Quantum Dots

Quantum Dots

CHAPTER 4 Quantum Dots M.G.C. Pereira Universidade Federal de Pernambuco, Department of Pharmaceutical Sciences, Recife, Brazil E.S. Leite Universid...

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Quantum Dots M.G.C. Pereira Universidade Federal de Pernambuco, Department of Pharmaceutical Sciences, Recife, Brazil

E.S. Leite Universidade Federal de Pernambuco, Department of Chemical Engineering, Recife, Brazil

G.A.L. Pereira Universidade Federal de Pernambuco, Department of Fundamental Chemistry, Recife, Brazil

A. Fontes Universidade Federal de Pernambuco, Biophysics and Radiobiology Department, Recife, Brazil

B.S. Santos Universidade Federal de Pernambuco, Department of Pharmaceutical Sciences, Recife, Brazil

4.1 Fundamentals of Quantum Dots Nowadays, nanotechnology is a field that stimulates the interest of many research groups, and nanomaterials have become important elements for science and technology. The optical and electronic properties of organic, inorganic, and hybrid materials can be modified when their size is reduced to nanoscale. The correlation of the material properties with size and morphology has become the key for nanotechnology excellence. An emerging group of nanomaterials with these characteristics is constituted by quantum dots (QDs). These nanomaterials have been revealed to be a powerful tool in numerous applications that involve fluorescence, such as electroluminescent displays, optical switching, and photovoltaic cells, and in biomedical applications.1 QDs are colloidal particles of semiconductor materials, with dimensions of approximately 2e10 nm, that have unique photophysical properties; QDs are being thoroughly studied as fluorescent probes in the biomedical sciences and as active components in opto-electronic technologies. When compared with conventional organic fluorescent probes, QDs present significant advantages and complementary characteristics. The main advantages offered by QDs are1b,2: 1. size-tuneable fluorescence emission, which provides access to a wide range of wavelengths by changing only the particle diameter (Fig. 4.1A); Nanocolloids. http://dx.doi.org/10.1016/B978-0-12-801578-0.00004-7 Copyright © 2016 Elsevier Inc. All rights reserved.


132 Chapter 4 (C)

Wavelength (nm)






Wavelength (nm)

Wavelength (nm)

Figure 4.1 Unique optical properties of quantum dots (QDs). (A) Emission spectra as a function of the QD size distribution with the same composition; the colored circles represent particle size. (B) Typical absorption (solid line) and emission spectra (dashed line) of QDs. (C) Absorption (solid line) and emission spectra (dashed line) of a typical organic fluorophore.

2. a broad absorption spectrum, which allows electronic excitation at different wavelengths (Fig. 4.1B); 3. narrower emission bands compared to organic fluorophores, a symmetric luminescence spectrum (full width at half-maximum, w25e40 nm) that can range from the ultraviolet (UV) to the near-infrared (IR) region, and a large Stokes shift; this can be seen in Fig. 4.1B and C, where the absorption and emission bands of QDs and organic fluorophores, respectively, are compared. These allow multicolor imaging avoiding spectral cross-talk, which is more usual be observed with organic dyes; 4. a longer emission lifetime (dozens to hundreds of nanoseconds) when compared to organic fluorophores, allowing, for example, luminescence detection during a longer period and autofluorescence elimination, which has a considerably shorter lifetime; 5. higher brightness (caused by the high fluorescence quantum yield) and great photostability (in general, photodegradation is not observed in a period of several hours) that results in an increased resistance to photobleaching (1000 times higher than organic compounds); 6. an active surface for chemical conjugation. QDs can be conjugated with a variety of organic molecules, becoming nanostructured assemblies (inorganicebiological) that combine the fluorescence properties of QDs with the (bio)chemical functions of the conjugated molecule. QDs are semiconductor nanocrystals that are quantum-confined in all three dimensions. Their three-dimensional (3D) quantum confinement defines changes in optical properties that differ from those of the same material at a macroscopic size (ie, bulk). Particularly for semiconductor materials, the quantum confinement regime occurs between 2 and 10 nm. Briefly, quantum confinement can be explained by the following approach: semiconductors are characterized as having a band gap (Eg) between their valence band (VB) and conduction band (CB), and their characteristic fluorescence is caused by electronic transitions between the two bands. Thus the band gap is the minimal energy required to promote an electron from the VB to the CB, and its magnitude depends on the nature of the semiconductor material.

