Synthesis, properties and biomedical applications of carbon-based quantum dots: An updated review

Biomedicine & Pharmacotherapy 87 (2017) 209–222

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Original article

Synthesis, properties and biomedical applications of carbon-based quantum dots: An updated review Pooria Namdaria , Babak Negahdarib , Ali Eatemadib,* a b

Mechanical Engineering, Sharif University of Technology, Tehran, Iran Department of Medical Biotechnology, School of advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, 69971-18544, Iran

A R T I C L E I N F O

Article history: Received 7 October 2016 Received in revised form 24 December 2016 Accepted 26 December 2016 Keywords: Carbon quantum dots Nanomedicine Optical property

A B S T R A C T

Carbon-based quantum dots (CQDs) are a newly developed class of carbon nano-materials that have attracted much interest and attention as promising competitors to already available semiconductor quantum dots owing to their un-comparable and unique properties. In addition, controllability of CQDs unique physiochemical properties is as a result of their surface passivation and functionalization. This is an update article (between 2013 and 2016) on the recent progress, characteristics and synthesis methods of CQDs and different advantages in varieties of applications. © 2017 Elsevier Masson SAS. All rights reserved.

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis of CQDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical ablation . . . . . . . . . . . . . . . . . . . . . . . 2.1. Electrochemical carbonization . . . . . . . . . . . . . 2.2. Laser ablation . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Microwave irradiation . . . . . . . . . . . . . . . . . . . . 2.4. Hydrothermal/solvothermal treatment 2.4.1. Chemical structure of CQDs . . . . . . . . . . . . . . . . . . . . . Optical properties of CQDs . . . . . . . . . . . . . . . . . . . . . . 4.1. Fluorescence . . . . . . . . . . . . . . . . . . . . . . . . . . . Phosphorescence . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Electro-Chemiluminescence (ECL) . . . . . . . . . . 4.3. Adsorption property . . . . . . . . . . . . . . . . . . . . . 4.4. 4.5. Electrical properties of CQDs . . . . . . . . . . . . . . Biological properties of CQDs . . . . . . . . . . . . . . 4.6. Bio-applications of CQDs . . . . . . . . . . . . . . . . . . . . . . . Bio-imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. 5.2. Cellular imaging . . . . . . . . . . . . . . . . . . . . . . . . Bio-sensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. 5.4. Drug/Gene delivery . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Authors’ contribution . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author at: Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, No 88 Italia Street, P.O. Box. 1417755469, Tehran, Iran. E-mail addresses: [email protected] (P. Namdari), [email protected] (B. Negahdari), [email protected] (A. Eatemadi). http://dx.doi.org/10.1016/j.biopha.2016.12.108 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.

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1. Introduction Carbon quantum dots (CQDs) are defined as small carbon nanoparticles (Fig. 1a) with outstanding features such as good conductivity, high chemical stability, environmental friendliness, broadband optical absorption, low toxicity, strong photoluminescence (PL) emission and optical properties, easier to synthesize at large-scale with low cost, as comparable to quantum dots. Carbon Quantum Dots components and structure determine their diverse characteristics. Most of the carboxyl moieties on the surface of the CQD gives a great solubility in water and biocompatibility [1]. CQDs are as well appropriate for surface passivation and chemical modification with several polymeric, inorganic, organic, or biological materials. The physical and fluorescence characteristics are improved by surface passivation. (Fig. 1b) [2–6]. They were first discovered by Xu et al. in 2004 by chance during single-walled carbon nanotubes purification [7].

These findings geared extensive studies to exploit the fluorescence characteristics of CQDs. Much improvement has been achieved in the synthesis, features, and applications of CQDs [8]. Carbon nano-crystals unique characteristics have been applicable in biomedical fields like bio-imaging and optical sensing. Their small size and biocompatibility features enable them to efficiently serve as effective carriers for drug delivery while their rare catalytic and physicochemical properties are applicable in several biomedical fields [9,10]. Fluorescent-based quantum dots are of two types namely graphene quantum dots (GQDs) [11–13] and carbon quantum dots (Fig. 2). They make up a new class of semiconductor nano-crystals with a size range between 2 and 10 nm called quantum dots (QDs) [14,15], and have received extensive and significant attention due to their great potential like highly tunable photoluminescence (PL). Recently, this types of quantum dots emerged as efficient, superior and universal fluorophores [14,15]. Based on their characteristics,

Fig. 1. a Satructures of the different carbon nanoparticles in order of discovery. Fig. 1b Structural depiction of CQDs. Image adapted from [14,15].

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Fig. 2. Three kinds of carbon dots: polymer dots (PDs), carbon nanodots (CNDs) and graphene quantum dots (GQDs). Adapted from [1].

