and nontoxic to be useful for molecular imaging purposes. They also need to bind to a range of metabolites. The zero point charge value of seven makes oxides stable only in highly acidic or basic aqueous media. This drawback in their surface chemistry causes considerable aggregation and precipitation in solution phase. Also, low hole mobility, electronhole recombination and electon-trapping, and oxygen-deficient iron sites yield poor photocurrent efficiency. However, coating the particles with silica, dextran, carbodextran, poloxamines or poly(ethylene glycol) followed by their bioconjugation with various ligands gives them both stability and specificity. Magnetic ironoxides need high r1 and r2 relaxivities, as well as surface engineering, to fine tune their size and structure, before being used for in vivo applications [7]. The ferromagnetic nanoparticles magnetization fluctuates with temperature, fluctuations are generally larger at higher temperatures and smaller at lower temperatures. When the time between two magnetization fluctuations (Néel relaxation time) is shorter than the time used to measure the magnetization of the nanoparticles, in the absence of external magnetic field, the nanoparticles show an average zero magnetization. This is called superparamagnetism. Materials having superparamagnetism have a high saturation magnetization and zero coercivity and remanence. The Néel relaxation time is highly temperature dependent, it fluctuates randomly by thermal fluctuation at high enough temperatures. The thermal energy decreases at lower temperatures and blocks the magnetic moments. This temperature is called the blocking temperature. It is a function of the particle size and increases with increasing particle size. Thus, superparamagnetism increases with the decrease in size of the nanoparticle. Below blocking temperature, the preferred direction of magnetization of superparamagnetic material is lost in zero magnetic fields. When the temperature rises above the blocking temperature, the nanoparticles show no hysteresis. With these fascinating superparamagnetic properties, IONps find their utility in ferrofluids, hyperthermia and MRI contrast agents. future science group

| Review

Synthesis

Reverse micelle and precipitation are two commonly used techniques for the synthesis of iron oxides [8]. The simplest of all the methods to prepare IONps is the coprecipitation of a 2:1 stoichiometric mixture of Fe2+/Fe3+ salts in an aqueous medium of pH between 8 and 14. The magnetite forms black colored precipitates. The overall reaction is written as: Fe2+ + 2Fe3+ + 8OH- → Fe3O4 + 4H2O Equation 2

The particle size depends on numerous factors such as Fe3+/Fe2+ ratio, temperature, ionic strength, nature of salts, pH and addition of chelating agents. Generally, the nanoparticle size decreases with an increase in the pH, Fe3+/Fe2+ ratio and ionic strength of the medium. The aqueous iron salt solutions essentially form reverse micelles with the hydrophilic head towards the core of the micelle and the hydrophobic tail directed outwards. Reverse micelles solubilize large amounts of water, which can be controlled, for nanoparticle production. A wide range of iron oxide nanoparticles can be synthesized by altering the nature and amount of surfactant, solvent and cosurfactant. They can also be synthesized using techniques such as sonochemistry, microwave irradiation and autogenic pressure reactor [9]. A new method to produce nanocrystals is glass crystallization [10]. In total, 15–20 nm sized, monodisperse, Fe3O4 nanoparticles are synthesized by decomposition of iron (II) acetate at 400°C. IONps of desired size and dispersity are also synthesized by heating iron-oleic complex at 320°C in 1-octadecene for 30 min. Hydrothermal treatment of iron powder and iron chloride solution in urea solution for 20 h at 130–150°C yields iron rods of nearly 80 nm. „„Photoelectrochemical

applications of biomagnets The chemistry of iron oxide nanoparticles can be manipulated to have magnetic properties that find their importance in magnetic resonance imaging, biotechnology and effective hyperthermia (Figure 2). Iron-oxide nanoparticles as hyperthermia & MRI contrast agents

MRI is a noninvasive technique that combines the characteristics of high spatial resolution, www.future-science.com

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Review | Loomba & Scarabelli Magnetite

Nanobiomagnets

Used in hyperthermia, in biotechnology as genomagnetic Maghemite Photoelectrochemical capturer, as MRI contrast agents and to magnetically focus applications the drug at tumor sites Haematite

Figure 2. Nanobiomagnets and their photochemical applications.

nonionizing radiation and multiplanar tomographies in cellular imaging. Superparamagnetic iron oxide nanoparticles comprise a class of novel MRI contrast agents that are composed of a ferrous iron (Fe2+) and ferric iron (Fe3+) core, and a layer of dextran or other polysaccharide coating [11]. The iron nanoparticles have a very large magnetic moment, which leads to local magnetic field inhomogeneity. Consequently, they serve to enhance the image contrast and, thus, improve the sensitivity and specificity of MRI in mapping information from tissues [12]. In vivo, nonspecific superparamagnetic iron oxide nanoparticles are mainly captured by the reticuloendothelial system, and they are more suitable for liver, spleen and lymph node imaging [13]. Because of their long plasma half-life, superparamagnetic iron oxides are also used as blood pool agents in magnetic resonance angiography. Haematite nanoparticles, 1.8 nm in size, when coated with polysaccharides such as chitosan and alginate, respond superparamagnetically with very low coercivity. These nanoparticles can either be converted to magnetite by reduction or used directly for imaging [14]. The intensity of magnetic field of iron-based nanoparticles, having a layer of bis-carboxyl-terminated poly(ethylene glycol) on them, induces more effective hyperthermia than uncoated iron particles. They are far better MRI contrast agents and provide a focused approach for in vivo applications and cancer therapy [15]. Iron oxide nanoparticles manipulated with Herceptin® – an antibody present in breast cancer cells – or chlorotoxin – a peptide that binds MMP-2 in gliomas, show enhanced in vivo tumor-targeting properties [16]. Mammary tumors contain overexpressed levels of urokinase-type plasminogen activator. Amino-terminal fragment conjugated IONps can effectively bind the over­expressed receptors in breast cancer tissues and help in vivo imaging [17]. The nanocomposites of maghemite, 1184