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When an electron (e) absorbs energy and is excited to the CB, it leaves a hole (hþ) in the VB. During the short period of time that the absorption occurs, the Coulomb interaction between the e and the hþ forces them to bond, and the pair ehþ formed is called an “exciton.”3 This pair is also called a “hydrogen-like species” or an “artificial atom,” and the distance between the e and the hþ is the exciton Bohr radius (aB). When the semiconductor particles become smaller than the exciton Bohr radius, it means that their three dimensions are reduced to a few nanometers. We can say that they are in the quantum confinement regime, and in this case the nanoparticles are called QDs. For example, the exciton Bohr radius (aB) of cadmium selenide (CdSe) and cadmium telluride (CdTe) are approximately 5 and 7 nm, respectively; thus particles with a size smaller than that dimension are considered QDs.4 When going from a macroscopic to a nanosized regime, and as a consequence of quantum confinement, a level discretization on the energy bands, as well as an energetic variation in the band gap, are observed, leading to changes in the physicochemical properties of the QDs when compared with the corresponding bulk material. The scheme in Fig. 4.2

Figure 4.2 Scheme illustrating the quantum confinement effect that occurs in semiconductor materials of a direct band. (A) Distribution of energy levels for the bulk materials in the form of bands. CB, conduction band; Eg, band gap; VB, valence band. (B) Representation of a macroscopic particle and the energy level characteristics of the semiconductor material of a direct band. (CeE) A decrease in the particle size and an increase in the band gap, accompanied by a small discretization of the energy levels close to the VB and CB, are observed as consequence of the quantum confinement.

134 Chapter 4 illustrates this variation. An important consequence of these changes is the modification of the emission wavelength with the particle size. Therefore, QDs produced with the same material, but with different sizes, can present fluorescence emission in different regions of the electromagnetic spectrum, from UV to IR, as represented in Fig. 4.1A. The QD’s emission is proportional to its band gap energy; thus, with decreasing size, a blue shift (higher energy) of a QD’s emission wavelength is observed. Quantitatively speaking, the energy gap between the bands, which determines the fluorescence energy, is inversely proportional to the square of the QD size (Eg f 1/d2).3 The absorption and emission spectra of QDs can provide important information. The position and width of the first maximum of the absorption spectrum are related to the QD’s average size and the nanoparticle size distribution, respectively, and can give an estimation of the colloidal suspension concentration.5 On the other hand, the width of the emission spectrum is related to the presence of crystal defects that result in discrete trapping electronic states between the VB and CB. These electronic states cause a red shift and an enlargement of the emission band and are related to the passivation of the QD’s external layer.2a Usually, a QD’s central semiconductor particle (core) is capped with a layer of another semiconductor material (shell). The QD’s core is responsible for the optical properties (such as absorption and emission), whereas the external layer is used to passivate the QD’s surface (Fig. 4.3). The passivation layer is formed by some monolayers of a second semiconductor and guarantees the physical separation of the core, which is optically



stabilizer core

Figure 4.3 Schematic representation of a functionalized coreeshell quantum dot conjugated with a biomolecule.

Quantum Dots


active, from the surrounding medium, improving its optical properties and reducing chemical degradation and sensitivity to environmental changes such as the presence of oxidative species, oxygen, and pH. Generally, the shell semiconductor material presents a band gap energy higher than the gap energy of the core material.1b,6 The fluorescence quantum yield of the coreeshell system is higher when compared with the fluorescence quantum yield of nonpassivated QDs. This can be explained by the fact that photodegenerated excitons are prevented from being trapped in surface defect energy levels, forcing them to recombine while being confined spatially to the core. This luminescence enhancement is an indication of the formation of the proposed structure, since it is difficult to confirm the existence of such a thin chemical layer (only a few atomic monolayers).2a Several coreeshell systems have been prepared and reported in the literature: such as CdS/Ag2S,7 CdS/ZnS8 CdS/HgS,9 CdSe/ZnS,10 CdSe/CdS,11 CdTe/ CdS,12 CdS/Cd(OH)2,13 and PbSe/PbS.14 QDs are generally constituted of atoms of elements from groups IIeVI (eg, CdS, CdSe, and CdTe) or groups IIIeV (such as InP and InAs) of the periodic table. Semiconductors from these two groups have been studied extensively and can be prepared using colloidal synthesis involving organic or inorganic building blocks, depending on the solvent (organic or aqueous, respectively).15 In colloidal synthesis, several consecutive stages can occur: (1) nucleation from a solution; (2) growth of the crystal nucleus into isolated particles, giving the desired mean size; and (3) treatments after preparation, such as colloidal purification and precipitation according to the size and surface modifications caused by UV light exposition (photoactivation). The common synthesis strategy of colloidal IIeVI QDs starts with a rapid injection of solutions containing species from groups II and VI into another solvent at a high temperature (c.a. 90 C or >200 C for aqueous and organic media, respectively) and with rapid stirring. The solution containing the divalent cations also contains species that coordinate with the surface of the precipitated QDs. The group IIIeV colloidal QDs are more difficult to prepare in colloidal media because of their higher degree of covalency. These systems need to be grown in an inert atmosphere (without the presence of air or water) at elevated temperatures and with longer reaction times.15b,16 In colloidal synthesis, QDs are end-capped with organic or inorganic compounds (ie, surfactants or stabilizers), which maintain the nanocrystals’ separated from each other, preventing agglomeration and precipitation.2a,3 Further reactions may be performed to accomplish the covalent attachment of targeting biomolecules (Fig. 4.3) to their surface for specific biological marking purposes. Traditional methods to prepare QDs generate “sol”-type colloidal systems of solid nanocrystals dispersed in a liquid continuous phase. However, some scientific and

