Synthesis and Biomedical Applications of Copper Oxide Nanoparticles

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Review

Synthesis and Biomedical Applications of Copper Oxide Nanoparticles: An Expanding Horizon Nishant Verma, and Nikhil Kumar ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.8b01092 • Publication Date (Web): 13 Feb 2019 Downloaded from http://pubs.acs.org on February 14, 2019

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Synthesis and Biomedical Applications of Copper Oxide Nanoparticles: An Expanding Horizon Nishant Verma1* and Nikhil Kumar2 1

Room no. 312, SCDT building, National Centre for Flexible Electronics, Indian Institute of

Technology,

Kanpur,

Kalyanpur,

Kanpur,

Uttar

Pradesh-208016,

India.

Email:

[email protected]

2Faculty

room, Department of Biotechnology, National Institute of Technology, Raipur, G.E.

Road,

Opposite

Science

College,

Raipur,

Chhattisgarh-492010,

[email protected]

*Author for Correspondence: Email: [email protected] Tel: 0512-259-6659


India.

Email:

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Abstract Synthesis of copper oxide nanoparticles with tunable size and desirable properties is a foremost thrust area of biomedical research domain. Though, these features primarily rely on the synthetic approaches involved, but with advancement in this area, it has been documented that the synthesis parameters and surface modifiers have a direct impact on the morphology and eventually on its biomedical properties. ‘Sensing’ remains a major application of nanomaterials owing to its small size and unusual physicochemical properties, but in past few years, it has undergone a paradigm shift toward ‘theranostic’ combining the sensing and therapeutics features on a single platform. Copper oxide nanoparticles have been efficiently used for sensing and targeting both, in-vivo and in-vitro environment, although few key challenges are yet to be resolved before implementing at a commercial level. This review article attempts to summarize the recent advancements in the various synthetic approaches toward copper oxide nanoparticles and their biomedical applications. It highlights various synthetic methodologies including electrochemical, chemical and biogenic methods, the role of surface modifiers in growth mechanism, and their impact on biomedical applications. Finally, the current status, key challenges and future perspective of copper oxide nanoparticles will be discussed that inevitably have an impact on their current and future scenario.

Keywords: Copper oxide nanoparticles; Nanomedicine; Cancer therapy; Sensor; Biomedical applications

Introduction In recent years, the field of nanotechnology have drawn much interdisciplinary effort and is being integrated into all aspects of life. Nanomaterial, in general, corresponds to a material having at least one critical dimension in the size range 1-100 nm for more than 1% of their



number, ‘but a sensible definition has proved hard, if not impossible, to arrive at’.1 It is quite challenging to classify a material as “nano” since the term is quite subjective and depends on the application or end property of interest. With a grain size below 10 nm, mostly optical and electronic properties change, while their physical, mechanical and chemical properties tend to deviate from bulk in the range of 50-100 nm.2 Thus, a material may be classified as a nanomaterial with a nano-dimension below which the property of interest varies significantly. Different fields such as chemical industry, food industry, electronics, and healthcare are embracing nanotechnology because of their many desirable and unique properties that meet the needs of end users.3-5 Among these fields, the biomedical area is greatly influenced by the advancement in nanotechnology. Nano-structured materials are currently being exploited for a range of applications including biosensing, imaging, diagnosis, and therapy.6-10 There is always an effort to provide adequate health care service in a minimum cost to improve the survivability and quality of life. Nanomaterials, therefore, providing a backbone to these efforts by setting a personalized platform with the possibilities of integrating diagnosis and therapeutics into a single system.11 In recent years, nanostructured metal oxide, a particular class of nanoparticles, has gained considerable attention from the scientific community owing to their unexpected physical and chemical properties that comes from the quantum confinement at nano-dimension.12-13 Copper oxide (CuO) is one of the smart transition metal oxides with a narrow bandgap (~2.0 eV) and at the nanoscale, it possesses distinct features such as good electrochemical activity, high specific surface area, proper redox potential, and excellent stability in solutions.14-15 It is one of the center of attraction after noble metal nanoparticles, thanks to its promising applications in a variety of areas such as catalysis,16-20 electrochemistry,21-23 sensors/biosensors,24-27 energy storage,13,

28-29

anti-fouling coating,30-31 and biocidal agents.32-34 With the advent of

nanotechnology in biomedical research, it has prompted a spectacular development in the


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research activities involving CuO nanoparticles. They have been widely used in the nonenzymatic sensing of clinically relevant analytes because of the high specific surface area and the possibility of promoting electron transfer reactions at lower over-potential.35-38 CuO nanoparticles have shown their potential in pharmacological activity, specifically in anti-tumor therapy.39-41 After being recognized as antimicrobial materials by the US Environmental Protection Agency (EPA), nanoparticles of copper and its oxides have received much attention to be used in biomedical devices to prevent bacterial infection.42 From sensing to therapeutics, CuO nanoparticles are being incorporated into all aspects for the development of new technologies and improving the existing ones. The scope of this review is to present a comprehensive overview covering the up-to-date advancement in various approaches engaged in the synthesis of CuO nanoparticles that represent all oxide types, the growth mechanism involved in determining the final morphology followed by a detailed discussion of their biomedical applications.

Fabrication techniques Despite the different approaches reported to synthesize CuO nanoparticles with desired morphology, it is still challenging to tune its size and shape simultaneously.43 Fabricating nanoparticles with desirable properties need precise control over the synthetic strategies which in turn results in the formation of different copper oxide nanostructures with controllable dimensions. Copper oxide nanostructures have been synthesized in various forms such as nanowires,44 nanocubes,45 nanoribbons,46 nanoflowers,47 nano octahedron,48 nano-shuriken,14 and nanofilms,49 each requiring a different synthetic approach such as colloidal synthesis, template synthesis, thermal oxidation, sonochemical and solvothermal techniques.44, 50-54 To simplify the overview, synthesis of CuO nanoparticles is grouped into three different categories based on technique involved i.e. Electrochemical, Chemical, and Biogenic methods.



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Electrochemical methods It is one among the widely available methods reported for the synthesis of metal oxides in nano-domains owing to its simplicity, low-temperature operation and feasibility at the commercial level. Different electrochemical techniques have been developed to fabricate CuO nanoparticles of desired morphology including nano-disk,55 nano-rods,56 nanosheets,57 nano-spheres,58-59 nano-ribbons,60 nano-spindles,61 nano-whiskers, and nanodendrites.62 The ideal process in electrochemical synthesis is the anodic dissolution of copper in an alkaline solution.63 It involves the electrolysis of a copper material such as copper plate or foil in a two-electrode electrochemical cell containing supporting electrolyte at varying potential for different time periods. A typical reaction is as follows:58 Anode: ― 𝐶𝑢 + 𝐶𝑙 ― = (𝐶𝑢𝐶𝑙)𝑎𝑑𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛

(1)

― + (𝑛 ― 1)𝐶𝑙 ― ―𝑒 = (𝐶𝑢𝐶𝑙)1𝑛 ― 𝑛 (𝐶𝑢𝐶𝑙)𝑎𝑑𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛

(2)

(𝐶𝑢𝐶𝑙)1𝑛 ― 𝑛 + 2𝑂𝐻 ― = 𝐶𝑢(𝑂𝐻)2― +𝑛𝐶𝑙 ―

(3)

2𝐶𝑢(𝑂𝐻)2― = 𝐶𝑢2𝑂 + 𝐻2𝑂 + 3𝑂𝐻 ―

(4)

Cathode: 2𝐻2𝑂 + 2𝑒 ― = 𝐻2 + 2𝑂𝐻 ―

(5)

𝑇𝑜𝑡𝑎𝑙 𝑟𝑒𝑎𝑐𝑡𝑖𝑜𝑛: (6)

2𝐶𝑢 + 𝐻2𝑂 = 𝐶𝑢2𝑂 + 𝐻2

Different parameters such as electrolyte concentration, deposition potential, deposition time, reaction temperature and presence of additives play a crucial role in determining the morphology and yield of nanoparticles. Among these variables, the phase composition of nanomaterials is highly dependent on the solution temperature as it enhances the decomposition of copper hydroxide to CuO nanoparticles.56 In another approach, disc-