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such as those with bentonite and raffinose-modified trypsin, are used as MRI contrast agents for the gastrointestinal tract and magnetic carriers for trypsin immobilization, respectively [18]. Fluorescence and magnetism can be uniquely combined over maghemite nanoparticles. Congo-red or rhodamine dyes hybridize with g-Fe2O3 to serve as biomarkers for in vivo Alzheimer’s disease diagnosis [19]. Ferrite nanoparticles ranging from 20 to 200 nm in diameter are being used for biosensing and as contrast agents for MRI, when attached with europium these spheres can emit fluorescent radiations at 618 nm to help detect cancer [20]. Nanobiomagnets in biotechnology

Biotechnology can rely on the magnetic powers of IONps to separate specific proteins from a group of biomolecules. For example, dopamine grafted IONps can be used for protein separation. The bidentate enediol ligands of the dopamine molecule tightly bind with unsaturated iron sites. The nanostructures so produced enhance specificity for protein separation and provide tremendous stability to heating and high salt concentrations. In the same manner, magnetic nanoparticles are ideal candidates for gene detection. In the diagnosis of diseases involving genetic expression, the separation of rare DNA/ mRNA targets with single-base mismatches in a mixture of various bio complexes is critically important. Genomagnetic nano capturers have been formulated using IONps to detect DNA/RNA molecules with one single-base difference. Nanobiomagnets can transfer drugs into the body and are held at the target site by an external magnet. The purpose of this is to concentrate the drug at the tumor site for long enough for it to be absorbed and release the drug on demand. The control of drug delivery using biomagnets can reduce the dosage by 60–75%, thus enhancing drug efficacy while decreasing future science group

Metallic nanoparticles & their medicinal potential unwanted systemic uptake. This mechanism can find its utility in control of insulin-dependent diabetes. Recent studies report that the iron oxide nanoparticles can adhere to red blood cell’s surface for nearly 4 months. This can help to release drugs slowly into the body and can lead to controlled treatment of many immunogenic diseases. Q-dots „„Types, properties & synthesis of Q-dots

| Review

contravariant band layout so that both the conduction and valence band edges of the core lie within the bandgap of the shell; for example, CdSe/CdS, CdSe/ZnS and InAs/CdSe; For reverse Type-I Q-dots, the bandgap of the core is wider than the shell, and the conduction and valence band edges of the shell lie in the core; for example, CdS/HgS, CdS/CdSe and ZnSe/CdSe;

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Type-II Q-dots have one type of charge carrier in the core while the shell carries the other type. It maintains covariant band layout in which the valence and conduction band edge are either lower or higher than the band edges of the shell; for example, Type-II Q-dots that attract holes are GaSb/GaAs and Ge/Si, and those that attract electrons are InP/InGaP and InP/GaAs.

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Types

Q-dots are tiny particles, traditionally chalcogenides (selenides or sulfides) of metal such as cadmium or zinc (CdSe/ZnS) ranging from 2 to 10 nm. The electrons and holes of the semiconductor cores being confined to a point significantly modifies the energy spectrum of the carriers. Q-dots have a metallic core made of semiconductors, noble metals, and magnetic transition metals, shielded by a shell. Depending on the variation in the constituents of the core, Q-dots are classified into various groups: Group II–IV series Q-dots contains ZnS, ZnSe, CdSe and CdTe cores;

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Group III–V series Q-dots have InAs, InP, GaAs and GaN cores;

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Group IV-VI series Q-dots have PbTe, SnTe, SnS and SnS2 cores.

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Q-dots are also classified as Type-I, Reverse Type-I and Type-II: Type-I Q-dots have a core that simultaneously traps electrons and holes giving rise to

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Properties

Q-dots are basically made of three parts – a core, a shell and the outer coating (Figure 3). The core region, when excited by a photon, triggers its electron in the semiconductor band gap, leaving behind a positive hole in the lower energy band. An increase in excitation increases the absorption in the band gap giving rise to broad absorption spectrum. Since the energy gap between higher and lower energy bands is responsible for emission energy, and the energy gap is low, the emission spectrum is narrow. The shell covers the surface defects of the electron–hole nanocore, and thus protects it from oxidation, fluorescence and chemical reactions. The shells having large energy gaps increase the quantum yield and enhance photostability. A Biological applications

Cap (disulfide bridge, silane)

Q-dot core (CdSe)

S

Cellular and assay labeling

Biomolecule (protein/DNA)

High-resolution cell imaging

Q-dot-FRET biosensing

Shell (ZnS)

Figure 3. A biofunctional quantum dot and its biological applications. FRET: Fluorescence resonance energy transfer; Q-dot: Quantum dot; S: Sulfide bridge.

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Review | Loomba & Scarabelli coating of functional ligands over the Q-dot shell improves their solubility in polar solvents and also labels them. The mono or dithiol dihydrolipoic acid ligands improve stability for over 1–2 years; phospholipids induces stability over a wide pH range while thiolated peptides or poly histidine residues provide both dispersion and bio-functionalization. The electronic properties of Q-dots are intermediate between those of bulk semiconductors and discrete molecules. The most apparent of these is the emission of photons under excitation, which are visible to the human eye as light. The wavelength of these photon emissions depends on their size. The smaller the dot, the closer it is to the blue end of the spectrum and the larger the dot, the closer to the red end. The characteristics of Q-dots that attract the attention of biomedicine are brightness, time resolved imaging because of 20 s lifetime of fluorescence, and the ability to image many colors simultaneously without overlapping, due to narrow fluorescence emission. Moreover, Q-dots require a minimum amount of energy to induce fluorescence, resulting in high quantum yields. Their coreshell structure makes them highly stable against photobleaching. Synthesis