136 Chapter 4 technological applications require the removal of the nanocrystals from the solvent in which they were synthesized. For example, QDs vaporized by spray on metallic surfaces can be used in new efficient solar cells; in this case the solid nanocrystals serve as precursors for a coating of a thin film of nanostructures.

4.2 Applications of Quantum Dots Since the first reports of colloidal QDs in the 1980s, great progress has been made in this research field. Many nanostructured QD-based systems have been applied in several areas ranging from biomedical applications to very modern opto-electronic applications. Colloidal IIeVI and IIIeV QDs are being applied in IR detectors,17 quantum computing,18 telecommunications,19 diodes and lasers,11b,20 solar cells,16 and as fluorescent markers for biological systems.1b,2 The main current research fields and applications of QDs are represented in Fig. 4.4. Some of these applications are presented and briefly discussed in the following sections.

Figure 4.4 Summary of the main research fields and applications of colloidal quantum dots.

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4.2.1 Biomedical Applications In 1998, Bruchez et al.21 and Chan and Nie22 reported independently the first biological applications of QDs. Bruchez et al. stained 3T3 mouse fibroblast cells using CdSe/ZnS coreeshell QDs. They observed that QDs coated with trimethylsilyl propyl urea and acetate groups were found in the cell nucleus, whereas QDs covalently bound to biotin labeled specifically the F-actin filaments. On the other hand, Chan and Nie incubated HeLa cells with nonconjugated CdSe/ZnS QDs and with transferrineQD conjugates. These authors observed that only the transferrineQD conjugates were observed inside the cells and suggested that receptor-mediated endocytosis had occurred. Since then, QD studies and applications have been growing exponentially, and QDs have been used for many applications in biomedical sciences. Because of QDs’ resistance to photobleaching (they can be manipulated even in daylight) and relatively low cytotoxicity, they have also been used as fluorophores for in vivo applications, although their safe use is still debated. Preliminary experiments with near-IR-emitting QDs in animals have shown promising results for the sensitive detection of tumors in live systems.23 QDs become useful sensors for interactions with biological systems (eg, cells) after biocompatibilization through association to specific biomolecules. Bioconjugation can be noncovalent or covalent. Noncovalent bioconjugation can occur by adsorption or electrostatic interactions. Covalent bonding can be obtained between carboxyleamine groups (using carbodiimide conjugation methodologies), amineeamine groups (using aldehydes or maleic anhydrides), or thioleamine groups (using maleic anhydrides).24 However, the bioconjugation process is still a challenge; after this procedure the final assembly needs to maintain its chemical stability and biochemical function. In addition, each biomolecule presents a different size and composition, and thus different bioconjugation protocols are required. QDs as fluorescent labels Interactions of QDs with cells and tissues have been tested in many systems, and there are an increasing number of published papers in this research area. The labeling of biological systems with QDs can be nonspecific, to study QDs’ behavior in the presence of biological systems, or specific, for diagnostic purposes or to understand particular diseases or biological mechanisms. Nonspecific fluorescent probes have unspecific interactions with the biological system; these interactions are usually mediated by electrostatic or hydrophobic interactions between the particle surface and the molecules in suspension, or the particles’ attachment to the cellular membrane.25 Although the first successful attempts at using QDs as fluorescent probes in 1998 showed specific targeting, the majority of reports published in