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shaped copper oxide nanoparticles were synthesized by thermal decomposition of copper succinate nanoparticles that were synthesized by the conventional electrochemical process and optimized by Taguchi’s robust design.55 Mancier and group reported a sonoelectrochemical approach to produce copper oxide nanopowders in which mechanical energy from sonotrode results in a cavitation in the liquid to enhance a specific chemical reaction.64 A slightly modified version of the electrodeposition method, ‘plasma electrochemistry’, has recently been used for the synthesis of CuO nanoparticles.43,

65

Discharge plasma, being electrically neutral medium containing reactive radicals, have the potential to synthesize copper oxide nanoparticles. This method involves replacing an electrode with a gaseous discharge of plasma which favors nanoparticles formations at plasma-liquid interaction zone.65 Though these electrochemical methods are well established and share a common ground, a shift toward “environmentally benign manufacturing” is a recent trend that includes room temperature synthesis, use of aqueous electrolyte, minimal synthetic steps, and additive free shape control.50

Chemical methods Chemical methods, undoubtedly, are the widely used conventional methods used for metallic nanoparticles synthesis. A number of chemical methods have been reported for CuO nanoparticles including hydrothermal,66-67 solvothermal,68 sonochemical,51 mechanochemical,13 reverse microemulsion,12 and few other methods. The most common approach for the synthesis of copper oxide nanoparticles is chemical reduction of the copper salt precursor by organic and inorganic reducing agents. In a typical reaction, the salt precursor is reduced by a reducing agent, and the resulting precipitate is then washed and calcined to obtain nanostructure with different morphology. Different precursors such as copper sulfate, copper nitrate, copper acetate, and copper chloride have been reported for CuO nanoparticles synthesis however the final morphology can be controlled by changing the



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precursor counter ions and its concentration.69-71 Spindle-shaped copper oxide nanostructures with an average size of 60 nm and 32 nm were synthesized using copper acetate and copper nitrate salts respectively, while flower-shaped nanoparticles (~16nm) were reported with copper sulfate.69 In another study, cubical and spherical CuO nanoparticles were obtained by using copper sulfate and copper nitrate salts, respectively.72 Moreover, the concentration of precursor and the choice of capping agent also affects the CuO nanoparticles morphology as an increment in the particle size was obtained with a higher salt concentration,51 while different shapes (nanocubes, nanorods, nanowires, and nanobelts) were obtained by replacing the capping molecule (ascorbic acid, adipic acids, fumaric acids, and succinic acids).71 Currently, the microwave assisted chemical methods are gaining a lot of interest because of fast kinetics, rapidity, and efficiency. The efficiency of microwave heating is given by the following equation:73 P = cE2ƒε″

(7)

where P is the microwave power dissipation per unit volume in a solvent, c is the radiation velocity, E is the electric field in the material, ƒ is the radiation frequency and ε″ is the dielectric loss constant. ε″ is the most significant parameter that determines the ability of a material to heat in the microwave, and that is why a solvent, such as 1,3-Propanediol, benzyl alcohol, and 1,4-butanediol, with a higher boiling point, is generally used. This technique has been explored for the synthesis of CuO nanostructures with different morphology such as spherical,16, 74 tubular,75 and cubical.72 Two parameters, irradiation time and power applied, must be optimized to get particles of desired nano-shape and dimension. A gradual change in the growth and morphology of nanoparticles was observed on enhancing the power from 360W to 800W with an extended irradiation time of 5 min.16 In a slightly different approach, the sonochemical technique has been explored for fabricating CuO nanoparticles. It involves the use of ultrasound waves that induce physical


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and chemical changes in the system during cavitation that creates a local region with extreme temperature and pressure conditions, a condition suitable for nanoparticle synthesis. Through this technique, uniformly dispersed CuO nanoparticles with a size range of 5-10 nm have been synthesized at room temperature and embedded in poly(vinyl alcohol) for better dispersion.76 However, in some cases, a very high calcination temperature has been used to improve the crystallinity and particle size of copper oxide nanostructures.77-78

Biological Methods Although electrochemical and chemical processes are the most conventional and widely used methods for the synthesis of metal and metal oxide nanoparticles, they are quite expensive and involve the use of harsh chemicals. Environmentally benign biological approaches are attractive especially if the resulting nanoparticles are intended for biomedical applications. Biological processes present a safe, rapid, facile, and an ecofriendly approach for nanoparticles synthesis without the requirement of any sophisticated equipment, controlled environment, and toxic chemicals.79-81 Biogenic method is an initiative of green chemistry which is focussed on the methods that are directed toward the minimum usage of material and energy with least waste production.82 Among various green approaches that generally include the use of naturally occurring reducing agents such as carbohydrates, enzymes, unicellular/multicellular microorganism, biodegradable polymers, the extract of plant and its parts (i.e. stem, flowers, leaves, and roots) seems to be the best candidates because of easy sampling and cost-effectiveness for large scale production of nanoparticles.83-84 The ability of plant material to reduce metal ions has been known since the early 1900s. It has been realized for plant-mediated nanomaterial synthesis that the reducing agent itself can acts as a stabilizing agent, thus eliminating the need of any external stabilizers.85-88 Besides induction of the metal precursor reduction,



these phytochemicals also adsorbed on the surface of synthesized nanoparticles, and enhance its stability, kinetics of surface reactions, preventing agglomeration and deforming of nanoparticles. For the biosynthesis of CuO nanoparticles, a number of plant extracts have been reported including but not limited to Solanum lycopersicum,34 Aloe vera,89 Camellia japonica,86 Rheum palmatum L.,87 Piper betle,90 Tabernae montana divaricate,32 Carica papaya,91 Aloe barbadensis Miller,80 Tamarix gallica,83 Calotropis gigantea,81 Rauvolfia serpentinia,92 Thymus vulgaris L.,79 and Theobroma cacao L. seeds.93 In all the biogenic methods reported so far, the only mechanism of nanostructure synthesis is the reduction of the precursor salt by one or more reducing agents present in the plant extracts. Plants extracts are usually prepared by boiling and crushing the plant and/or its parts in a solvent (mostly distilled water), and carefully collecting the supernatant after the centrifugation. It is highly probable that the extensive chemical composition of a plant including phenolics compounds, flavonoids, alkaloids, terpenoids, quinol and chlorophyll pigments have the potential to reduce the metal ions.94 However, it is quite difficult to exactly point out that specific ingredient that involves in the reduction process as it may be combined action. Starch, another major constituent of a plant, also has the reducing abilities.95-96 Under alkaline conditions, starch glucose undergoes mutarotation through a highly reactive open structure, and the free aldehyde group of this open chain has the tendency to reduce the metal ions.97-98 The rate of particle synthesis and the morphology of the particles can easily be controlled by altering various parameters such as pH, temperature, substrate concentration, and exposure time to the precursor.99 In addition to plants, microorganisms such as bacteria, yeast, fungi, and actinomycetes have also been described for the extracellular/intracellular production of nanoparticles. A whiterot fungus, Stereum hirstum, has been reported for the green synthesis of spherical shaped CuO nanoparticles in the size range of 5-20 nm.100 Biomass of three fungi, Penicillium aurantiogriseum, Penicillium citrinum, and Penicillium waksmanii, has been used for the


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extracellular production of monodispersed CuO nanoparticles.101 Although several microorganisms have been exploited for metallic nanoparticles synthesis, only a few have been reported for copper oxide nanoparticles synthesis. Table 1 summarizes some of the properties of CuO nanostructures synthesized by different approaches discussed above.