The binary semiconductor nanocrystals such as cadmium selenide, cadmium sulfide, indium arsenide and indium phosphide could be synthesized by fabrication, colloidal synthesis or as viral assembly. Bulk quantities of semiconductor dots are produced by colloidal synthesis based on a three-component system composed of precursors, organic surfactants and solvents. The high temperature turns the reaction medium to monomers [21]. Fabrication produces 5–50 nm sized dots, defined by lithographically patterned gate electrodes, or by etching on 2D electron gases in semiconductor heterostructures [22]. The biocomposite structures of Q-dots could be genetically engineered using bacteriophage viruses (TMV, M13 or Fd) [23]. Subjecting the organometallic precursors (CdO, Cd-acetate) and solvent-ligand (trioctyl phosphine–tri octyl phosphine oxide) mixture to high temperatures yields CdSe Q-dots with high crystalline cores. „„The

utility of Q-dots in medicine The initial Q-dot bioconjugate was reported in 1998. Over the past decade, the study of Q-dots has extended from high-resolution 1186

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cellular imaging to labeling, tumor targeting, and diagnostics. Q-dots in cellular & assay labeling

When introduced in cells, Q-dots found applications in cell tracking, immunoassays, determining the metastatic potential of cells and unleashing various cellular and metabolic processes. The labeling of cells and assays with Q-dots is an initial step of imaging processes and can be achieved by extracellular or intracellular modes. The proteins as well as receptors associated with membranes help in extracellular labeling of Q-dots to understand biological pathways such as signal transduction, chemotaxis, cellular organization and diffusion behavior of metabolites. Studies have been successfully carried out with biotinylated-coated dots and glycosyl–phosphatidyl–inositol conjugated avidin Q-dots to understand the diffusive behavior of the plasma membrane [24]. To demonstrate intracellular labeling, cells can be microinjected or incubated with Q-dots via nonspecific endocytosis. The peptide-mediated intracellular delivery of Q-dots allows passive intake of biomolecules, such as cytokeratin, mortalin, microtubules, liposomes and oligonucleotides, into the cells. The streptavidin–biotin complex links easily, through covalent bonding to the Q-dot surface to control intracellular delivery. The difference between invasive and non­ invasive cancer cell lines can be demonstrated by in vitro cell motility assay based on the phagokinetic uptake of Q-dots. The cell lines move across the homogeneous layer of Q-dots and leave a fluorescent-free trail. On calculating the ratio of trail-to-cell area, the tumor invasiveness can be easily distinguished. Q-dots coated with DNA serve as probes for the detection of multiallele DNA and human metaphase chromosomes. They also act as specific DNA labels for highly sensitive in situ hybridizations [25]. Multiple toxin ana­lysis in immunoassays and marking Her2 breast cancer cells has been possible by conjugating Q-dots with antibodies [26]. Q-dots have also been used to diffuse glycine receptors in neurons and in near-infrared emission identification of lymph nodes during live animal surgery [27]. Recently, CdTe Q-dots have been reported to control the nerve cells. Light energy excites electrons in the Q-dot, which causes the immediate environment to become negatively charged. This cause the ion channels to open future science group

Metallic nanoparticles & their medicinal potential in the cancerous tissue, allowing the thoroughfare of ions in and out of the cells. The ion channel openings generate action potential over nerve cells, which in turn can be controlled by external voltage on Q-dots to depolarize the unwanted cells [28]. High-resolution cell imaging with the help of Q-dots

Q-dots have the ability to overcome the limitations of fluorescence imaging of live tissues, which is greatly hindered by the poor transmission of visible light. Q-dots act as the inorganic fluorophore for intra-operative detection of tumors using fluorescence spectroscopy as they are 20-times brighter and 100-times more stable than the traditional fluorescent reporters [29]. The improved photostability of Q-dots allows the acquisition of many consecutive focal plane images that can be reconstructed into a high-resolution 3D image. The extraordinary stability makes them a probe to track cells or molecules over extended periods of time. The ability to image single-cell migration in realtime renders their importance in embryogenesis, cancer metastasis, stem-cell therapeutics, lymphocyte immunology and in vitro imaging of prelabeled cells [30]. Fluorescent Q-dots can be tagged to antibodies that target cancerous cells or cells infected with tuberculosis or HIV [31], and could also be used to diagnose malaria by making them target the protein that forms a mesh in the blood cell’s inner membrane. The shape of this protein network changes when cells are infected with malaria, so scientists are able to spot malaria infection from the shape produced by the dots [32]. Q-dots have earned success in sentinel lymph node biopsy, a technique that locates the first draining lymph node at the cancer site. The background tissue autofluorescence is an avid limitation of blue dye and radioisotopes used in biopsy, which is overcome by Q-dots emitting at the near-IR range. This allows surgeons to undertake biopsy with high accuracy and minimum invasiveness.

| Review

and conformations in biological systems. Q-dots can transfer their energy to quencher analytes through FRET, thus minimizing the fluorescence from the Q-dot donor. Gold rods readily quench the fluorescence from the Q-dots. This exciting property of FRET between Q-dots and the surface of gold nanoparticles helps to explore many DNA properties [33]. The friendship between FRET technology and Q-dots can reduce background signal due to time-gating and increase the possibility of measuring long distances. FRET-based Q-dots biosensors have been developed to detect Aspergillus amstelodami. The Q-dots conjugated to IgG antibodies transfer their energy to quencher-labeled analytes through FRET. The high-affinity target analytes replace the quencher analytes during detection to increase Q-dot fluorescence signal. The sandwich immunoassay then detects Aspergillus, as low as 103 spores/ml, in 5 min. The idea can be further exploited to detect other biological threats [34]. Multiple colored Q-dots can tag various antibodies uniquely. Recently, researchers demonstrated a novel idea to multiplex the utility of Q-dot biosensors, by applying simultaneous FRET to five different Q-dots on terbium complex with emission maxima at 529, 565, 604, 653 and 712 nm [35]. CdSe-ZnS core-shell Q-dots coated with dihydrolipoic acid and conjugated with human phosphoinositide-dependent protein kinase-1 have been designed to identify selective inhibitors of protein kinases. The response of this biosensor is tested in molecular dyad incorporating an ATP ligand and a chromophore. The organic dye allows nonspecific adsorption on the surface of nanoparticles promoting FRET from Q-dot to quencher dye. The assay demands study of new strategies to prevent energy adsorption on the nanoparticle donor surface [36]. Cochleates „„Types, properties & synthesis of cochleates Types