138 Chapter 4 the 1990s and early 2000s reported the use of these systems as nonspecific labels. The nonspecific labeling gave preliminary information about the interaction between these nanoparticles and the biological systems and, most important, the optical properties of QDs in a biological environment. Nonconjugated QDs have been used to study the internalization process used by living cells and interactions with intracellular structures. The studies showed that the internalization process depends on the QD size, surface functionalization, and charge; it seems that endocytosis is the major pathway of QD uptake by cells.26 Some authors reported the encapsulation of QDs as an alternative strategy to deliver QDs inside cells.27 This work opened new perspectives for the intracellular delivery of QDs conjugated with biomolecules to label specific sites in the cell cytosol. This will, for example, allow the monitoring of drug delivery and paths of cellular signaling. QDs have been studied as specific fluorescent markers for biological systems after conjugation with biomolecules such as proteins, antibodies, and nucleic acids.1b,28 For example, QDs were conjugated with monoclonal anti-A antibody to label the membrane of red blood cells,13 with HER2 monoclonal antibody for gastric cancer imaging and treatment,29 and with arginineeglycineeaspartic acid peptide30 and epidermal growth factor antibody31 for the diagnosis of glioblastoma brain tumors. Elucidation of the structures and function of glycoconjugates on the cellular surface is important for the understanding of many biological processes; these molecules can be used to identify differentiation, cell adhesion, and the immune response. Experimental studies have shown that tumor development can be associated with a variety of glycosylation patterns in altered cells.32 CdTe QDs conjugated with concanavalin A (ConA) by adsorption, and covalently with Ulex europaeus I (UEA-I) were used to detect a-D-glucose/mannose and L-fucose residues, respectively, in normal human breast tissue and in benign (fibroadenoma) and malignantly transformed breast tissues (invasive ductal carcinoma). These authors observed distinct staining patterns using the ConA or UEA-I conjugates, showing a difference in a-D-glucose/mannose and L-fucose residue expression and distribution in these tissues. ConA conjugates strongly labeled the stroma and moderately labeled the ductal cells, and UEA-I conjugates strongly labeled the ductal cells and weakly labeled the stroma. The results obtained show that the conjugated QDelectins can be used as potential molecular probes; are useful in obtaining information about cellular structures, molecular content, and tumors; help to elucidate biological processes; and open new possibilities in medical diagnostics.32b QDeConA conjugates have also been used in the labeling of glucose/mannose residues in Candida albicans12e,33 (Fig. 4.5). These conjugates labeled the cell wall specifically, whereas nonconjugated QDs did not label the cells. Thus these results open new

Quantum Dots


Figure 4.5 (A) 3D reconstruction of C. albicans biofilm labeled by QD-ConA. The arrows pointed to denser saccharides accumulations. (B) C. albicans cells suspentions labeled with QDs-ConA, hyphae (arrow) and yeast cells (asterisk). Scale bar ¼ 10 mm.

possibilities to label saccharide-rich structures and to study the membrane carbohydrates in microorganisms. One example of QD application in vivo is the work by Chen et al.34 They conjugated QDs with folic acid and used them for in vivo active tumor targeting studies in nude mice. They observed that after 4 h the tumor had good fluorescence contrast compared with the other organs, showing that the QDefolic acid conjugates specifically targeted the tumor. Because of the clinical potential of QD bioconjugates, the actual tendency is to develop and optimize QD bioconjugation methodologies to label specific targets outside and inside cells. Thus, it will be possible the elucidation of several biological processes using QDs as specific labels, sensible and versatile both in diagnostic as in monitoring therapy.35 To achieve this, new methodologies both for QD conjugation with biomolecules and for the preparation of other types of QDs are needed, as are new strategies for cellular staining and for the delivery of QDs inside cells.35a QDs in photodynamic therapy Photodynamic therapy (PDT) is a treatment based on the dye-sensitizer photo-oxidation of target cells or tissues. PDT is considered a promising clinical treatment procedure for several diseases, such as oral lesions and bacterial biofilms,36 microbial infections,37 cancers, and superficial tumors (such as esophageal tumors, prostate tumors, and melanoma).38 The basic principle of PDT is that the photosensitizer (PS), after being photoactivated, promotes energy or charge transfer for molecular oxygen (or molecules containing

140 Chapter 4 oxygen) present in the environment, forming reactive oxygen species (ROS) such as superoxide, hydroxide, oxygen peroxide, and singlet oxygen, which react immediately with intracellular components, causing damage and cell death.39 In 2003 Samia et al.40 presented the first attempt at using QDs as photosensitizers for ROS production. They observed that the direct photoactivation of QDs produce singlet molecular oxygen (1O2) through energy transfer from QDs to triplet molecular oxygen (3O2). However, the efficiency of energy transfer was low. Samia et al.41 and Clarke et al.42 observed that the continuous energy transfer from QDs allows the use of these nanomaterials for PDT purposes. Based on the high light absorption coefficients, narrow tuneable emission bands, and high quantum yields of QDs, Samia et al.40 proposed a conjugated PS-QD model in which the QD absorbs light, then acts as a donor of energy to the PS via Fo¨rster resonance energy transfer (FRET) mechanisms. The first studies of QDs in PDT were followed by a growing number of reports showing the use of QDs conjugated to PSs, or at least in the presence of PSs, for photoinactivation purposes.43 QDs can act as energy donors for conventional PSs through FRET mechanisms or by direct energy or charge transfer to oxygen molecules, forming ROS or singlet oxygen.44 Fig. 4.6 shows a schematic representation of the cell death mechanism by PDT using free QDs and QDs conjugated with PSs.