Growth mechanism Nanomaterials with controlled and reproducible morphology can easily be formed if their growth mechanism has been explored properly. Like other metallic nanoparticles, the growth mechanism of copper oxide nanomaterials typically depends on the synthetic approach employed. For chemical-based approaches, two important mechanisms have been proposed for the growth of metallic nanoparticles: nucleation growth and seeded growth (Figure 1a). Nucleation growth mechanism involves the reduction of metal ions to zero valent nuclei followed by its growth into nanoparticles while in seeded growth mechanism, reducing agent oxidizes on a seed surface followed by mild reduction of metal ions on the surface.102 However, both models have been combined for colloidal nanofabrication where the seed itself catalyzes the nucleation and growth of nanoparticles. Nucleation is the first stage of crystallization in which atoms aggregate into small clusters (nuclei), and this cluster after attaining a critical size locked itself into a well-defined structure called ‘seed’. It is the shape of the seed that initially determines the morphology of a nanoparticle.103-104 It is worth mentioning that the final shape and size of nanoparticle do not solely depend on the seed shape but also on the growth rate of a seed (Figure 1b). Once a seed is formed, its growth is influenced by the preferential adsorption of capping agents on specific crystal planes that are responsible for shape formation by kinetically controlling the growth rates of crystal facets.105 It has been proposed that if the capping agents adsorb more strongly to one facet of the nanocrystal, the other face will grow faster, and this kinetic difference produces nanomaterial of various morphology.106 The difference in the speed of growth of one facet is caused by the varying surface free energy due



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to varying strength of capping agent adsorption. This free energy concept has been supported in the context of Wulff’s theorem, according to which it is the relative surface free energy that determines the final shape of a crystal by minimizing the total interfacial free energy (γ) of the system within a given volume. The interfacial free energy can be defined as the energy required for creating a unit area of a surface:104 dG

(8)

γ = (dA)

𝑛𝑖,𝑇,𝑃

where G is free energy and A is surface area.

Suramwar and co-workers proposed a growth mechanism for copper oxide nanoparticles in which the stabilizing agent, starch, produces spherical nanocrystals by preferentially adsorbing to (1 1 0) planes of nuclei, thereby increasing the area ratio of (1 1 1) to (1 1 0) that results in the evolution of spherical shaped CuO nanoparticles.107 In another approach, the growth mechanism of nanobat-like copper oxide nanostructures with a diameter of 70 nm, thickness 8 nm, and length 174 nm has been explained on the basis of polar surfaces of copper oxide crystals and crystallographic planes. It has been proposed that the difference in the growth rate of planes with the scenario (0 1 0)length> (1 0 0)breadth> (0 0 1)height, the slowest growing step (0 1 0) dominates the crystal, and results into typical rectangular nanobat like structure.108 They also reported that the reaction precursor and alkalinity of the solution have a direct impact on the morphology of nanostructures as a slight increment in the pH value produces copper oxide nanorods while changing the precursor resulted into nanopetal like copper oxide nanostructures. Poly (vinyl pyrrolidone) (PVP), a common stabilizer used during nanoparticles synthesis, plays a crucial role in determining the crystal shape.109 By varying its concentration from 0.5 mM to 9 mM, cubical shaped CuO nanoparticles get changed to truncated octahedra, octahedra and finally spherical shaped nanostructures (Figure 1c). Their growth mechanism was further analyzed by the time-dependent study of octahedral CuO nanoparticles in which small-sized nano-octahedra produced large-sized nano-octahedra by the process of Ostwald


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ripening (i.e., “the smaller NPs sacrifice themselves to make the larger nanoparticles in order to decrease surface-to-bulk ratios”) (Figure 1d).109-110 Here, it may be convenient to summarize that the final morphology of nanoparticles depends on several parameters involved in a particular synthetic approach employed. In electrochemical methods, these parameters include electrolyte concentration, deposition potential, reaction temperature, and pH. In chemical and biological approach, precursor material, precursor concentration, the presence of any capping agent (that influence growth rate of seed), type of capping agent, the alkalinity of the reaction medium, the temperature of reaction medium are the key factors. In comparison to the biological method, electrochemical and chemical methods are quite useful in synthesizing nanoparticles of various morphology due to better control over the reaction parameters. Biological methods, on the other hand, offers limited modulation features due to the complex nature of the reducing extract. It is evident from Table 1 that biological methods mostly produce spherical shaped nanoparticles while different shapes of CuO nanostructures can be obtained with other two approaches. Thus, depending on the requirement of the intended application, a particular approach may be used to synthesize CuO nanoparticles with desired morphological features.

Biomedical Applications Recent advances in the fabrication of nanomaterials with desired characteristics and biocompatible nature have paved the way for the development of advanced analytical devices with high selectivity, sensitivity, and throughput than conventional bioanalytical methods. From diagnosis to therapeutics, nanomaterials can be integrated into the system or can act as a system itself to improvise the performance of the intended application. In comparison to other metallic nanoparticles, copper-based nanostructures are the most promising material due to some unique features. For instance, copper is highly reactive and can perform a variety of catalytic reactions involving one/two electron pathway due to the presence of a wide range of



oxidation states (Cu0, CuI, CuII, and CuIII).110 This feature may be exploited to design and construct third-generation sensors for physiologically relevant electro-active analytes such as glucose, uric acid, dopamine, ascorbic acid, and L-cysteine. Copper also possess intrinsic antibacterial, anti-fungal, and anti-inflammatory properties which make copper-based nanomaterials a suitable candidate for designing microbes-resistant medical devices, ointments, and bandages. Moreover, copper is an essential trace element that is required as a cofactor for normal functioning of various metabolic enzymes.111 This property can be used to synthesize anti-tumor formulations that induce killing of tumor/diseased cells by altering the intracellular level of copper ions. Due to their small size, they are easily accessible to the micron-sized human cellular entity and can readily interact with the biomolecules present on the cell surface and intracellularly.112 Considering the distinctive properties of copper, CuO based nanomaterials are gaining importance in biomedical sciences. This section provides an overview of the diverse and exciting application of CuO nanostructures in the biomedical field that includes both, diagnosis and therapy (Table 2).

Sensors Glucose sensors According to the World Health Organization, the global prevalence of diabetic patients has nearly doubled since 1980 from 4.7% to 8.5%. Though the first sensor developed for glucose monitoring was an enzyme-based sensor, the recent trend is focussed on nonenzymatic sensor considering the stability and complexity issues with the enzymes or other biomolecules involved. CuO nanoparticles provide an excellent platform for glucose electro-oxidation by facilitating higher electron transfer rate on the electrode surface. A number of papers have been reported wherein the glassy carbon electrode has been modified with various forms of CuO nanoparticles for non-enzymatic detection of glucose


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in alkaline condition.36,

50, 69, 113-115

Though the detection principle seems to be

straightforward, the oxidation mechanism of glucose on CuO modified electrode in alkaline medium is still under debate with the possible reaction as follows:116

𝑪𝒖𝑶 + 𝑶𝑯 ― →𝑪𝒖𝑶𝑶𝑯 + 𝒆 ―

(9)

𝑪𝒖𝑶𝑶𝑯 + 𝒆 ― + 𝑮𝒍𝒖𝒄𝒐𝒔𝒆→𝑪𝒖𝑶 + 𝑶𝑯 ― + 𝑮𝒍𝒖𝒄𝒐𝒏𝒊𝒄 𝒂𝒄𝒊𝒅

(10)