CQDs have been combined with semiconductor nanoparticles such as Ag3PO4, TiO2, and Fe2O3 to improve their photocatalytic property [2–6]. Polymeric dots are cross-linked or aggregated polymer, prepared from linear monomer or polymer. This type of dots is an aggregation of carbon core and connected polymer chains [3,16]. In this review, we extracted updates from articles (between 2013 and 2016) on the recent progress, characteristics, fabrication methods of CQDs and different advantages in varieties of applications. 2. Synthesis of CQDs The methods of CQDs synthesis are divided into two, “topdown” and “bottom-up” routes (Fig. 3). These methods can be realized through physical, chemical, or electrochemical method [7]. The CQD synthesized could be optimized during preparation or post-treatment [1]. This modification enables good surface characteristics which are crucial for solubility and selected applications[1]. Various methods of manufacturing nanotubes

are comprehensively discussed in reference [17]. Table 1 summarized the different synthetic methods for CQDs preparation [18–20]. 2.1. Chemical ablation In this methods of CQDs synthesis, strong oxidizing acids carbonize small organic molecules to carbonaceous materials, which can further be cut into small sheets by controlled oxidation [32,33]. Harsh conditions is one of the major shortcomings of this process. Peng and Travas-Sejdic showed a simple route of synthesizing luminescent CQDs in an aqueous solution by dehydrating carbohydrates with concentrated sulfuric acid, this is then followed by breaking the carbonaceous materials into individual CQDs with nitric acid, and finally passivating with amine-terminated compounds (4,7,10-trioxa-1,13-tridecanediamine) [33]. Surface passivation was important for the photoluminescence (PL) of these CQDs. CQDs emission wavelength can be tuned by differing the duration of the nitric acid treatment and starting material. The multicolor emission ability and nontoxic nature enable them to be applied in bioscience research.

Fig. 3. Synthesis route for CQDs: Top-down and bottom-up methods. Image adapted from [35].

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Table 1 The characteristics of the different synthetic techniques used for the preparation of quantum dots (QDs). Synthetic technique

Size range/color

Quantum yield

Chemical ablation

Thickness of 2–3 nm (corresponding to 2–3 graphene layers) and diameters of tens of nanometers. Monodisperse with a uniform diameter of ca. 3–5 nm, present a green luminescence

Laser ablation

–

Microwave irradiation

Greenish yellowluminescent GQDs (gGQDs) showed an average diameter of 4.5 nm mostly single layered or bilayered

Hydrothermal/ solvothermal treatment

5–13 nm (9.6 nm average diameter) single layered or bilayered

QY of as-prepared C-dots could be further improved through doping with inorganic salts (e.g. zinc acetate and Na2S or NaOH), in which the dopants (e.g. ZnS and ZnO) likely functioned as a secondary passivating agent for the Cdots [37]. The resulting doped C-dots showed strong PL (QY 45%) when – The PL QYs of single step of moderately gGQDs and reducing gGQDs with NaBH4, the bluebGQDs were luminescent GQDs (bGQDs) were as high as obtained with almost the same 11.7% dimension and and 22.9%, height respectively Average height – The prepared dots possessed strong fluorescence with PL quantum was 1.2 nm yields as high as 11.4% and could be dissolved in water and most polar organic solvents without further chemical modifications

Electrochemical carbonization

Photoluminescence transformation

Range?

Merits

Demerits

References

– Quantum yield of up to 4.34%

–

Most accessible, various sources

[18,19,21]

25.6%

The topographic heights were between 1 and 2 nm, indicating the architecture of 1–3 graphene layers excited at 450 nm.

Size and nanostructure are controllable, stable and one-step

Harsh conditions, drastic processes, multiple-steps, poor control over sizes Few small molecule precursors

Can be stably retained in water for several months without any changes.

QYs ranging from 4.0% to 10%

Photoluminescent CQDs were prepared in one-pot using polyethyleneimine (PEI), which is a cationic branched polyelectrolyte, via HNO3 oxidation and carbon as the source of the QD. In contrast to the generally reported pH-insensitive CQDs, the PL of these CQDs was very pH-sensitive, i.e., the PL intensity reduced as pH increases from 2 to 12. Furthermore, the pH response of the PL manner was reversible. These characteristics supports their potential to serve as proton sensors in the process of cellular metabolism monitoring with proton release. When they are incubated with HeLa cell line, the CQDs could easily penetrate the cell membrane and possesses a low cytotoxicity and favorable biocompatibility, which is crucial for HeLa cell imaging. 2.2. Electrochemical carbonization Electrochemical soaking is a powerful technique for synthesizing CQDs using several bulk carbon materials as precursors [34]. However, these methods of CQDs is rear. Zhang et al. introduced the synthesis of CQDs through the electrochemical carbonization of low-molecular-weight alcohols [23]. They utilized two Pt sheets as the auxiliary and working electrode, and a reference calomel electrode mounted on a freely adjustable Luggin capillary. The alcohols were changed into CQDs after electrochemical carbonization in basic environment. The graphitization degrees and size of these CQDs increase with the increasing applied potential. The resulting CQDs with amorphous core possesses excellent excitation and size dependent PL characteristics without complicated