Figure 4.6 Schematic representation of quantum dots (QDs) acting as photosensitizers (PSs) in photodynamic therapy. Three possibilities are outlined: (1) reactive oxygen species (ROS) ¨rster resonance energy transfer generated via light emission in bare QDs; (2) ROS generated by Fo (FRET) mechanisms in QDs associated to PSs; and (3) charge transfer from bare QDs after cellular photostimulation.

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The demonstration of the potential for QDs to be used in PDT increased the interest in their conjugation with PSs for photodynamic efficiency evaluation.43a,43b,45 In ROS production there is not an exclusive mechanism of light deactivation within the QDs. For instance, charge and energy transfer from QDs to PSs was observed by Rakovich et al.,46 associating QDs to the PS methylene blue (MB) (QDeMB). According to these authors, the QDs’ luminescence is quenched by charge transfer, although FRET can also occur if there is sufficient overlap between the emission of the QD and the absorption bands of the MB. Rakovich et al. also investigated the effect of adding QDeMB conjugates on the growth of cancerous cells (HepG2 and HeLa) under UV excitation; they observed an increase in the cell-killing efficiency of the QDeMB conjugate. Similar observations were reported by several research groups.43a,43b,45 The efficiency of FRET depends on several factors, including the size and surface properties of the QDs,47 the number of PS molecules per QD,48 and the energy overlap between the emission spectrum of QDs and the absorption spectrum of PS. In a great number of reports the conjugation of QDs to PSs lower the photoinactivation of the PS; authors attributed this to several energy-wasting processes such as self-quenching of the PS on the QD shell, photo-induced charge transfer processes, and competition of ROS production with the self-oxidation of the QDs’ surfaces.43e,44a,49 Although a reasonable number of studies have already been performed, the short efficiency of PDT in biological environments and the low ROS production using QDs show that further investigation is still needed.50 There are some unanswered key questions in applying these systems in PDT, and other studies should be performed to evaluate the in vivo efficiency and safety of these nanoparticles, both free and conjugated to other molecules, in clinical PDT applications. Paramagnetic and/or superparamagnetic QDs as bimodal probes In the past decade QDs associated to other compounds that possess distinctive physicochemical properties have been developed, generating multifunctional systems. To be used as bimodal probes for optical and magnetic resonance imaging (MRI), QDs can be associated with paramagnetic and/or superparamagnetic compounds that induce an enhancement in the contrast of the obtained images. MRI is one of the most powerful diagnostic techniques developed to date. It is based in nuclear magnetic resonance (NMR) and is a noninvasive technique that produces images with anatomical detail that is able to infer the diagnosis of many diseases.51 MRI makes use of NMR signals of the hydrogen atoms (1H) from the water molecules that exist in the body. The 1H in water molecules should be monitored mainly because of the natural abundance of water in living organisms and the high sensitivity of 1H to NMR. Since the water molecules (or, better, the 1H atoms present in the water molecules) are especially sensible to the magnetic field used in this technique, MRI is very efficient in revealing

142 Chapter 4 differences in the water composition (and its mobility) of different body tissues. This is particularly important in tumor detection and to verify the existence of anomalies in the soft tissues of the body, such as the brain, spinal cord, and heart. This differentiation in the observed images of normal tissue and those that have some morphologic or metabolic alteration is only possible because of the variation in the nuclear magnetic relaxation times (T1 and T2) of the proton water molecules present in the tissues.52 To obtain a contrast enhancement in the generated image, contrast agents (CAs) are widely used in clinical procedures. Paramagnetic compounds cause a decrease in relaxation times T1 and/or T2, thereby enhancing the contrast of the imaging.53 Despite the high spatial resolution of the MRI technique,54 the study of molecular events at a cellular level is still a challenge because it requires a high local concentration of CAs (105 mol/L) to achieve an observable contrast increase. One approach that has been studied to overcome this limitation is the use of nanoparticle-based CAs, which may be able to increase the local concentration of paramagnetic ions in a more efficient way.53,55 A variety of nanosystems containing Gd3þ ions have been described, such as polymers,56 dendrimers,57 proteins,58 micelles,59 liposomes,60 and carbon nanotubes,61 among others.62 The design of new synthetic routes for the association of nanometric systems with different functionalities has resulted in new bimodal probes. Superparamagnetic and paramagnetic compounds such as iron oxide63 and Gd3þ ion chelates64 have been chemically associated to QDs. Moreover, QDs with associated ions in their structures have been prepared and tested.65 The schematic representation in Fig. 4.7 shows two possible approaches that can be used to obtain magnetic and optical QD-based bimodal probes. Mulder et al.,66 for instance, used paramagnetic CdSe/ZnS nanoparticles coated with a mixture of PEGylated and paramagnetic lipids to study tumor vasculature formation (angiogenesis). The paramagnetic lipid contains the Gdediethylenetriamine pentaacetic acid complex, and the QDemicelle systems were functionalized by a covalent chemical

Figure 4.7 Schematic representation of two quantum dot (QD)ebased bimodal probes containing superparamagnetic nanoparticles (MNPs) (A) and paramagnetic chelates (B).