In a study shuriken-like nanostructures (SLNs) of copper oxide were synthesized and used for the fabrication of a three-electrode configuration glucose sensor as shown in Figure 2. The electrodes were prepared by sputtering silver metal on the silicon surface and then modified with CuO SLNs mixed with a conducting binder (butylcarbitol acetate). The resulting prototype demonstrated excellent performance in a linear range of 0.01 μM to 11.0 mM with an ultra-low detection limit of 0.035 μM.14 It is worth mentioning that the sensitivity of a sensor is highly dependent on the final morphology of CuO nanostructures.69, 117 Different nanostructures of CuO were synthesized by in-situ growth on carbon clothes and a comparative electrochemical performance was done. It was observed that CuO nano-sheets resulted in a higher sensitivity of 4902 µA mM-1 cm-2 at a potential of 0.55 V in alkaline condition when compared to CuO nano-wires (2973 µA mM-1 cm-2).117 In a similar approach, different morphologies of CuO nanostructures were prepared by using different salts of copper and analyzed for glucose sensing. Flower-like CuO nanostructures formed from copper sulfate showed the highest sensitivity toward glucose than spindle-shaped nanoparticles formed through copper acetate and copper nitrate (Figure 3).69 Considering the fact that the performance of any nanomaterial including CuO nanoparticles can further be enhanced in a composite form, researchers have tried incorporating CuO nanoparticles with other nanomaterials, such as



graphene/graphene oxide,118-121 carbon nanotubes,36, 122-123 and platinum nanoparticles114 as the electrode modifying material. A highly sensitive and selective sensor based on CuO/grapheme nanocomposites-modified glassy carbon electrode has been reported for amperometric detection of glucose with a sensitivity of 1330.05 µA mM-1 cm-2 with a response time of only 3s.113 Detection limit in the nano-molar range could be achieved by incorporating copper oxide nanostructures with single-walled carbon nanotubes.123 Recently, printing techniques, such as screen printing and ink-jet printing, are considered as a promising tool to attach nanomaterials on the electrode surface in a very fast and reproducible manner that barely be achieved by a simple and conventional drop-casting method. In inkjet-printing, CuO nanoparticles in the form of ink are directly printed on a suitable substrate using drop-on-demand piezoelectric inkjet nozzle (Figure 4a). The inkjet printed CuO nanoparticles based sensor showed a high sensitivity of 2762.5 µA mM-1 cm-2 with a detection limit of 0.5 µM.116 The stability and reproducibility of the printed sensors come from the formation of a pore-like structure on the electrode surface that prevents the conglomeration of CuO nanoparticles. Microplotter technology, a high resolution, and dimensionally accurate printing technique have recently been explored for the fabrication of a disposable glucose sensor prototype based on copper oxide nanoparticles ink printed on the gold electrode as shown in Figure 4b.124 The sensor consists of three electrodes (working, counter and reference) printed on a flexible polyethylene terephthalate substrate, and the developed sensor showed no sign of detachment and deterioration during voltammetric studies even after extended periods of stirring.

Hydrogen peroxide sensors Hydrogen peroxide (H2O2), an essential intermediate in many biomedical reactions, is of utmost importance in clinical and pharmaceutical research. H2O2 estimation is critical for


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the detection of oxidative stress and hypoxic conditions in the cell and tissues.125 H2O2 detection also forms a backbone of other biosensors such as of glucose and cholesterol where it is formed as a by-product, and thus its concentration correlates with the analyte concentration. Among the conventional methods, the electrochemical technique is quite promising owing to its simple, rapid and cost-effective characteristics, however, these techniques need a stable and high-performance electrocatalyst in the form of meta/metal oxide nanoparticles.126 Though an enzymatic sensor employing ‘Horseradish peroxidase’ as a biological element can achieve high sensitivity and selectivity, but due to intrinsic nature of enzyme including low stability and reproducibility, more attempts have been made to fabricate a non-enzymatic sensor for peroxide detection.127-131 CuO nanoparticles have the potential to oxidize various chemical compounds and reported to mimic the peroxidase activity.129,

132-133

Based on the fact that the catalytic properties are highly

dependent on CuO morphology, different nanostructures including nano-flowers,130 nanoplatelets,134 nano-wires,135 nano-cubes,126 and nano-leaf136 have been synthesized and further used for non-enzymatic determination of H2O2. It is highly probable that there is an interconversion among various structures as a function of time, reactants concentration and other reaction parameters as observed during the synthesis of 3D CuO nano-flowers.130 In another approach, four different morphologies

(cubic, rhombic dodecahedral,

octahedral and extended hexapod) of CuO nanomaterial were synthesized by hydrothermal method and evaluated for their catalytic efficiencies.126 Despite having a small surface area, the extended hexapod and dodecahedra nanocrystals showed higher electrocatalytic reduction toward H2O2 as compared to cubic and rhombic nanostructures. This improved reaction mechanism has been explained based on the presence of different amounts of (111)

facets

of

copper

oxide

nanocrystals

in

the

order:

extended

hexapod>octahedral>rhombic dodecahedra, with the absence of (1 1 1) facets in the cubic nanocrystal. The electrocatalytic properties of copper oxide nanostructures in H2O2 sensors



can further be enhanced by the incorporation of graphene nanomaterials as advanced composite materials.127, 137-139 It has also been reported that besides improving the sensor performance, graphene in the form of nanosheets (GNS) also reduces the toxicity of CuO nanoparticles. In a cytotoxicity experiment, CuO: GNS were found to be more biocompatible than standalone CuO nanoparticles by inducing low levels of reactive oxygen species.140 These findings support the possibility of CuO-graphene nanocomposites as an implantable sensor for continuous in-vivo monitoring of H2O2.

Immunosensors Highly specific and sensitive detection of trace amounts of analytes is a pre-requisite for earlier point-of-care diagnosis as disease-related protein biomarkers are often present in ultra-low levels and thus require ultra-sensitive methods. In this respect, electrochemical immunosensors (EIA) provides a promising approach that relies on antigen-antibody interaction wherein the immunological materials are directly immobilized on the transducer surface. So far, a number of nanomaterials have been used in EIA to enhance the electrochemical signal and electron transfer ability leading to highly sensitive sensing.141 In general, nanoparticles or nanocomposites are used as a label to conjugate secondary antibodies, the concentration of which would increase at a higher level of antigen eventually produces a higher electrocatalytic current toward the reduction of the fixed concentration of hydrogen peroxide as shown in Figure 5a.142-143 However, considering the complexities involved in the labeling process, label-free immunosensor are the recent trends in which the target analyte hinders the direct electron transfer during hydrogen peroxide reduction (Figure 5b).144-145 Copper oxide nanostructures have been widely used as nanocomposites, such as Au@Ag core shell-CuO,146 ferrocene-CuO,147 palladium-CuO,143 ceric dioxide-CuO,145 platinum-CuO,148 and Ag-CuO142 for tumor-


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specific biomarkers, such as carcino-embryogenic antigen,142, antigen,143,

146-147

and alpha-fetoprotein.144,

149

147

prostate-specific

In an interesting study, a multiplexed

photoelectrochemical immunosensor platform labeled with copper oxide nano-seeds was fabricated on ITO glass surface for multi-detection of tumor markers including PSA, alpha-fetoprotein, and cancer antigen 125. It consists of three working electrode, specific for each antigen, with a hydrophobic paper strip that allows irradiation of one working electrode at a time as shown in Figure 6.149 It has been demonstrated that the copper oxide nanoparticles produce a synergic effect in accelerating the signal transduction, thereby lowering the detection limit up to femtogram ml-1 level.

Dopamine Sensors In mammalian, Dopamine (DA) is an important catecholamine neurotransmitter that plays a key role in regulating the function of central nervous system, renal, and cardiovascular system. It is usually present at a level of 10-8-10-6 M, however, a low level may induce some neurological disorders such as Parkinson’s, Alzheimer's, Huntington’s schizophrenia disease, epilepsy, and senile dementia.150-153 Thus, a highly sensitive and rapid detection is of utmost importance concerning its serious impact on human health. Electrochemical detection of DA involves its oxidation at working electrode with the reaction as follows:154

(11) For

DA

sensor,

nanospherical,156

various

copper

nanohexagonal,157

oxide

nanostructures

nanoflakes,158


including

nanoplatelets,152

nanorice,155 hollow-


nanospheres153 have been reported for DA analysis in the real samples. Glassy carbon electrodes modified with copper oxide nanoparticles in conjugation with other nanomaterials have been widely used for DA sensor with improved sensitivity.150-151, 159161