Q-dot-fluorescence resonance energy transfer biosensors

A f luorescence resonance energy transfer (FRET) is an energy transfer between two chromophores through dipole–dipole interactions. The process of energy transfer enjoys an inverse relationship to the sixth power of the distance between donor and acceptor molecules. FRET can wonderfully detect molecular interactions future science group

Cochleates are multilayered delivery vehicles made of alternating layers of divalent counter ions (Ca 2+/Zn 2+) and bridging phospholipid bilayers, all rolled up in a spiral [37]. They are made up of three constituents: the lipid bilayers, the cations and the agent to be delivered; on varying one or more of these constituents, various permutation combinations are possible, as shown in Box 1. www.future-science.com

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Review | Loomba & Scarabelli Box 1. The various constituents of a cochleate. Cations Zn , Ca , Mg , Ba 2+

2+

2+

2+

Lipids

Drugs

Phosphotidylserine phosphatidic acid Phosphotidylinosotol Phosphotidyl Glycerol Phosphotidylcholine Phosphotidylethanolamine Diphosphotidylglycerol Dioleoyl phosphatidic acid Distearoyl phosphatidyl serine Dipalmitoylphosphatidylglycerol

Protein Peptide Polynucleotide Antiviral agent Anaesthetic agent Anticancer agent Immunosuppressant Anti-inflammatory agent Tranquilizer Nutritional supplement Vitamins or Vasodilator agent

Properties

Cochleates are rod-like, rigid, internally hydrophobic sheets made from small unilamellar liposomes condensed by bivalent cations. The positive charge on cations such as Zn2+, Ca2+, Mg2+ and Ba2+ interacts with negatively charged lipid to condense it and rolling further makes them resistant to their immediate environment. The high tension at the bilayer edges of cochleates is the driving force of cochleate’s interaction with the tissue membrane [38]. The cell membranes fuse with the lipid bilayer structure of cochleates, which unfolds to release the internal contents into cells. Another hypothesis put forward is the idea of phagocytosis for nanocochleates’ delivery. The phosphatidylserine receptors are common between the liposomal membranes of macrophages as well as those of cochleates. When in close proximity, the liposome membrane and the outer cochleate layer fuse to release the drugs into cell cytoplasm. The alternating lipid layers entrap the drug molecules without chemically bonding to it and potentially protect it from digestive enzymes in the stomach. Encochleation is a medium to extend the shelf-life of drugs because the cochleate cores are resistant to water and oxygen, two components that act as leading agents of drug decomposition and degradation. Synthesis

Cochleates can be produced in submicron size using methods known as hydrogel-isolated cochleation, trapping, binary aqueous–aqueous emulsion, liposome before cochleates dialysis, direct calcium dialysis, or simply by increasing the ratio of multivalent cationic peptides over negatively charged liposomes. The hydrogel method immerses unilamellar liposomes loaded with drug in two sets of immiscible polymers. The polymer miscibility results in a two-phase aqueous system, which is crosslinked by a cation salt. The tiny 1188

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cochleates so formed are washed and then suspended in a buffer. The trapping method involves dropwise addition of calcium salt and water phase to the formative layer of phosphatidylserine liposomes. The binary aqueous–aqueous emulsion method injects the primary dextran–liposome phase into a secondary non-miscible polyethylene glycol polymer. The divalent cations are then diffused from one phase to another forming cochleates, less than 100 nm in size. The liposome before cochleates dialysis method suspends a detergent–lipid mixture in a two-phase polymer system. The mixture is dialyzed with a buffer to form protein–lipid vesicles. The cochleate precipitates from the vesicles by addition of calcium ions. Large needle-shaped cochleates are formed by the direct calcium dialysis method, in which lipid detergent mixture is dialyzed against CaCl2 solution [39]. „„The

cochleate technology for nanomedicine Cochleate means spiral shell. In 1975 Papahadjopoulos and Wilschut discovered cigar-like nanocochleates nearly 500 nm in size. Since then, cochleates have been used to formulate a variety of biologically active molecules, mediate effective oral drug bioavailability and reduce toxicity. There is a budding interest of scientists to explore cochleate efficacy in gene delivery. Effective drug delivery by cochleates

Cochleate technology is a new means of overcoming the poor oral absorption of drugs such as amphotericin B and to facilitate the bioral drug delivery of cochleate-administered oral doses of amphotericin B, ranging from 0 to 40 mg/kg of body weight/day fortnightly in a murine model of systemic aspergillosis. This leads to a reduction of more than two logs of colony counts in hepatic, pulmonary and renal organs [40]. Cochleates increase the efficacy of antibacterial drugs such as clofazimine used against tuberculosis. To protect mice from lethal acute graft-versus-host disease the immunosuppressive, water-insoluble compound 3-(2-ethylphenyl)-5-(3-methoxyphenyl)1H-1,2,4-triazole was subcutaneously administered through an oily vehicle. The oral administration of 10 mg/kg of this compound after encochleation reduced lethality, and increased the survival rate to 100%, whereas the control with empty nanocochleates was inactive [41]. Cochleates serve as delivery vehicles for antiinflammatory drugs such as naproxen, ibuprofen and acetaminophen. Macrophages use the future science group