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bond to the cyclic arginineeglycineeaspartic acid peptide, which recognizes the aVb3 integrin and is used to detect angiogenesis. These probes were tested in vitro and showed promising relaxivities (r1 w 14.4 mM1 s1, at 6.3T) for high-contrast image acquisition. Another example is the preparation of manganese (Mn)-doped ZnSe QDs (ZnSe:Mn) by Sharma et al.67 These QDs were obtained at a small size (6.5 nm) with 3.2% Mn in the structure. They presented emission at 585 nm, with a fluorescence quantum yield of 18% in water, and an observable relaxivity (r1 w 2.95 mM1 s1, at 3T) for MRI. This novel class of bimodal systems has several challenges still to be overcome, including their preparation as well as their effective utilization. Specific challenges are listed below68: 1. The toxicity and the precursor reagent’s influence should be minimized by multistep synthesis and purification in each step of the process. 2. QDs fluorescence should not be reduced during their conjugation; thus a stable passivation layer needs to be provided. 3. Minimization of the particle’s aggregation in aqueous solutions should be guaranteed, as well as their easy re-dispersion, maintaining their colloidal characteristics. The association of optical imaging techniques and MRI using bimodal systems offers a more accurate combination of imaging modalities for nanomedicine research and clinical applications. QDs have also been used in the development of other bimodal imaging probes for optical/positron emission tomography and optical/computed tomography.69

4.2.2 Analytical Applications of QDs: Sensing and Biosensing The potential for QDs in the development of chemical sensors and biosensors has been studied by several research groups.70 Because of the semiconductor and optical properties of QDs, they can be used both separately and simultaneously in optical and electrochemical sensors.71 QDs present attractive properties for use in analytical sensors when compared with other nanoparticles, such as70: 1. 2. 3. 4.

smaller size that can lead to an increase in the surface area of the electrode simpler and cleaner synthesis a quasi-isotropic form that enables organized deposition on the electrode surface functional groups (amine and/or carboxylic acid) already exist on the surface, allowing their conjugation to biomolecules either by electrostatic interaction or covalent bonding, facilitating their application

QDs have been applied in optical sensors using the FRET phenomenon,72 which depends on the distance between the donor and acceptor molecules (needs to be <5 nm) and the spectral overlap between the emission band of the donor and the absorption band of

144 Chapter 4 the acceptor. Thus, with respect to an immunosensor, the FRET effect occurs only when the antigen and the antibody are linked, indicating the presence of the analyte, and the observed fluorescence signal is proportional to its amount. Therefore the optical properties of QDs are advantageous for FRET, especially their broad absorption spectrum. Another key point is that QDs enable the presence of several acceptors at their surface, increasing the FRET efficiency and consequently the biosensor efficiency. Because QDs are semiconductors, they can facilitate electron transfer and improve the catalytic response in electrochemical sensors. In this context QDs have been used in amperometric and impedimetric biosensors.73 Another advantage of using QDs in electrochemical biosensors is that they may facilitate electron transfer that is hindered after the formation of the self-assembled monolayers, for example.74 Despite the established use of QDs in optical biosensors, the electrochemical area is still under development.75 Biosensors are analytical devices used to measure specimens and are associated to (1) a biological receptor element, which recognizes the analyte; (2) a transducer element, which turns the bonding into a signal that can be measured; and (3) electronic components, which amplify and allow visualization of the signal. The application of nanostructured materials such as carbon nanotubes and metallic nanoparticles (gold, silver, and platinum) in biosensors brought several advantages related to detection speed and sensitivity, in addition to increasing the specificity of detection. The pioneering applications of QDs in optical biosensors based in FRET were developed by Willard et al.10b They showed that the specific bonding between biotinylated bovine serum albumin and streptavidin labeled with tetramethylrhodamine can be quantitatively correlated to fluorescence by the FRET effect, where the bonding of biotinylated bovine serum albumin and tetramethylrhodamine-labeled streptavidin leads to a change in the fluorescence emission in response to the concentration variation (16e160 nmol/L) (Fig. 4.8). Since then, several QDs functionalized with different ligands have been used in biosensors, taking advantage of QDs optical properties.71a,72 Based on the FRET effect, QDs have been used for the detection of many biomolecules, such as glucose,76 antigeneantibody-specific bonding,77 proteins,78 enzymes,79 nucleic acid hybridization,80 pathogens,81 and toxins.82 The application of QDs as electrochemical biosensors has also been studied. Hansen et al.83 used CdS QDs for the detection of lysozyme and PbS QDs for the detection of thrombin by utilizing aptamers. Pinwattana et al.10c developed an electrochemical imunosensor based on CdSe/ZnS QDs for the detection of bovine serum albumin. The QDs were used to amplify the electrochemical signals, and the authors observed