[4,19,22– 24]

Fast, effective, highly tunable

[25] Low quantum yield, poor control over sizes, modification is necessary.

Fast, scalable, inexpensive, eco-friendly

Poor control over sizes

[26,27]

Inexpensive, eco-friendly, non-toxic

Poor control over sizes

[28–31]

purification and passivation procedures. Note that the quantum yields (QYs) of these CQDs can reach 15.9%. CQDs can be synthesized from different small molecular alcohols showing low toxicity to human cancer cells. 2.3. Laser ablation Sun et al. used a Q-switched Nd:YAG laser (10 Hz, 1064 nm) for the ablation, during which the carbon target was in a flow of argon gas carrying water vapor (via a water bubbler) at 900
C and 75 kPa [25,35–37]. They reflux in nitric acid for 12 h and passivate the surface by attaching simple organic molecule like PEG1500N (amine-terminated polyethylene glycol) and poly(propionylethyleneimine-coethyleneimine) (PPEI-EI) [38,39], a bright luminescence emission was obtained. Du et al. reported the fabrication of fluorescent CQDs by laser irradiation of a suspension of carbon materials in an organic solvent [39]. By organic solvents selection, the CQDs surface characterization could be modified to achieve a tunable light emission. Regarding experimental control, the origin of the luminescence was related to the surface states of ligands localized on the surface of the CQDs. Li et al. studied a simple laser ablation technique for synthesizing CQDs using nano-carbon materials as the precursor material and a liquid solvent [25]. In a typical procedure, 0.02 g of nano-carbon material was dispersed in 50 mL of solvent (such as acetone, ethanol, or water). Following the process of ultrasonication, 4 mL of the suspension was dropped into a glass cell for laser irradiation. A Nd:YAG pulsed laser with a

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second harmonic wavelength of 532 nm was used for suspension irradiation. Following this step, the solution was centrifuged to get the supernatant containing the CQDs. 2.4. Microwave irradiation Microwave irradiation of organic compounds is a fast and cheap technique for synthesizing CQDs [26,40]. Using a disaccharide; sucrose as the carbon source and diethylene glycol (DEG) reaction media, green luminescent CQDs were produced within one minute under irradiation [40]. These DEG-stabilized CQDs (DEGCQDs) could be well-dispersed in water with a transparent feature. An increase in the excitation wavelength results in the increase in PL intensity to 360 nm (maximum excitation) followed by a decrease. There was no observable shift of the PL peak over an excitation range from 320 to 380 nm. However, these DEG-CQDs could be effectively incorporated into a C6 glioma cells with a low cytotoxicity, showing their potential in bioimaging. Liu et al. studied microwave-mediated pyrolysis of citric acid using several amine molecules to produce a highly luminescent CQDs [26,41]. The amine molecules, particularly the primary amine molecules, displayed a dual function as N-doping starting material and surface passivating agents for the CQDs, which promoted the PL performance. The QY values is greatly elevated with an increase in N content for the CQDs synthesized from citric acid and 1,2ethylenediamine, showing a QY up to 30.2%. The resultant CQDs are highly biocompatible and have great potential for biomedical applications.