For example, nano-sized CuO/CNTs/Nafion composite has been used to improve the

electrocatalytic activity toward DA oxidation with improved peak current signals.154 In another instance, hemoglobin was used as an inexpensive enzyme alternative for the oxidation of DA at the electrode surface. It was electrostatically immobilized to positively charged CuO nanoparticles and then mixed with CNTs before fabricating carbon paste graphite electrode.150 It has been shown that ‘haem’ acts as a potential electron transfer mediator during the reaction thus lower the oxidation potential by acting as a catalyst. Though the development of DA sensor looks straightforward, the electrochemical detection of DA in physiological samples is quite challenging and has been greatly impeded by the presence of several potential coexistent compounds such as ascorbic acid, uric acid that interferes with the selectivity of the sensor with overlapping oxidation peaks.154,

156-157

However, to improve the selectivity, incorporation of copper oxide

nanoflakes on working electrode resulted in the separation of oxidation peak potential of DA and ascorbic acid by 0.28 V.158 Recently, modification of electrode surface by copper oxide nano-rice has been reported to provide an enhanced peak separation of 0.15 V between DA and uric acid. In a similar approach, CuO nanoparticles in composite form have the potential to improve the peak current and their separation due to synergistic effect and increased surface roughness of nanocomposites.162 In a comparison among electrodes modified with different films (polyglycine/CuO nano-flakes, SDS/polyglycine/CuO nanoflakes and CTAB/polyglycine/CuO nano-flakes), SDS/polyglycine. CuO nano-flakes modified electrode shown to exhibit a higher peak current with high selectivity.158 It has been demonstrated that electrodes modified with CuO nanoparticles and MWCNTs separate the peak potentials of DA and uric acid as a result of fast electron transfer rate.154,


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156

In a different approach, molecular imprinted electropolymers and CuO nanoparticles

modified electrode was developed in which the CuO nanoparticles were used to enhance the number of the template on the electrode surface.163 Since this sensor was based on the structural similarities between DA and the template (Figure 7), the cavities could not bind to the interfering molecules due to different structures, thus providing excellent selectivity to the sensor with a detection limit of 8 nM.

Other sensors In addition to the molecules discussed earlier, CuO nanoparticles have also been used for the sensing of some other clinically relevant analytes, though the reports are few. For example, a bi-enzymatic electrochemical sensor for cholesterol was developed using ultrafine monodispersed CuO nanoparticles and chitosan by electrophoretically deposited them on indium tin oxide glass substrate.164 Due to the biocompatible and antimicrobial nature of the resulting bioelectrode, development of in vitro and in vivo biosensors is quite possible. In another study, a colorimetric non-enzymatic cholesterol sensor was developed by the use of CuO-graphene nanospheres.140 The resulting electrode was also found to be biocompatible, and shown higher sensitivity for cholesterol with a detection limit of 78 µM. Mixed metal oxides, ceria oxide-copper oxide, nanoparticles were synthesized and used for the construction of a lactate biosensor.165 These mixed metal oxide nanoparticles were reported to have enhanced oxygen storage capacity, thus avoiding the errors caused due to the fluctuations in the oxygen concentration. In a novel approach, CuO nanoparticles along with single-walled carbon nanotubes were used for the specific detection of DNA sequence on glassy carbon electrode surface.166 This technique is quite beneficial in identifying the DNA sequences of virus and bacteria for diagnosis of disease in early stages. Not only for the DNA detection, but CuO nanoparticles have also been



used for the analysis of anti-HIV drug, nevirapine (NEV), in the complex matrices including human serum samples and pharmaceutical preparations.167 The reported biosensor was constructed by electrochemical deposition of CuO nanoparticles onto carbon nanoparticle film coated electrode, and it showed a wide linear range with a detection limit of 66 nM.

Cancer nanomedicine A healthy body is maintained by a normal and regular process of controlled programmed cell death including apoptosis and autophagy, triggered by some upstream signals such as reactive oxygen species or organelle damage. It is the ability of a tumor cell to evade the cellular apoptosis process leading to its uncontrollable propagation, an important characteristic feature of cancer. According to the World Health Organization fact sheet, 2017, cancer is one of the key reason for leading morbidity and mortality rate worldwide, with approximately 70% of deaths occur in low and middle-income countries. Conventional approaches to cancer therapy involve biopsy, surgery, catheters application, chemotherapy, and radiation.112 Chemotherapy is one of the highly recommended treatment techniques for cancer, but due to the non-specificity of the chemicals involved, it induces a lot of severe side effects such as metastasis, anemia, nausea, loss of appetite, and alopecia being the common one. Moreover, development of resistance to the chemotherapeutics drugs with time is another major drawback.168 Recently, medicines in various nanostructured forms, called ‘Nanomedicines’, have been emerged as an alternative chemotherapeutic medicine for cancer therapy. Nanomaterials have drawn a great interest due to their toxic effects in humans and other organisms, however, it is quite challenging to confine their activity to tumor mass only. CuO nanoparticles have been proven as a potential therapeutic agent that selectively induce apoptosis of tumor cells, and


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inhibit the growth and metastasis of melanoma.169-170 The anti-tumor activity of copper oxide nanoparticles is based on the fact that copper plays a crucial role in the regulation of normal endothelial cell growth and due to the toxicity of free copper, normal cells usually have a system to evade a higher intracellular copper level using cytosolic chaperones such as ATOX1 and CCS.40 Further, the presence of copper in some drugs also shown to have selective anti-tumor effects that support the aptness of CuO nanoparticles as potential antitumor agents. In fact, CuO nanoparticles with or without chemical modifications have been used against a wide range of cancer variants including tumor of kidney,40,

171

lung,39

brain,172 liver,173 breast,174 eye,170 and prostate9. Once these nanoparticles enter the cell or nucleus, it leads to a cascade of reactions involving various genotoxic reactions such as mutations, alternation of gene expression, DNA damage and mitochondrial localization.40 CuO nanoparticles have shown to specifically target the mitochondria inside the cell and initiate the mitochondrion-mediated apoptosis signaling pathway by creating oxidative stress conditions in the cell (Figure 8-1). The anti-tumor effects of CuO nanoparticles therapy on subcutaneous melanoma and metastatic lung tumors revealed that CuO nanoparticles inhibit the growth and metastatic of melanoma in tumor-bearing mice.39 The diameter of all CuO nanoparticles treated tumor was comparatively smaller than those of glucose-treated group (control) (Figure 8-2). A TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick end labeling) assay was used to confirm the apoptotic behavior of CuO nanoparticles in B16-F10 cells in vivo. CuO nanoparticles were also known to decrease the mitochondrial membrane potential, a common phenomenon occurred during apoptosis.173 In another study, fluorescent microscopy data revealed that CuO nanoparticles induced the intracellular production of reactive oxygen species such as superoxide anion, hydroxyl radicals and non-radical hydrogen peroxide in HepG2 and SKHep-1 cells in a dose-dependent manner (Figure 9a).175 They also analysed the effect of CuO nanoparticles on glutathione redox cycle, a process that maintain the level of



glutathione during detoxification of reactive oxygen species, and observed a significant decrease in the level of GSH/GSSG ratio at 10 μg ml-1 with a morphological change in both types of cell lines after an incubation of 24 h (Figure 9b-c). Although the use of nanoparticles in vivo conditions is still debatable due to their adverse effect on normal cells, less or no toxicity has been reported by some researchers while investigating the anti-cancer properties of CuO nanoparticles. For an instance, in a study, CuO nanoparticles have been reported to selectively induce autophagy and apoptosis in uveal melanoma cells and human renal cell carcinoma cells without affecting retinal pigment epithelium cells and human embryonic kidney cells. Targeted cancer therapy is an important aspect of future nanomedicines in which there is a targeted internalization of nanoparticles for selective degradation of tumor cell only without affecting the normal cells. Without this, nanoparticles could enter any cell and damage it. In an interesting study, the selectivity of CuO nanoparticles was improved by the polyethylene glycosylation of nanoparticles which enhances their permeation and retention properties, thus can easily penetrate through the leaky vasculature of tumor cell avoiding tight vasculated normal cells.176 In a different approach, Folate receptors, which are found to be over-expressed in different cancers including brain, breast, and kidney, have been used for the targeted delivery of CuO nanoparticles. The underlying idea was to conjugate CuO nanoparticles with folic acids to facilitate the folic acid-folate receptor binding on tumor cells only as normal cells have no or few folate receptors.8 In vivo study revealed that administration of CuO and folic acid conjugated CuO nanoparticles extended the life-span of tumor-bearing mice up to 19 days (CuO nanoparticles) and 29 days (folic acid-CuO nanoparticles). Though the initiation of a tumor, its metastasis and recurrence is initiated by cancer stem cells, CuO nanoparticles have shown their potential in inhibiting and killing melanoma stem cells invitro and in-vivo conditions.9,