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Aceptor Emission

Figure 4.8 Applications of quantum dots (QDs) in biosensors based in QDs with a core of CdSe and a shell ¨rster resonance energy transfer (FRET) with streptavidin-rhodamine. bBSA, of ZnS for Fo biotinylated bovine serum albumin; TMR, tetramethylrhodamine.

that the measured current was proportional to the concentration of the bovine serum albumin. As an example, Kja¨llman et al.84 prepared and studied the sensibility and selectivity of an electrochemical DNA sensor based on QDs and self-assembled monolayers. The hybridization step was detected by electrochemical impedance measurements. The sensor showed different responses, depending on the probe density, regarding changes in the charge transfer resistance and the impedance at the electrode interface. QDs have also been used as electrochemiluminescent biosensors, using the combination of optical and semiconducting properties to enhance the charge transfer process. One example is the work using CdSe QDs and thrombin mobilized by aptamers on an indium and titanium oxide surface, using electrochemical methods (electric properties of QDs) to measure fluorescence intensity (optical properties of QDs), showing results similar to those achieved by traditional techniques.85 In addition to their application as immobilized probes in biosensors, colloidal QDs are being studied as ultrasensitive luminescent sensors for ions and small molecules. These sensors take advantage of the sensitivity of QDs’ fluorescence to changes in their surface states. Thus any chemical or physical interaction between QDs’ surfaces and chemical species can result in changes in their optical properties, which affect the radiative electronehole recombination, either improving or quenching QDs’ luminescence.70,86 QDs functionalized in an appropriate way could be used to detect by fluorescence certain metallic ions in water, such Cu(II), Ag(II), Fe(III), and Zn(II). They have also been studied as optical nanosensors for pesticides and food toxicants.70,86b,87

146 Chapter 4 The first use of QDs as chemical sensors in water was reported by Chen and Rosenzweig.88 They prepared CdS QDs capped with polyphosphate, cysteine, and thioglycerol, and studied their interaction with copper and zinc ions. Their study found that polyphosphate-coated QDs were nonselective toward copper and zinc ions, whereas CdS capped with cysteine presented selectivity to zinc ions, and CdSethioglycerol showed selectivity and high sensitivity toward copper ions. QDs present great potential for use as optical chemical sensors and biosensors, and have become a new tool for analytical sciences. However, the challenge in the near future is the synthesis of QDs with lower toxicity, higher quantum yields, and better photostability to be incorporated or used as chemical sensors or biosensors.

4.2.3 Opto-electronic Applications Aqueous and nonaqueous suspensions of semiconductor nanocrystals can be printed or coated onto different glass, plastic, and metallic substrates, bringing about a new scenario of low-cost opto-electronic devices.89 Compared with large-scale vacuum crystal growth procedures (eg, molecular beam epitaxy and metalorganic chemical vapor deposition), colloidal materials can be fabricated and processed via low-cost, solution-based techniques that are compatible with lightweight, flexible substrates.90 The unique opto-electronic properties of QDsdnamely, an Eg greater than the thermal carrier energies, which inhibit thermal depopulation of the lowest energy band, resulting in a low, temperature-insensitive optical-gain thresholddcombined with the narrow emission bands and high-temperature stability, opened up a great variety of potential applications for QDs as active semiconductor materials in photonic devices. It is worthwhile to mention the rapid development in recent years of QD-based solar cells, photodetectors, and light-emitting diodes. Among several research ideas and applications, the most relevant technological developments are the following: • • • • • • • • • •

down-converters in backlit displays91 light-emitting diodes92 optical fiber amplifiers low-threshold lasers93 photodetectors94 switching optical selectors containing QDs self-assembled photonic arrays photovoltaic cells95 optical temperature probes high-speed signal-processing filters96