2.4.1. Hydrothermal/solvothermal treatment Hydrothermal carbonization (HTC) [41] or solvothermal carbonization is a cheap, environmentally friendly, and nontoxic technique to fabricate novel carbon-based materials from several starting materials. Ideally, a solution of organic precursor is reacted and sealed in a hydrothermal reactor using a high temperature. CQDs were prepared through HTC from many starting materials such as protein, citric acid [28], glucose [42], chitosan [29], and banana juice[43]. Mohapatra et al. synthesized a highly photoluminescent CQDs with a QY of 26% in one step by HTC of orange juice, then they centrifuged the resultant mixture [44]. These CQDs with sizes of 1.5–4.5 nm were used in bioimaging due to their low toxicity and high photostability. Liu et al. studied a one-step fabrication of amino-functionalized fluorescent CQDs by HTC of chitosan at 180
C for 12 h [31]. Solvothermal carbonization followed by organic solvent extraction is a common technique to synthesize CQDs [31,45]. Ideally, carbon-yielding compounds were heated in a high boiling point organic solvents, this is then followed by extraction and concentration procedure. Bhunia et al. fabricated two types of CQDs, hydrophilic and hydrophobic with a diameters less than 10 nm from carbohydrates carbonization [31]. The hydrophobic CQD were produced by mixing different amounts of carbohydrate with octadecylamine and octadecene before heating to 70–300
C for 10–30 min. The hydrophilic ones can be produced by heating an aqueous solution of carbohydrate within wide range of pH. The hydrophilic CQDs with red and yellow emissions can also be fabricated by mixing an aqueous solution of carbohydrate with concentrated phosphoric acid, then heating at 80–90
C for 60 min. Problems arising from CQDs synthesis include; (i) Carbonaceous aggregation during carbonization, which can be by-passed using electrochemical synthesis, solution chemistry, or confined pyrolysis methods. (ii) Uniformity and size control, which is crucial for uniform characteristics and mechanistic study, can be optimized

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through post-treatment, such as centrifugation, gel electrophoresis, and dialysis. (iii) Surface characteristics that are crucial for solubility and selected applications, can be tuned during synthesis or posttreatment. The features of different synthetic methods for the preparation of CQDs are summarized in Table 1.

3. Chemical structure of CQDs Carbon is usually a black material, and remained commonly considered to have weak fluorescence and low solubility in water. Owing to strong luminescence and good solubility, carbon-based quantum dots has been received wide attention, so they are named as carbon nanolights [14,46,47]. The structures of carbon-based quantum dots regulate their various properties. Numerous carboxyl moieties on the CQD surface convey outstanding biocompatibility and water solubility [1]. CQDs are also appropriate for surface passivation and chemical modification with various polymeric, biological, organic, or inorganic materials. By surface passivation, the physical and fluorescence properties of CQDs are improved. Based on carbon, CQDs keep such properties as good photochemical stability, benign chemical composition, and conductivity [48]. The chemical structures of CQDs are diverse according to the several synthesis methods (Fig. 4) [49,50]. CQDs are spherical in shape and they are sub-divided into carbon nanoparticles with/ without a crystal lattice [51]. The distance between the layers of CQDs is ca. 0.34 nm, which conforms to (002) spacing of the crystalline graphite. CQDs exhibit network of connected or modified chemical functional groups on the surface, such as oxygen-based and amino-based groups etc. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) can be used to assess the functional group of the CQDs in terms of their physical and chemical structures (Fig. 4) [49,50]. In bottom-up methods, CQDs are synthesized from polycyclic aromatic compounds through the processes of dehydration and carbonization. There are several techniques used for the dehydration and carbonization processes, amongst them are the hydrothermal [42], carbonization in a micro-reactor [52], microwave-hydrothermal [52] and plasma-hydrothermal [53] methods. Although, these methods allow for excellent control of the properties of the final product. 4. Optical properties of CQDs 4.1. Fluorescence Demonstrating photoluminescence (PL) mechanism and adapting CQDs for novel applications depends on the PL properties of CQDs. When compared with the general organic fluorophores, the main merit of CQDs is non-blinking PL and excellent photostability. The non-blinking PL ability enables single-molecule tracking while the photo-stability is responsible for long-term real-time imaging. The PL intensity of C-dots synthesized by laser ablation method reduces by only 4.5% after 4 h of irradiation as against the time (minutes) it takes organic fluorophores photo to bleach [25]. In recent research studies, one special characteristics of the PL of CQDs was the clear lex dependence of the emission wavelength, and intensity resulting from quantum effect and/or different emissive traps on the CQDs surface [54,55]. However, several studies have came-up with a lex independent emission position [56,57], which may be associated with their uniform size and surface chemistry. Fortunately, the excitation- dependent PL behaviors can be applied in multicolor imaging applications [58]. The mechanisms of fundamental to the tunable PL properties of

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Fig. 4. Schematic chemical structure of CQDs. Image adapted from [45,46].