Metallic nanoparticles & their medicinal potential enzyme nitric oxide synthase during inflammation. In vitro studies of encochleated aspirin and acetaminophen show tenfold more effectiveness against nitric acid synthase in the macrophagederived cell line J774. In vivo data of a third of aspirin cochleate in carrageenan rat model demonstrated a reduction in gastric inflammation by nearly 70% compared with the free drug [103]. A naturally occurring, HDL ApoA1 mediates enzymatic esterification of cholesterol, transporting cholesteryl esters to the liver, thus lowering the risk of atherosclerosis and other coronary heart diseases. ApoA1 being a protein, is ingested by gastrointestinal enzymes, but when delivered through nanocochleates ApoA1 readily controls high blood cholesterol levels. The bridging counterions can be easily extracted out of the inter-bilayer spaces to convert cochleates to liposomes, making it an excellent delivery system for insoluble ingredients [42]. Gene delivery through cochleates

Gene therapy is an emerging field of medicine that combines a DNA plasmid and proteins with a delivery vehicle to insert into the genome of a defective cell. Gene transfer was first reported in animals in 1988. The treatment holds the potential to cure many genetic disorders such as sickle cell anemia, cystic fibrosis, hemophilia, Gaucher’s disease and many other immunodeficiency diseases. DNA protein cochleates are handsome candidates for gene therapy applications. Cochleate formulations facilitate stable gene transfer in CD34+ neonatal cord blood cells. In vitro gene transfer ability of cochleate complexes in human hematopoietic cells holds latent potential to treat many genetic and infectious diseases [103]. Scientists have tested for the feasibility of using rhodamine-labeled cochleates to deliver a green fluorescent protein (GFP) plasmid in cell lines and primary cells. They found that cochleates are efficiently accumulated by macrophages in both cell lines and primary cells in vitro and in vivo [43]. In animal models, cochleates have been reported to be proficient in the delivery of antisense oligonucleotide for chronic lymphocytic leukemia [44]. Toxicity of metallic nanoparticles Even the inert metals gold and silver, at nanoscale dimensions, bustle with energy compared with their larger counterparts. A decrease in particle size increases the surface area to volume ratio, and in turn raises chemical and physiological activity. The determination of nanotoxicity is a future science group

| Review

crucial subject as it highly affects the relationship of nanometals with humans and the environment. A precise knowledge of adverse effects of nanostructures can help in overcoming health risks and potential cytotoxicity if inadvertently released into the human body during clinical applications. The toxicological consideration of the aluminosilicates, iron-oxides, Q-dots and cochleates are presented in the following sections. „„Aluminosilicate

nanoparticles Aluminosilicates being used in military goods, as surgical gauges, coatings and propellants, increase the probability of their exposure to military personnel. The cellular interaction of aluminosilicates demonstrates the release of free radicals and oxidative stress. Kaolin dust causes in vitro toxicity and DNA damage in lavaged rat pulmonary alveolar macrophages. The cytotoxic effects are delayed when the same dust is treated with dipalmitoyl phosphatidylcholine – a pulmonary surfactant [45]. Aluminosilicate clay kaolin, at concentrations from 0.25 to 1.0 mg/ml, is twice as active as quartz on a mass basis and about half as active on a surface area basis. The phagocytotic ability and viability of cells is greatly hindered. Fetal bovine serum greatly reduces the toxic effects of the clay particles [46]. Oscillating bubble tensiometry techinque has been used to study the influence of bentonite, halloysite and mont­morillonite nanoparticles on biophysical activity of pulmonary surfactant. The study indicates that the aluminosilicate particles at concentrations 0.1 mg cm-3 or above in the pulmonary liquid deviate the minimum surface tension, stability index and the size of surface tension hysteresis of the alveolar region. This alters the dynamic biophysical activity of the pulmonary surfactant leading to undesirable health issues [47]. Aluminosilicate nanoparticles, when exposed to HeLa cells, are known to express toxicity depending on their size, composition, dose and shape. Nanozeolites containing aluminum-like, ZSM-5, LTL and LTA, demonstrate a dose-dependent toxicity by inducing cell necrosis rather than cell apoptosis by the damnification for the cell membranes. By contrast, pure silica nanozeolite silicalite-1 at the same concentration is found to be nontoxic [48]. Microarray-based toxicogenomics studies on 75 cell cycle-related genes of adult Drosophila melanogaster, after being fed with nanoparticles-mixed media for 15 days, show that silver, zinc oxide and alumino silicate nano­particles adversely influence cell cycle genes, www.future-science.com

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Review | Loomba & Scarabelli whereas gold and silica nanoparticles exert the least effect on these genes [49]. The opposing face of the aluminosilicates coin reveals a different story. Raw aluminosilicate nanoparticles pretreated with iron and manganese salts serve as selective sorbents for anionic contaminants of As/Sb/Se polluted aqueous systems. Silica-coated, bismuth-doped, aluminosilicates nanoparticles are not only simple to prepare, but also exhibit long-lived photoluminescence, high photostability, low toxicity and smooth penetration into tissues. Pregnant rats fed on an aflatoxin-contaminated diet (2.5 mg kg(-1) diet) and then on a diet mixed with 0.5% (w/w) aluminosilicates and bentonite for 20 days have not shown any major malformations. However, aflatoxin alone can lead to toxicity and growth deformities [50]. The nanosilicate platelets derived from natural montmorillonite clay have been tested for genotoxicity using five strains – TA98, TA100, TA102, TA1535 and TA1537, of Salmonella typhimurium. The Comet assay test on Chinese hamster ovary cells in vitro involving incubation with 1000 µg/ml platelets for 24 h indicates no DNA damage. The micronucleus assay in vivo and the Salmonella gene mutation assay results in no micronucleus induction in the Chinese hamster ovary cells. Even 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release assays on Chinese hamster ovary cells, after 12 h incubation, demonstrate feeble cytotoxicity under 1000 µg/ml [51]. Another study conducted recently, involving lipophilically coated silica nanoparticles and alumina nanoparticles in the hexagonal closepacked a structure, found that the nanoparticles have potential to fight Grasserie, a lethal polyorganotrophic disease caused by Bombyx mori nucleopolyhedrovirus, the fifth instar silkworm larvae. The nanoparticles cause morphological transformation of Bombyx mori nucleopolyhedrovirus polyhedra, and thereby reduce virusinduced cytopathic effect and plaque formation. This study can contribute to the development of new antiviral nanomedicines [52]. In vitro cytotoxicity experiments conducted on nanozeolites and monodisperse amorphous silica nanoparticles of similar size range (25–100 nm) and concentration (500 µg/ml) report lower toxicity in nanozeolites [53]. The potential toxicity of organophyllosilicates on cells from lung epithelial cancer, colon epithelial cancer, lung fibroblast and skin fibroblast is not apparent even in the concentration range of 500–1000 µg/ml [54]. 1190