177

The Wnt signaling pathway is most crucial for

maintaining the stemness and self-renewal stability of cancer cell, and CuO nanoparticles


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attenuate the stemness through this signaling pathway as reported in prostate cancer.9 Some of the crucial genes involved in Wnt signaling pathway including Wnt1A, FZD7, cMyc, and Cyclin-D1 were found to be under-expressed in a dose-dependent manner in PC3 cells treated with CuO nanoparticles for 48 h. As mentioned above that the nanoparticles induce apoptosis by producing reactive oxygen species and/or by mitochondrial injury, the mechanism of how they interact with mitochondria and cause its rupture was described by Wang and co-researchers.169 With the help of electron microscopy, they analysed HeLa cells treated with 30 μg ml-1 CuO nanoparticles for 3-4 h and observed that the uptake of CuO nanoparticles into the cell occurs in the form of vesicles followed by the binding of these vesicles to the mitochondrial membrane through special membrane proteins, and finally fusion of membranes of vesicles and mitochondria releasing the nanoparticles into it. The released nanoparticles cause tumescence of targeted endoplasmic reticulum and its rupturing. However, generation of highly reactive oxygen species by CuO nanoparticles action damage the lipid membrane of any cell including cancerous cells by initiating the lipid peroxidation.169,

173, 176

Considering all the mechanism discussed above in the

targeted killing of tumor cells, CuO nanoparticles offers a highly selective strategy in the field of cancer nanotherapy.

Microbial Warfare agents In developing countries with poor socio-economic development, an outbreak of infectious disease is a serious issue in healthcare with a lot of financial burdens. Most of the diseases are caused by water/food/soil borne pathogens that include bacteria, viruses, and parasites. Different drugs in the form of antibiotics have been developed but microbes generally develop a trait of intrinsic resistant toward the different class of antibiotics, thus an alternative antimicrobial therapeutic agent is highly requisite.178 Considering the excellent



antimicrobial property of CuO nanoparticles, it has raised considerable interest in various biomedical applications including topical antimicrobial ointments, wound dressing bandages, and antimicrobial coating of biomedical devices.33, 179-181 In fact, copper and its compounds have been recognized as antimicrobial material by the US Environmental Protection Agency (EPA).182 They have been widely used as potential anti-microbial agents against various strains of infectious organism such as E.coli,183-184 Staphylococcus aureus,181,

185

Pseudomonas aeruginosa,186 Enterobacter aerogenes,187 Pseudomonas

desmolyticum,92 Streptococcus faecalis,188 Stenotrophomonas maltophila and Candida albicans.189 Prevention of bacterial adhesion and biofilm formation on medical devices is a major function of CuO nanoparticles. In a study, CuO nanoparticles were synthesized using a liquid phase chemical synthesis method to determine the efficacy in preventing biofilm formation. The addition of a small amount of CuO nanoparticles resulted in high inhibitory effects on both Gram-positive and Gram-negative bacteria.181 However, the efficacy of CuO nanoparticles against microbes is significantly determined by different factors such as particle size, morphology, concentration and reaction pH. For instance, CuO nanoparticles were found to be more efficient against Staphylococcus aureus strains at a pH of 5, while a higher pH reduced its toxicity.190 The phenomenon was explained on the basis of enhanced penetration ability of CuO nanoparticles under acidic condition. In another study, nano CuO reported having a higher toxicity against E.coli and L. brevis than their micro-sized counterparts at the same concentration.191 Smaller sized CuO nanoparticles have been correlated with a significant antibacterial activity for both, Grampositive and Gram-negative bacterial strains.52,

192

The antimicrobial activity is also

dependent on the morphology of CuO nanoparticles, though all the forms are bacteriostatic in nature. It has been reported that as the morphology changes from cubic to octahedral, the anti-bacterial property improves from general bacteriostatic to highly selective.188 This toxicity variation is justified on the basis of different surface facets of CuO nanocrystals


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that ultimately would have a different adsorption and desorption tendency toward the bacteria. In a similar study, the structure-function relationship was established for CuO nanoparticles as a function of anti-microbial activity.193 The CuO nanosheets demonstrated enhanced biocidal activity as compared to nanopowder and bulk copper oxide. Two mechanistic explanations were proposed for the shape-dependent activity of CuO nanoparticles. The physical mechanism explained on the basis of the interaction between the nanoparticle and the bacterial cell. There is a variation in the level of interaction for each sample with the bacterial cell, though the TEM analysis confirms the internalization of all sample types in the cell (Figure 10). Since the nanosheets have irregular edges, it resulted in the perturbation of cell wall from physical interaction or puncturing, thus, provide a superior anti-microbial activity. The chemical mechanism demonstrated a higher biochemical reactivity of nanosheets during GSH oxidation assay, and CuO nanosheets exhibited enhanced oxidation potential compared to the other two types. The exact mechanism underlying CuO nanoparticle toxicity has not been comprehensively investigated and is a subject of intense debate. It has been proposed that the toxicity of CuO nanoparticles arises from the contact killing mechanism in which copper ions are released which in turn generate reactive oxygen species leading to disruption of cellular membrane and/or cellular function.190 It is believed that the redox cycling between Cu (I) and Cu (II) generates superoxide species that contribute to the degradation of biomolecules. CuO nanoparticles react with endogenous hydrogen peroxide to generate hydroxyl radicals in a process analogous to Fenton reaction.42 However, there are some reports of CuO nanoparticles mediated inactivation of certain cellular enzymes crucial for metabolic pathways.194 The role of copper oxides in contact-killing of bacteria has been thoroughly investigated by Hans research group.195 It has been elucidated that there is a strong difference in the contact killing behaviors between copper and its oxides due to a different release of copper ions per unit surface area. This difference in the release of



copper ions has been correlated with the antibacterial efficacy with maximum release obtained with pure copper followed by cuprous and cupric oxide. Wound healing is another allied application of CuO nanoparticles.179-180, 196 It exemplifies the category of those nanomaterials which possess intrinsic properties beneficial for wound treatment while the other category represents therapeutics delivery vehicles.197 In a recent study, an anti-microbial textile nanocomposite has been fabricated using CuO nanoparticles synthesized by in situ process.180 This nanoparticle modified cotton fabric provides an excellent antibacterial activity of 99.9% for Gram-negative bacteria E.coli and Grampositive bacteria S. aureus. Moreover, the fabricated textile also offered a controlled release of copper ions into the physiological saline solution that is quite beneficial for infection prevention. The wound healing activity of CuO nanoparticles was further proven in male Wistar Albino rat model.179 The nanoparticles were synthesized using Ficus religiosa leaf extract as biological reductant and applied topically at a concentration of 1.0 mg cm-2 on a 2 cm2 full thickness excision wound for 12 successive days. It was observed that the CuO nanoparticles treated wound exhibited no signs of bleeding, pus formation, and microbial contamination whereas control wound showed prominent inflammation. The wound healing mechanism of copper oxide was proposed by Borkow research group.196 They studied the healing process of copper oxide-containing wound dressing on genetically engineered diabetic mice by analyzing the expression of 84 genes involved in angiogenesis and wound healing. Hif-1 alpha, a regulatory sub-unit of Hif-1 transcription factor, expression was up-regulated in the mice treated with copper oxide dressing at 5 and 10 days. This Hif-1 alpha protein is a protein which is produced under stress condition such as oxidative stress and presence of reactive oxygen species, and also involved in wound angiogenesis and wound healing. Some other wound-healing enhancing factors such as epidermal growth factor receptor, inducible NO synthase, endothelial NO synthase, platelet-derived growth factor, interleukin VIII and heat shock


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protein (hsp90) were also up-regulated on the application of copper oxide impregnated dressings.