CQDs are not entirely understood, mainly because of the unpredictable experimental clarifications caused by the large heterogeneity of individual particles from the same synthesis together with less- precisely defined properties of carbon nanodots obtained from different processes. For example, the supposed sizedependent emission of GQDs (i.e., smaller diameter GQDs emits a shorter wavelength due to bandgap opening by quantum confinement), this has not been investigated by experiments [59]. The experimental determination depends on controllable synthesis of well-defined CQDs, which are still poorly developed. A good knowledge about CQDs PL properties is impeded by the fact that the PL properties of CQDs are extremely sensitive to several factors. Isolation and removal of these influences caused by the factors can be done via theoretical modeling and calculations. Sk and his colleagues recently investigated that PL of a GQD is effectively originated from the quantum limitation of conjugated p-electrons in sp2 carbon network and can be delicately tuned by its size, edge configuration, shape, attached chemical functionalities, hetero-atom doping and defects via the use of densityfunctional theory (DFT) and time-dependent DFT calculations [60]. CQDs also have been described to be sensitive to pH [61–63]. The sensitivity of CQDs' PL to pH, expand permanency, and an intensive care range for the determination of proton concentration, possibly because of its effects on exciton trap sites and a function of surface modifications, leading to its applications as a pH probes [64]. 4.2. Phosphorescence The phosphorescence properties of CQDs were discovered recently. A pure organic room temperature phosphorescent (RTP) material was obtained based on water-soluble CQDs and its phosphorescent duration was increased to the sub-second order [65]. By dissolving the CQDs into a polyvinyl alcohol (PVA) matrix, clear phosphorescence could be detected at room temperature when excited with UV light. Introductory investigations suggested that the phosphorescence originated from the triplet-excited states of aromatic carbonyls on the surface of the CQDs. The matrix

PVA molecules can efficiently protect the triplet excited state energy from vibrational loss by solidifying these groups with hydrogen bonding (Fig. 5) [65]. 4.3. Electro-Chemiluminescence (ECL) Both semi-QDs and C-dots display ECL properties. In brief, C-dots (cat. 2 nm) synthesized from the electrochemical oxidation of graphite show ECL emission with the maximum at 535 nm as the potential cycles between +1.8 and 1.5 V. Recently it was reported that when C-dot was dissolved in ethanol solution containing 0.1 M tetrabutyl ammonium bromide (TBAB), a dual ECL peak was recorded [66]. Recently the ECL behavior of QDs has been identified [67,68]. The striking merits of QDs include more stable ECL and onset potential closer to 0 V presumably due to accelerated electron transport by a high content of sp2 carbon. In brief, the onset potential of the QDs hydrothermally produced from graphene oxide (GO) sheets is as low as 0.4 V, and stable ECL signal with relative standard deviation (RSD) of only 1.0% is measured during continuous cyclic scans [69]. In recent research conducted by Xu et al., they investigated how the configuration, morphology, and surface structure of QDs affects the PL and ECL in selected applications (Fig. 6a) [70], QDs with low and high oxidation levels with r-CQDs and o-CQDs respectively, were produced through a carbonization–extraction strategy and carbonization–oxidation process, respectively [70]. The results demonstrated that the electrochemical response was controlled by the diffusion of o-CQDs onto the electrode surface (Fig. 6b) [70]. The ECL wave initiated at 1.10 V and reached its highest peak value at 1.30 V (Fig. 6c)[70], which is continuous with the oxidation peak in the cyclic voltammograms (CVs), thereby ECL emission was connected to the direct oxidization of o-CQDs. Fig. 6d [70] established that ECL under continuous cyclic scans with high reproducibility. The ECL at the cathode end of the o-CQDs/K2S2O8 system is shown in Fig. 6b. The loose shell accelerates the electro-generation of o-CQDs with oxygen-containing groups on the o-CQDs. SO4 radical, a strong oxidizing agent produced by the chemical

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Fig. 5. Analysis of the feasibility sensitivity of the CDs (1) and (2) Digital photographs and the corresponding spectra of CQDs. (3) Phosphorescence excitation spectrum (olive dots) and absorption spectrum (blue dots) of CQDs dispersed in water. (4) Time-resolved phosphorescence spectrum. Image adapted from [62].

reduction of S2O82 accepts an electron from the anionic o-CQD to form the emitters for ECL emission. 4.4. Adsorption property Research studies have demonstrated that Carbon quantum dots possess some similar optical properties in regards to their absorption and fluorescence abilities (Fig. 7) [35,71]. CQDs generally display maximum optical absorption in the UV region (230–320 nm) with a tail extending to the visible range. For the carbon core shell, a maximum peak at ca. 230 nm is assigned to the p–p* transition of aromatic CC bonds, whereas a shoulder at 300 nm is assigned to the n–p* transition of C¼O bonds or other connected groups [72]. Furthermore, the connected chemical functional groups may be partly responsible for the absorption at the UV–visible regions.