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Despite the good documentation of respirable-sized aluminosilicates being responsible for pulmonary diseases, for generations, aluminosilicates have also been considered as versatile and benign. A careful methodology involved in the preparation of aluminosilicates, to avoid their aggregation or adsorption in the biological media, could render them more stable in nanomedicine. „„Iron

oxide nanoparticles The different types of iron oxides hold different cytotoxic levels at varying concentrations. Scientists recently studied potential adverse biological effects of four different iron nanoparticles, namely dextran-coated Endorem®, carboxydextran-coated Resovist®, lipid-coated magnetoliposomes and citrate-coated very small iron oxide particles. They found magnetoliposomes have the highest level of safe concentrations in cells followed by Endorem, Resovist and small iron oxide particles. This study is significant in evaluation of nontoxic concentrations and choice of particles for cell labeling techniques [55]. Excessive levels of nearly 1000 mg Fe/ml, of these iron oxide nanoparticles localized in perinuclear surfaces of murine C17.2 neural progenitor cells and human blood outgrowth endothelial cells demonstrate detrimental effects on cell migration and differentiation [56]. Superparamagnetic iron oxide nanoparticles (SPIO), which are considered as the gold standard for MRI cell tracking, have the potential to perturb the actin cytoskeleton, alter gene/cellular expression, impair cell-cycle regulation and disturb iron homeostasis and pancreatic functioning. In some cases SPIO-labeled cells produce hyperintensities on T2/T2-weighted MRI, making it difficult to distinguish from other hypointense regions such as damaged tissues or blood clots. Also, SPIO are known to cause inflammation, mitochondrial disintegration, chromosome condensation and formation of apoptotic bodies and reactive oxygen species [57]. The SPIOs, Feridex® (also known as Endorem or ferumoxide) and Resovist (also known as cliavist) have been known for their utility as T2 MRI contrast agents due to their ability to shorten T2 relaxation times in the liver and spleen, by selective uptake and accumulation in the cells of the reticuloendothelial system. These SPIOs being synthesized in aqueous media have poor crystallinity and, in turn, relatively low r2 relaxivities, which makes them unfit for ultrasensitive MRI. Since 2009, both Feridex and Resovist have been future science group

Metallic nanoparticles & their medicinal potential abandoned from their use in humans due to their adverse side effects such as severe back pain, leg pain, vasodilation and paraesthesia [58]. Scientists believe that it is chemical instability or surface reactivity of metallic nanoparticles that causes them to produce in vitro toxicity. Nanoparticles that are readily oxidized, reduced or dissolved carry good potential to be genotoxic or cytotoxic. Oxidation of zero valent iron nanoparticles into lepidocrocite (gFeOOH) and magnetite (Fe3O4) in contact with E. coli leads to the generation of reactive oxygen species through the fenton reaction inducing oxidative stress [59]. Oxidative stress is considered the main mechanism behind cytotoxicity and this can be suppressed to some extent by use of surface coatings such as citrate, polyvinyl alcohol and meso-2,3-dimercaptosuccinic acid, which reduces the number of oxidative sites and also prevents direct contact between nanoparticles and cells. Tetramethylammonium 11-aminoundecanoate-coated iron nanoparticles are found to be nontoxic at 0.110 mg/ml and cytotoxic at 100 mg/ml [60]. For clinical utility, efforts should be made to improve magnetic properties of iron oxide nanoparticles, and thereby increase relaxivities by controlling the composition, oxidation state, aggregation and toxicity due to presence of other harmful transition elements such as Co and Mn. Very recently, magnetite nano­cubes of 40–120 nm, encapsulated in polyethylene glycol-phospholipids, have been used as highly sensitive contrast agents for MRI of single cells both in vitro and in vivo [61]. Magnetic iron oxide nanoparticles are toxic at 300 g/ml, but are very promising in orthopaedic applications at a low concentration of 20 g/ml [62]. Manganese-doped SPIO nanocomposites of nearly 80 nm shows T2 relaxivity of 270 (Mn+Fe) mM-1s-1 in a magnetic field of 1.5 T. The relaxivity is much higher than a single manganese-doped SPIO nanoparticle containing lipid–PEG micelles and is highly useful to form ultrasensitive MRI contrast agents for liver imaging [63]. These high-yield designs, along with suitable detoxification pathways of nanoparticles, hold immense implications for safe utility in the human body. „„Q-dots