Conclusion and Future Perspective A tremendous advancement in the synthesis and biomedical applications of nanomaterials has been witnessed over the last decade. With most of the research focused on metallic nanostructures, metal oxide nanomaterials research is still in its infancy. CuO nanoparticles have many attractive physicochemical properties that can be tailored at different levels to achieve novel and desirable properties. Electrochemical and chemical methods are the most convenient methods of nanoparticles synthesis, but there is a remarkable development in the biogenic methods of CuO nanoparticles synthesis owing to its less toxicity. However, control of particle size and morphology is still challenging which will then have a direct impact on its application due to the structure-function relationship. As discussed above the role of capping agents in determining the final morphology, the exact mechanism of their binding and therefore allowing growth in particular facets needs to be thoroughly investigated. A slight variation in the reaction parameters could significantly impact its physicochemical and biological properties and may affect their biomedical applications. Nanomaterials are the first materials to be recognized as theranostic agents with single moiety displaying both, diagnostic and therapeutic features. CuO nanomaterials provide an expanding horizon for the development of in-vitro and in-vivo sensing and therapy applications in the biomedical field, though the combined theranostics application of CuO nanostructure is yet to be explored. The application of CuO nanoparticles is now leading toward the detection of biomarkers associated with diseases such as diabetes, tumors, stress, hypoxia, neurological disorders, and cardiac syndromes. Considering the excellent sensing abilities of CuO nanoparticles, they could further be explored for the fabrication of miniaturized implantable sensors for real-time monitoring.



With improved electrical conductivity, thermal and chemical stability, nanocomposites represent a new generation of novel materials with a wide range of applications. It has been evident that the potency of CuO nanoparticles could be amplified in a composite form in order to blend the diverse functionalities of each material. Nano-medicines, an advanced version of therapeutic drugs, have the potential to transform the conventional approaches to human health and diseases. It leads to the creation of a new domain of research, ‘nanobiotechnology’, an interdisciplinary field which is bringing the nanotechnology and clinical research on a single platform accomplishing the demand for future research. Targeted cancer therapy is one of the exciting areas of this research in which researchers have been developing nanomaterial-based drugs that can selectively kill tumor cell by sparing normal cells. The presence of specific receptors on cancerous cells seems to be a promising approach for therapeutic action by modifying CuO nanocrystals with a specific ligand as shown by folate-folic acid interactions. However, there are few challenges that need to be tackled before their successful applications in healthcare services. For example, in cancer therapy, ‘biocompatibility’, which includes nontoxicity, non-immunogenicity, and non-carcinogenicity, is one of the biggest issues with nanomaterials-based therapeutics. A biocompatible nanomaterial should be non-toxic in nature, but it is not necessary for a non-toxic nanostructure to be biocompatible. Also, for invivo sensing purposes, biocompatibility is a primary concern while designing the sensors. Since the potential biomedical applications of CuO nanoparticles highly relies on different parameters including particle size, shape, concentration, surface features, and operational environment, careful selection of these parameters would prevent them from constraining their broad-spectrum applications. In conclusion, a perspective toward a better understanding of phenomenon related to metal oxide nanoparticles including nucleation process, growth mechanism, biocompatibility, toxicity, and surface chemistry will be supportive in regulating the nanomaterial interface to affect the interactions with biomolecules for various biomedical applications.


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The author declares no competing financial interest.

Acknowledgment This work is supported by DST-SERB funding agency (PDF/2016/001540).

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Figure Captions: Figure 1. (a) Two different mechanism (Nucleation-Growth and Seeded-growth) involved in the growth of nanoparticles. Reproduced with permission from ref [102]. Copyright 2014 Royal Society of Chemistry. (b) Schematic representation of the reaction pathway resulting in nanomaterials of different morphology. Reproduced with permission from ref [104]. Copyright 2008 John Wiley and Sons. (c) Shape evolution in copper oxide nanocrystals at varying PVP concentration. (d) Time-dependent morphological study of copper oxide nanoparticles. Reproduced with permission from ref [110]. Copyright 2016 American Chemical Society. Figure 2. Schematic representation of a typical sensor setup (a) with structure (b), and glucose detection principle (c). Reproduced with permission from ref [14]. Copyright 2014 Elsevier. Figure 3. Synthesis of CuO nanostructures with different morphology using different copper salts as a precursor and their effect on the electrochemical sensing of glucose. Reproduced with permission from ref [69]. Copyright 2016 Springer Nature. Figure 4. Fabrication procedure for Si/Ag/ CuO nanoparticles working electrode by inkjet printing for non-enzymatic sensing (a). Reproduced with permission from ref [116]. Copyright 2013 American Chemical Society. A three-electrode configuration screen-printed sensor employing a gold working electrode modified with CuO nanoparticles (b). Reproduced with permission from ref [124]. Copyright 2017 Elsevier. Figure 5. A typical schematic diagram of sandwich-type electrochemical immunosensor (a). Reproduced with permission from ref [142]. Copyright 2016 Elsevier. Label-free electrochemical immunosensor (b). Reproduced with permission from ref [144]. Copyright 2011 Royal Society of Chemistry.


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Figure 6. A photo-electrochemical immunosensor for multi-detection of tumor markers such as PSA, alpha-fetoprotein and cancer antigen. Reproduced with permission from ref [149]. Copyright 2015 Elsevier. Figure 7. Adsorption isotherms curves of dopamine on CuO@GCE and GCE with sensor fabrication scheme. Reproduced with permission from ref [163]. Copyright 2015 Elsevier. Figure 8. (1) Schematic representation of mitochondrion-mediated apoptosis signaling pathway in a tumor cell by CuO nanoparticles. (2) Anti-tumor effects of CONP therapy on subcutaneous melanoma and metastatic lung tumors. (a) Representative images of stripped subcutaneous tumors. The diameters of the subcutaneous tumors of the CONP group were obviously smaller than the diameters observed in the glucose group. (b) Representative images of mice bearing subcutaneous melanoma from the same study at day 12. (c) Plot of tumor mass versus time. The tumors of the CONP group were significantly smaller when compared with the tumors of the control mice. (d) Survival plot of mice bearing subcutaneous tumors. The survival of mice treated with CONPs was significantly longer than the mice in the glucose group. (e) TUNEL (terminal deoxynucleotidyl transferasemediated dUTP-fluorescein nick end labeling)-stained assay of the subcutaneous tumors of CONP-treated mice on day 8. The image shows that CONPs induced the apoptosis of the tumor cells in vivo (as indicated by pink arrow). (f) TUNEL-stained assay of the control mice in the glucose group. (g) Statistical analysis of the positive cells in the TUNEL assay showed that the CONPs induced apoptosis of the tumor cells in vivo. (h) Representative lung images from mice in the metastatic lung tumor experiment. The average diameter of the lung tumors of the CONP group was significantly lower than the diameter of the tumors of the glucose group. Both images Reproduced with permission from ref [39]. Copyright 2013 Springer Nature.



Figure 9. Fluorescent images of HepG2 and SK-Hep-1 cells after treatment with CuO nanoparticles for 24 h showing ROS generation (a) and quantification of ROS by microplate reader with extinction and emission wavelength of 480 and 570 nm, respectively (b). (2) GSH status analysis of Hep-G2 and SK-Hep-1 cells after treatment with varying concentrations of CuO nanoparticles for 24 h showing a decrement in the GSH/GSSG ratio. SEM images of cells exposed to CuO nanoparticles for 24 h confirming a change in the cellular morphology of tumor cell (c). All images Reproduced with permission from ref [175]. Copyright 2015 Royal Society of Chemistry. Figure 10. (1) TEM and STEM-EELS images of E. coli with (a) experimental sample prepared for imaging, (b-c) control with no CuO nanoparticles exposure, (e-f) bulk CuO, (h-i) CuO nanopowder and (k-l) CuO nanosheets. TEM images of the aggregates of bulk (d), nanopowder(g) and nanosheets (j). (2) The relative glutathione oxidation potential of different CuO materials (a). The percent reduction of colony forming units (CFU) in comparison to the control normalized by mass, 0.01 mg ml-1 (b) and surface area (c). Error bars represent the standard deviation of compiled data. Both images Reproduced with permission from ref [193]. Copyright 2016 American Chemical Society.