4.5. Electrical properties of CQDs It should be noted that very few research work has been carried out on the electrical properties of QDs, beside some recent electrochemical capacities in the context of electro-synthesis, electro-catalysis, and sensing, very little is known [73]. The complex and efficient interaction between carbon core, functional groups, and doped heteroatoms are responsible for the electrochemical (electrical) features of QDs [74]. The sizeable specific surface area and ample edge sites aides the efficient electron transfer of QDs. Due to their small size, single-electron can be lodged in the quantum well formed between a QD and surface coating [34]. The electrochemistry of QDs is analogous to graphene oxide (GO) sheets when it carries oxygenated functional groups, these oxygen groups are responsible for disordering of the conductive sp2 carbon network at the basal plane thereby causing

Fig. 6. (1) Schematic sketch of the PL and ECL emissions of CQDs. (2) The process of ECL in the o-CQDs/K2S2O8 system. (3) ECL profiles of o-CQDs. (4) The reproducibility of ECL in a constant scan mode. Image adapted from [69].

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Fig. 7. (1) Absorbance and photoluminescence (PL) spectra with progressively longer excitation wavelengths of PPEI-EI QDs. (2) Photoluminescence (PL) of CQDs. Image adapted from [70,71].

impairment in electron transfer. If the oxygen groups are at the edges, they activate catalytic properties of QDs [75]. The extremely small size, high stability and good conductivity feature of QDs makes them applicable as electro-catalytic resources for oxygen reduction reaction (ORR). Li and colleagues recently reported a studies on graphene have suggested that doped nitrogen atoms in the form of pyridinium moieties, play a crucial role in enhancing the electro-catalytic activities of graphene QDs toward ORR [76] and their work is one of the research reports on the use of QDs as electro-catalysts for ORR. In Lis’ pioneering research, they established that N CQDs with oxygen-rich functional groups prepared through an electrochemical process are electro-catalytically active toward electrochemical reduction of oxygen. The potential onset of ORR was found to be 0.16 V (vs. Ag/AgCl), which is almost similar to that of commercial platinum-based electrocatalysts (Fig. 8), this result is similar to Yan and co-workers [77] and Liu et al. [73] with NCQDs synthesized by a different procedures from Lis. The electro-catalytic activity of QDs prepared from natural biomass-soy milk has been investigated by Zhu and colleagues [78] and it was reported that a more improved

electrochemical reduction profile of oxygen was obtained similarly to the N CQDs. 4.6. Biological properties of CQDs Previous research study by Sun and co-workers used CQDs synthesized by the arc-discharge of graphite rods, and then refluxed in HNO3 for 12 h for cytotoxicity assay. The bare CQDs were obviously nontoxic to cells up to a relatively high concentration of 0.4 mg mL1. Zhao and co-worker have reported that the human kidney cell line was not damaged by GQDs synthesized by the electrochemical treatment of graphite, by checking its cytotoxicity [71]. The cytotoxicity of the CQDs, lightly coated with functional groups, such as PEG [79], PEI, [80], BPEI (branched poly (ethylenimine)) [81] and PAA (poly (acrylic acid)) [82] were also evaluated in cytotoxicity assays. Furthermore, it has been reported that the PEGylated CQDs were found to be non-cytotoxic up to concentrations higher than the necessary amount needed for cell imaging and related applications [83].

Fig. 8. A graph of cyclic voltammograms of (1) NCQD and (2) commercial Pt/C on a GC electrode [1].

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Going by MTT assay, at high concentration a PEI free sample was evidently nontoxic to HT-29 cells. However, the PEI-functionalized QDs were more cytotoxic than PPEI-EI-functionalized CQDs which was as a result of more ethylenimine (EI) units within the PEI. It should be noted that free PAA at low concentration of about 50 mg mL1 was still found to be damaging to cells in a nonaqueous solution. In comparison, at the same CQD core-equivalent concentrations, both the PAA-functionalized CQDs and free PAA were both toxic to the cells within an exposure time of a day, but less toxic when the exposure time was 4 h. Conclusively, PEG and PPEI-EI with low cytotoxicity but at peaked concentrations are appropriate for CQDs functionalization for in vivo imaging and bio sensing. Molecules with higher cytotoxicity such as BPEI and PAA, with low and sustained concentration and reduced incubation time can still be applicable to functionalization of QDs used in vivo [80]. Table 2 summarized some of QDs characteristics for investigating nano-carrier behavior in biological systems. 5. Bio-applications of CQDs 5.1. Bio-imaging Much attention has also been given to the potential applications of CQDs in biological labeling, and bioimaging [36,79,84–86]. Most particular interest and significance is the present discovery that CQDs can show a PL emission in the near-infrared (NIR) spectral region under NIR light excitation. It should be noted that NIR PL emission of CQDs excited by NIR excitation is specifically significant and critical for in vivo (Fig. 9) bionanotechnology because of the body tissues transparency in the NIR “water window”[87]. Importantly, the PL from CQDs can be efficiently quenched by either electron donor or acceptor molecules in solution, showing that photoexcited CQDs are very good electron donors and acceptors. The interesting photoinduced electron transfer features of CQDs should give an exciting chance for light energy conversion, photovoltaic devices and related applications [88,89]. A CQDs can also be utilized as nanoprobes for sensitive ion detection[89]. By introducing the synthesis, structure and PL characteristics of CQDs in this review, we hope to shed more light into the potential controversial mechanism of their strong emission (particularly for UCPL), as well as to give further research