The health hazards posed by Q-dots depend on their size, concentration [64], type of metallic cores [65], bioactivity of outer coating [66] and their oxidative or photolytic stability [67]. The cytotoxicity of cellular Q-dots is mainly because of photobleaching in an in vivo aerobic environment through irradiation. The high future science group

| Review

photobleaching rate occurs in oxygen-rich conditions and at low Q-dot concentration subjected to high irradiation power density. The photochemical process results in transfer of an electron to an excited Q-dot oxygen molecule, which leads to the production of a superoxide anion that corrodes the nanoparticle surface. The photooxidation of CdTe has been observed in Euglena gracilis (EG 277) and human embryonic kidney (HEK 293) cells [68]. Cadmium-, selenium- and tellurium-containing Q-dots are toxic due to release of free metal, production of free radical species, and also intracellular distribution of Q-dot nanoparticles in cells, causing toxicity in the kidneys, lungs and nervous system, in addition to DNA damage. CdSe-incubated Bacillus subtilis have shown the heavy metal damage [69]. Moreover, each Q-dot is unique in its composition and physicochemical properties, which makes it difficult to generalize their biological and toxicological influence in various models. One study on a luminous bacteria Photobacterium phosphoreum, involving a series of Q-dots (CdSe, CdTe and ZnS-AgInS2), holds surface coating such as with MAA or dihydrolipoic acid, responsible for cytotoxicity [70]. Inhibition of the respiratory mechanism or membrane depolarization, as a result of interaction of metallic components of Q-dots with components of the electron transport chain, might be another cause of toxicity [71]. Dose-dependent cell motility has been found in Chagas’ disease causing protozoan Trypanosoma cruzi, where CdTe Q-dots with concentrations below 20 µM did not affect cell division of parasites, while 2–200 µM CdTe Q-dots caused a reduction in the percentage of DNA-duplicated parasites. T. cruzi epimastigotes incubated with 200 µM Q-dots, under ultrastructural analysis, reveal mitochondrial swelling, intense vacuolization in the cytosol, the appearance of endoplasmic reticulum profiles surrounding organelles and other cytosolic degraded structures. The presence of the nanoparticle could be observed inside the cytosolic vesicles and also on the epimastigote surface [72]. In vitro vascular endothelial toxicity, through activation of the mitochondrial death pathway and induction of endothelial apoptosis, of mercaptosuccinic acid (2-sulfanylbutanedioic acid)-capped Q-dots has been observed in plant cells [73]. The study of cytotoxicity of aqueous synthesized Q-dots, CdTe/CdS and CdTe/CdS/ZnS, reveals that the cytotoxicity of these Q-dots not only comes from the release of Cd 2+ ions, www.future-science.com

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Review | Loomba & Scarabelli but also intracellular distribution of Q-dots in cells and the associated nanoscale effects [74]. The cadmium leaching from the more soluble Q-dots is found on examination of multiple end points on nematodes using core (CdSe) and core–shell (CdSe/ZnS) Q-dots, at low (10 mg/l Cd), medium (50 mg/l Cd) and high concentrations (100 mg/l Cd). The core–shell Q-dots exhibit no effect on lifespan, fertility and growth while the core Q-dots cause acute effects similar to those found for cadmium salts. The lower lifecycle exposures to core Q-dots did not carry enough adverse biological attributes to the progeny compared with those subjected to higher concentrations [75]. Most of the studies on Q-dots cited in the literature are in vitro; however, a recent in vivo study of animal toxicity of CdSe–ZnS Q-dots does not report significant adverse effects [76]. CdSe Q-dots having a protective coating of tri-noctylphosphine oxide, one or two monolayers of ZnS and bovine serum albumin on their surface, which virtually eliminates their cytotoxicity [77]. The mobile charges present on the surface of Q-Dots cause photo brightening and blinking. A rapid alternation of Q-dots among emitting and nonemitting states produce blinking, on the other hand, excessive excitation increases fluorescence intensity to cause photo brightening. These photophysical limitations, once reduced, can further enhance the efficiency of Q-dots. „„Cochleates

Cochleates are considered safe oily vehicles. The AFCo1 cochleate produced from proteoliposome Neisseria meningitidis B, when tested for toxicological relevance in Sprague Dawley rats, was found to be nontoxic and fit for human consumption through the nasal route [78]. The efficacy of oral cochleate-amphotericin B to treat systemic candidiasis is well known. Administration of low doses (0.5 mg/kg body weight) through cochleates completely clears the fungal infection from kidneys and lungs, leaving behind no trace of toxicity. Cochleates have introduced a novel way to empower multidrug resistant bacteria, by working in coordination with membrane active oligo-acyl-lysyl sequence. The oligo-acyllysy-based cochleates act synergistically with various antibiotics, to decrease drug toxicity and increase dose-dependent therapeutic efficacy. The cochleates encapsulating amphotericin B do not induce hemolysis of human red blood cells even at high concentrations of 500 µg of amphotericin B/ml. These cochleates were also found 1192

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to be highly effective in treating mice infected with Candida albicans when administered intraperitoneally at doses as low as 0.1 g/kg/day [79]. Cochleates are considered to be highly efficient lipid-based modules for the treatment of visceral leishmaniasis, and also a highly reliable source to deliver nucleic acid-based therapies. When compared with the conventional drug amphotericin B deoxycholate, the in vitro activity of cochleates encapsulating amphotericin B is similar, having an ED50 of 0.021 µg/ml and the latter of 0.017 µg/ml; however, cochleates encapsulating amphotericin B unlike amphotericin B deoxycholate deoxycholate is not toxic to macrophages at concentrations as high as 2.5 µg/l [80]. Lipid formulations of amphotericin B deoxycholate (fungizone) circumscribe the nephrotoxicity and infusion-related side effects of this broad-spectrum antifungal drug. The formulations are available under the names of AmBisome®, a true liposome; Abelcet®, ribbonshaped; and Amphocil®, disc-shaped drug. They differ in size, shape, visceral diffusion and reticuloendothelial clearance but all of formulations contain amphotericin B with an effective dose range of 3–5 mg/kg/day [81]. Cochleates encapsulating a plasmid (3.75 µg/ml DNA) expressing GFP, when incubated in vitro in 4T1 murine mammary adenocarcinoma cells, exhibit GFP expression of 19.49–10.12% 96 h after addition; with GFP expression seen for up to 7 days postaddition [82]. Conclusion Currently, nanometals are a highly promising class of nanomaterials for medical progress as they control infection, inflammation, cancer, gene therapy and drug delivery, and even biosensing, imaging and labeling techniques. The biocompatible nature of the miniature-sized metals, juxtaposed with their photo absorbance or emission characteristics, renders them a ubiquitous place in nanomedicine to interplay both diagnostic and therapeutic properties. The health benefits of nanometals are no doubt transforming therapeutics; however, their potential adverse effects cannot be underestimated. The success of nanometals in medicine highly relies on the transition from their risk assessment to risk elimination. Researchers should consider a thorough investigation of nanoparticle concentration, distribution, sublethal cellular changes, cell type and experimental conditions of the cytotoxic assay; to overcome drawbacks associated with the applications of nanoparticles. future science group