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For Table of Contents (TOC) Graphic Synthesis and Theranostic Applications of Copper Oxide Nanoparticles: An Expanding Horizon Nishant Verma* & Nikhil Kumar



Figure 1. (a) Two different mechanism (Nucleation-Growth and Seeded-growth) involved in the growth of nanoparticles. Reproduced with permission from ref [102]. Copyright 2014 Royal Society of Chemistry. (b) Schematic representation of the reaction pathway resulting in nanomaterials of different morphology. Reproduced with permission from ref [104]. Copyright 2008 John Wiley and Sons. (c) Shape evolution in copper oxide nanocrystals at varying PVP concentration. (d) Time-dependent morphological study of copper oxide nanoparticles. Reproduced with permission from ref [110]. Copyright 2016 American Chemical Society. 346x169mm (150 x 150 DPI)


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Figure 2. Schematic representation of a typical sensor setup (a) with structure (b), and glucose detection principle (c). Reproduced with permission from ref [14]. Copyright 2014 Elsevier.



Figure 3. Synthesis of CuO nanostructures with different morphology using different copper salts as a precursor and their effect on the electrochemical sensing of glucose. Reproduced with permission from ref [69]. Copyright 2016 Springer Nature. 173x129mm (150 x 150 DPI)


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Figure 4. Fabrication procedure for Si/Ag/ CuO nanoparticles working electrode by inkjet printing for nonenzymatic sensing (a). Reproduced with permission from ref [116]. Copyright 2013 American Chemical Society. A three-electrode configuration screen-printed sensor employing a gold working electrode modified with CuO nanoparticles (b). Reproduced with permission from ref [124]. Copyright 2017 Elsevier. 173x111mm (150 x 150 DPI)



Figure 5. A typical schematic diagram of sandwich-type electrochemical immunosensor (a). Reproduced with permission from ref [142]. Copyright 2016 Elsevier. Label-free electrochemical immunosensor (b). Reproduced with permission from ref [144]. Copyright 2011 Royal Society of Chemistry. 346x104mm (150 x 150 DPI)


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Figure 6. A photo-electrochemical immunosensor for multi-detection of tumor markers such as PSA, alphafetoprotein and cancer antigen. Reproduced with permission from ref [149]. Copyright 2015 Elsevier. 121x74mm (150 x 150 DPI)



Figure 7. Adsorption isotherms curves of dopamine on CuO@GCE and GCE with sensor fabrication scheme. Reproduced with permission from ref [163]. Copyright 2015 Elsevier. 146x77mm (150 x 150 DPI)


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Figure 8. (1) Schematic representation of mitochondrion-mediated apoptosis signaling pathway in a tumor cell by CuO nanoparticles. (2) Anti-tumor effects of CONP therapy on subcutaneous melanoma and metastatic lung tumors. (a) Representative images of stripped subcutaneous tumors. The diameters of the subcutaneous tumors of the CONP group were obviously smaller than the diameters observed in the glucose group. (b) Representative images of mice bearing subcutaneous melanoma from the same study at day 12. (c) Plot of tumor mass versus time. The tumors of the CONP group were significantly smaller when compared with the tumors of the control mice. (d) Survival plot of mice bearing subcutaneous tumors. The survival of mice treated with CONPs was significantly longer than the mice in the glucose group. (e) TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick end labeling)-stained assay of the subcutaneous tumors of CONP-treated mice on day 8. The image shows that CONPs induced the apoptosis of the tumor cells in vivo (as indicated by pink arrow). (f) TUNEL-stained assay of the control mice in the glucose group. (g) Statistical analysis of the positive cells in the TUNEL assay showed that the CONPs induced apoptosis of the tumor cells in vivo. (h) Representative lung images from mice in the metastatic lung tumor experiment. The average diameter of the lung tumors of the CONP group was significantly lower than the diameter of the tumors of the glucose group. Both images Reproduced with permission from ref [39]. Copyright 2013 Springer Nature. 346x153mm (150 x 150 DPI)



Figure 9. Fluorescent images of HepG2 and SK-Hep-1 cells after treatment with CuO nanoparticles for 24 h showing ROS generation (a) and quantification of ROS by microplate reader with extinction and emission wavelength of 480 and 570 nm, respectively (b). (2) GSH status analysis of Hep-G2 and SK-Hep-1 cells after treatment with varying concentrations of CuO nanoparticles for 24 h showing a decrement in the GSH/GSSG ratio. SEM images of cells exposed to CuO nanoparticles for 24 h confirming a change in the cellular morphology of tumor cell (c). All images Reproduced with permission from ref [175]. Copyright 2015 Royal Society of Chemistry. 346x231mm (150 x 150 DPI)


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Figure 10. (1) TEM and STEM-EELS images of E. coli with (a) experimental sample prepared for imaging, (b-c) control with no CuO nanoparticles exposure, (e-f) bulk CuO, (h-i) CuO nanopowder and (k-l) CuO nanosheets. TEM images of the aggregates of bulk (d), nanopowder(g) and nanosheets (j). (2) The relative glutathione oxidation potential of different CuO materials (a). The percent reduction of colony forming units (CFU) in comparison to the control normalized by mass, 0.01 mg ml-1 (b) and surface area (c). Error bars represent the standard deviation of compiled data. Both images Reproduced with permission from ref [193]. Copyright 2016 American Chemical Society. 135x65mm (150 x 150 DPI)


ACS Biomaterials Science & Engineering 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

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Table 1. Properties of CuO nanoparticles synthesized by different approaches Method

Size (nm)

Shape

Highlights

Ref.

Electrochemical

22 ± 6

Polyhedral and star-like

Plasma electrochemistry with Cu plate as one electrode while Ar plasma in NaCl was used as another electrode

43

20-100

Nanodisk

Disk‐shaped copper oxide nanoparticles were obtained by thermal decomposition of cylindrical rod‐shaped copper succinate powder

55

35 (diameter) 550 (length)

Nanorods

Square pulse galvanostatic method was used

56

~35

Nanospheres

Copper and K2Cr2O7 were used as an electrode and additive, respectively

58

20-50 (diameter) 200-300 (length)

Nanospindles/nanorods

Sodium nitrate and copper were used as an electrolyte and sacrificial anode, respectively

61

~20

Nanopowder with spherical morphology

Ultrasound-assisted electrochemistry with a potentiostatic set-up was used

64

~22

Sphere-like assembly

Gaseous discharge plasma is used to replace the usual solid electrode in conventional electrodeposition

65

5-6

Flake-like

Hydrothermal method was used

66

27.7 (H)

Spherical and flake-like

Hydrothermal (H) and reflux (R) method employed

67

~7.7

Aggregates

Solvothermal technique was used

68

16/32/60

Flower/spindle

Different morphology can be obtained by using different

69

Chemical

12 (R)

precursor salts of copper


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200-500

Cubic/rod/belt

Different morphology can be obtained by using different

71

precursor salts of copper 150-200 (C)

Cubic (C)/spherical(S)

Morphology is highly dependent on precursor salt

72

38

Spherical

Microwave-assisted chemical synthesis

74

70-110

Spherical and tubular

Microwave-assisted chemical synthesis

75

600 (avg.)

Needle-shaped

Sonochemical technique employed

76

14-54

Spherical

Sonochemical technique employed

77

Synthesis and Biomedical Applications of Copper Oxide Nanoparticles

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