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on the future applications of CQDs, such as in bioimaging, and surface-enhanced Raman scattering. 5.2. Cellular imaging Sun and co-worker were the first to demonstrate the possibility of applying QDs as fluorescent labels for cellular imaging by using PEG1500N passivated QDs to stain Caco-2 cells [35] as such there has been several demonstrations of non-specific intracellular imaging of up-taken QDs in other cell types such as, HeLa cells [90], HepG2 cells [45], LLC-PK1 [91], NIH-3T3 fibroblast cells [92], human lung cancer (A549) cell [93]. Several research reports have investigated the application of QDs to label some cell types like T47D [94] HeLa [86] murine alveolar macrophage (MH-S) cells [95], human hepatic cancer cells (Huh7) [96], MCF-7 cells [97] and stem cells like neuro-spheres cells (NSCs), pancreas progenitor cells (PPCs), cardiac progenitor cells (CPCs) and neural stem cells [98]. In contrast to the generally reported pH-insensitive CQDs, the PL of these CQDs was very pH-sensitive, i.e., the PL intensity reduced as pH increases from 2 to 12. Furthermore, the pH response of the PL manner was reversible. This characteristics supports their potential to serve as proton sensors in the process of cellular metabolism monitoring with proton release[99]. When they are incubated with HeLa cell line, the CQDs could easily penetrate the cell membrane and possesses a low cytotoxicity and favorable biocompatibility, which is crucial for HeLa cell imaging. 5.3. Bio-sensing CQDs have been used as biosensor carriers due to their mentioned characteristics. The CQDs-based biosensors can be employed for visual monitoring of glucose [100], nucleic acid [101], phosphate [102], cellular copper, iron [103], potassium [104], and pH. CQDs can be used as an efficient fluorescent sensing platform for the detection of nucleic acid with selectivity single-base mismatch. The general concept was based on the adsorption of the fluorescently labeled single-stranded DNA (ssDNA) probe by CQD through p–p interactions, which is accompanied by substantial fluorescence quenching, followed by specific hybridization with its target to form double-stranded DNA (dsDNA) [101]. This led to the desorption of the hybridized dsDNA from the surface of CQD

Table 2 Quantum Dots characteristics for investigating nano-carrier behavior in biological systems. Quantum dot properties Small size

Explanation

Q-Dot core size of only 2–10 nm allows loading of several drug carriers with reduced side effect on carrier properties Multipurpose surface Compatibility with various surface-coating techniques. chemistry Tapered emission Identification of singular quantum dot populations is as a result of sharp profile distinctive emission peaks. Excellent brightness Excellent brightness allows detection of singular quantum dot probes within a given specimen Excellent photoProlonged quantum dot tracking is as a result of resistance to photo bleaching. stability Sizeable Stokes shift Reduction in the contribution of auto-fluorescence is a product of wide gap between excitation wavelength and emission peak. pH, surface passivation, and presence of drugs allows fluorescence of quantum High sensitivity to microdots which in-turn leads to micro-environment sensing capability environment High quantum dot contrast allows specific localization of nano-particle vehicles Electron-dense within cells. inorganic core

Application Tagging of complex multicomponent delivery carriers for tracking and monitoring of carrier breakdown Quantum Dots are applicable as traceable equivalents of other nano-carriers. Real-time observation of numerous nano-particle vehicles within the same model system Singularity study of nano-carrier performance within cells during uptake and intracellular trafficking. Simultaneous observation of nano-carrier uptake and trafficking Applicable in the in vivo study of nano-particle biodistribution and pharmacokinetics. Observing variations in local micro-environment during various stages of nano-carrier uptake and trafficking Its applicable in the study of nano-carrier trafficking and isolation within various intracellular partitions

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Fig. 9. A digital picture of an in vivo fluorescence images of a CQDs-injected mice taken at different excitation wavelengths. Image adapted from [35].