Metallic nanoparticles & their medicinal potential Future perspective The medicinal potential of nanometals will reach a new height if they can work synergistically

| Review

with biomolecules to be self-guided automatic machines, having enough force to precisely reconstruct the molecular structure of damaged

Executive summary Background The medicinal industry has seen an amazing growth in nanoscale science over the last four decades; to the extent that products containing metallic nanoparticles like aluminosilicates, nanobiomagnets, quantum dots (Q-dots) and cochleates have found their utility in wound healing, antibacterial growth, diagnostic imaging, biosensing, assay labeling, cancer therapy and drug delivery. Aluminosilicate „„

„„

Aluminosilicates are aluminium and silicon oxides broadly classified as orthosilicates, phyllosilicates and cyclosilicates and are mainly synthesized by hydrothermal method or a sol-gel route.

„„

Aluminosilicate nanoparticles are abundantly found in clay. Since time immemorial, kaolin clay has been used to prevent bleeding and help in the healing of skin wounds. Over the last few years, kaolin impregnated surgical dressings, and QuickClot® are being increasingly used by the medical personnel.

„„

The metal surfaces of aluminosilicates in clay like smectites and illites, prohibit the growth of various microbes including Aspergillus flavus, methicillin resistant Staphylococcus aureus and b-lactamase Escherichia coli.

Bentonite is another aluminosilicate, with commercial name ‘WoundStat™’, for wound dressings, pain, stings, burns and cuts. Nanobiomagnets „„

„„

Magnetite, haematite and maghemite are the various forms of iron oxides that serve as biomagnets. The magnetic behavior of these iron oxides is due to internal superexchange competition between their different tetrahedral and octahedral sites.

„„

The commonly used techniques to synthesize nanobiomagnets are reverse micelle, precipitation, sonochemistry, microwave irradiation, autogenic pressure reactor and glass crystallization.

Iron oxide nanoparticles are excellent hyperthermia and MRI contrast agents due to their high magnetic moment, which leads to local magnetic field inhomogeneity. Iron oxide nanoparticles are effective tools for separating proteins and detection of DNA/RNA molecules with a single-base difference. Q-dots „„

„„

Q-dots are 2–10 nm sized chalcogenides of cadmium or zinc. They constitute the metallic core of semiconductors, noble metals and magnetic transition metals shielded by a shell that cover surface defects and a coating of functional ligands as a cap.

„„

The electronic excitations in the semiconductor band gap of Q-dots bring forth a broad absorption spectrum, narrow emission spectrum, brightness, time resolved imaging, high quantum yield and stability against photobleaching.

Biomedicine utilize the properties of Q-dots in cell tracking, immunoassays, determining the metastatic potential of cells, high resolution cell imaging and fluorescence resonance energy transfer-based biosensing. Cochleates „„

„„

Cochleates are rod-like multilayer entities having unilamellar liposomes condensed by bivalent cations as zinc, calcium, magnesium and barium.

„„

These highly efficient drug-delivery vehicles are encochleated into a spiral by hydrogel method, trapping, binary aqueous–aqueous emulsion and dialysis.

„„

The internal environment of cochleate sheet is hydrophobic, which helps to safely administer the drugs even with poor oral absorption.

Gene transfer into a genome of defective cell or hematopoietic cells can be done by combining a DNA plasmid and proteins with cochleates. Many genetic disorders can be cured using this methodology. Toxicity of metallic nanoparticles „„

„„

The relationship of metallic nanoparticles with humans and the environment is greatly governed by their toxicity levels.

The amount of oxidative stress and free radicals released during their interaction with living tissues, and the concentration at which they are least destructive, are the points worth consideration before they are used for biomedical purposes. Conclusion „„

Nanometals have earned their position in medical sciences to be used as both diagnostic and therapeutic agents. However, a lot needs to be done to eliminate the risk factors associated with them. Future perspective „„

„„

If scientists today can make a nanoscale car with chassis, wheels and UV-driven engine that can ferry drug molecules, we can dream of nanometals as self-guided automatic machines having enough potential to tailor the damaged cells. The need to overcome the practical challenges of cytotoxicity, economical issues and lengthy clinical trials will help the tiny nanometallic-caterpillar to come out of its cocoon as a beautiful butterfly.

future science group

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Review | Loomba & Scarabelli cancer cells and perform surgeries. The real challenge lies in producing nanoparticles that can function in close proximity to cells and can use digital data such as ribosomes to lead synthesis of the genome with predictable and tailored properties. Since there is a large disparity in size and shape of these tiny metals, the biggest hurdle is to produce nanometallic medicines on a large scale with the same accuracy every time and with a strong control over their physicochemical properties. A thorough insight into the interaction of these metals with biochemical pathways, their toxicological effects, economical issues and exposure pathways, will allow future medicine to use them with confidence. The bright future

of nanometals in medicine needs to emerge from the clouds of lengthy clinical trials, risk assessment, long product approval processes and high associated expenses. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t­estimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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