accompanied with further recovery of fluorescence, probing the target DNA. Enhanced and multifunctional CQD-based fluorescence resonance energy transfer (FRET) probe for imaging and detecting mitochondrial H2O2 was demonstrated. The CQDs serve as the donor of energy transfer and the carrier for the sensing system. A boronate-based H2O2 recognition element, boronate-protected fluorescein, was linked covalently onto the CQDs [105]. It can be employed for tracking the exogenous H2O2 levels in L929 cells, and can also be utilized for visualizing the endogenously produced H2O2 in RAW 264.7 macrophage cells. 5.4. Drug/Gene delivery CQDs have been micro-sized, they are readily available for cell uptake and more biocompatible to reduce cytotoxic effects, thus, they are likely to be safe, potent, and good delivery vectors. Dai et al. reported the delivery of insoluble aromatic drug SN38 using a PEGylated nanographene oxide of a size between 5 and 50 nm [106]. The delivered cancer-killing drug has been said to be

1000 fold more potent than a FDA approved drug for clinical colon cancer treatment. (Fig. 10) Kim et al. coupled CQDs with gold nanoparticles for an assembly, followed by conjugation with PEI–pDNA for delivering of DNA to cells [107]. Fluorescence emissions resulting from the assembly of CQD-gold nanoparticles could be quenched by pDNA; thus, pDNA release could be probed by the recovery of the fluorescence signals. The experimental results showed that the assembly entered into the cells with the CQDs located in the cell cytoplasm and the pDNA released entered the cell nuclei, achieving critical transfection efficiency. Pandey et al. in their study used CQDs functionalized gold nanorods for the doxorubicin delivery in a multi-modality fashion, including photothermal therapy, drug delivery, and bioimaging using the similar platform [108]. The commonly used anti-psychotic drug haloperidol (HaLO)-grafted CQDs with cysteamine hydrochloride (CysHCl) as a linker can give a controlled release under physiological conditions for more than 40 h following the Hixson–Crowell model under standardized conditions [99]. A broad spectrum antibiotic; ciprofloxacin attached to CQDs with bright green fluorescence can not only

Fig. 10. A schematic diagram for gene delivery using CQDs. Image adapted from [120].

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Table 3 Methods used for the delivery of Quantum Dots. Strategy

Mode of action

Examples

Targeted cells

References

Facilitated delivery

Peptide-mediated

Histidine-Arginine-rich peptide gH625 (Herpes simplex virus derived-peptide) JB577 peptide (palmitoylated)

A549 (lung adenocarcinoma; cytosol) HeLa (cervical adenocarcinoma; cytosol)

[109,110] [111]

HEK, COS-1, A549, primary fibroblast, chick embryo, rat hippocampal neurons (cytosol) COS-1 (African green monkey kidney) A549 L929 (murine fibrosarcoma) B16F10 (mouse melanoma) Panc-1 HeLa, Araki Sasaki (human corneal epithelium) HepG2 (hepatocyte), MCF-7 HepG2

[112] [113] [114] [115] [116] [117] [118] [119] [120]

HeLa Rat cardiomyocyte (H9C2)

[121] [122]

A549 HeLa HeLa

[123] [124] [123]

Human primary epithelial

[125]

Polymers Small molecule

Active delivery

LAH, sweet arrow peptide Chemoselective peptides Chitosan Liposomes Triblock copolymer Lactose Galactose Gambogic acid

Nanoneedle injection Reversible membrane permeabilization Nanochannel electroporation Nanoblade Microfluidic cell ‘squeezing’

Passive uptake QD surface character/charge

Table 4 Scheme of the different photoluminescence mechanisms and their particular features. Nanodots type/characteristics

SQDs (Semiconductor quantum dots)

CQDs/GQDs

CNDs

Excitation Life span PL band Quantum confinement PL size

Excitation-independent PL Long lifetimes Narrow PL band Quantum confinement Size-dependent PL

Excitation-dependent PL Medium lifetimes Broad PL band Quantum confinement Size-dependent PL (no clear)

Excitation-dependent PL Short lifetimes Very broad PL band No quantum confinement Size-dependent PL

pave a way for bioimaging but also give an effective new nanocarrier for controlled drug release with a high antimicrobial activity under physiological conditions [108]. Tables 3 and 4 summarized some of methods for delivery of QDs [109–124]. 6. Conclusion Several research studies have demonstrated that CQDs are applicable in various areas ranging from energy garnering and storage to bio-analytics [126–129]. However, with this great potential, there still remain difficulties in the assembly of efficient and high-quality CQDs [9,130–132]. In this paper, we have reviewed the characteristics of CQDs and also discussed different advantages of CQDs in variety of applications, we focused on their novel application in in vivo imaging, this might be an advantage in the treatment of brain tumor and other types of tumor in future taking the advantage of their photoluminescence property.

Authors’ contribution PN and BN conceived of the study and participated in its design and coordination. AE supervised the whole study. All authors read and approved the final manuscript. Competing interests The authors declare that they have no competing interests.

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