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4.3 Scaling-up the Synthesis of Quantum Dots Nowadays, many companies around the world produce and sell QDs, providing standard specifications such as the average particle size, the optimal excitation wavelength for obtaining maximum fluorescence, and the maximum emission wavelength. Some QDs are very common, such as CdSe, CdS, and CdTe. Others have their characteristics improved by a core/shell composition, such as CdSe/ZnS and CdTe/CdS. Some QDs are less common, such as the cadmium-free InP/ZnS or the alloy combination CdSeS/ZnS formed by two different kinds of semiconductors mixed in the same solid crystal lattice. In general, a commercial sample of 5 mL of colloidal QDs costs more than the same product prepared in research laboratories. These QDs are sold preferably dispersed in organic media, rather than water, to guarantee quality and to maintain the integrity of the nanocrystals, preventing oxidation, photobleaching, and other types of degradation. QDs are not usually sold in the noncolloidal form as pure nanoparticle solids, because this would cause enormous risk of inhalation for users. The liquid-phase medium in the colloidal samples keeps QDs nonvolatile by intermolecular interaction and therefore makes them safer to handle.97 The expansion from laboratory synthesis to an industrial process is known in chemical engineering as “scale-up.” Therefore it is important to remark that there is no easy-toaccess literature about industrial processes for QD production because either it is an industrial secret or there may not yet be a general technology available. One can enumerate possible advantages and challenges in the large-scale production of QDs. An advantage of QD experimental synthesis, at least for group IIeVI, is that the preparation procedures are similar. Thus, to obtain QDs of different sizes or chemical compositions, it is sufficient to make small changes in the synthetic routes. For example, synthesis using different reaction times, temperatures, and precursors results in QDs with different size distributions and consequently with different emission wavelengths. This enables the production of different-sized QDs that can be considered for different applications. The experimental apparatus used in the classical synthesis of CdSe QDs, for example, can be scaled up with rather simple equipment when compared with other complex industrial processes. The synthesis would probably require high-pressure reactors, thermocouples for temperature control, jackets to maintain a stable temperature in the reactors without draining energy, valves for the generated vapors, mixing tanks, and other equipment for the peculiarities of each synthesis. It is noteworthy that the same industrial plant could, in principle, be used to obtain different QDs. Every scale-up, from laboratory synthesis to industrial scale, involves many challenges, and QDs are no exception. A difficulty for the industrial production of colloidal QDs is

148 Chapter 4 that it involves colloidal self-assembly from precursors that could impair product repeatability and reproducibility. It is difficult to know in advance whether the proportional increase in the amount of precursors may cause greater size dispersion, larger lattice defects, and larger surface defects in the nanocrystals. Colloidal stability may also be compromised in large-scale QD production; to solve this problem, the amount of stabilizing agents needs to be adjusted appropriately. However, processes carried out in an aqueous medium probably would present fewer difficulties than those carried out in an organic medium. Moreover, processes in organic media are more expensive, toxic, and hazardous because the solvents and reagents used can be pyrophoric. In general, industries prefer to use water as a dispersion medium rather than an organic solvent, because of issues related to cost, future disposal, and other environmental issues. Finally, another challenge in the manufacturing of QDs on an industrial scale is overall safety compliance.

4.4 Nanosafety Issues Many nanomaterials such as carbon nanotubes and gold nanoparticles have been incorporated in the manufacture of products since ancient times, even if revealed now only through advanced characterization techniques. One example is the Damascus Sabre dating back to the Middle Ages, which probably contains traces of structures that are very similar to carbon nanotubes.98 As far as we know, however, QDs are a type of engineered nanocolloid obtained exclusively by human production for only the past 30 years, and its presence in nature from another source has never been detected.99 The commercialization of QDs requires further studies of their toxicity and interference in humans and in the environment. In addition, until now there is none appropriate legislation for QDs or other inorganic nanomaterial products with respect to their use by researchers, industry workers, or final users. This means that every company that sells QDs, incorporated or not into other products, must answer for their safety. However, there is already a global concern about the safety of nanomaterials and several laboratories have studied the risks of its inhalation and skin contact.97,100 Meanwhile, considering that cadmium is a heavy metal, cadmium-free QDs have been widely investigated by researchers who seek to incorporate the concept of “green” chemistry in research related to nanotechnology.101

4.5 Conclusions and Outlook In this decade we commemorate the 30th anniversary of the first colloidal synthetic procedures and modeling reports of QDs. Since then, several new methods of preparation have been developed, expanding QD use to a great number of different areas. This chapter presented many applications of these systems in biomedicine and other technological

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fields. Throughout these years, there has been exponential growth in the applications of QDs, and new applications and new systems will certainly emerge soon. Among these new ideas, the development of systems aimed at theranostics (diagnostic probes also applied in therapy) are being highlighted. In science, a 30-year period is a short time, and there is still much to discuss and optimize related to QD preparation procedures, with the possibility of expansion to large-scale production and surface modification for more specific and precise applications.

Acknowledgments The authors are grateful to the members of the research group Nanotecnologia Biome´dica/UFPE for useful discussions; to Beatriz Saegesser Santos and Pedro Barroca for the drawings; and to Fundac¸a˜o de Amparo a Cieˆncia e Tecnologia do Estado de Pernambuco (FACEPE), Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (CNPq), Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de Nı´vel Superior (CAPES), L’OREAL, UNESCO, Philips, Academia Brasileira de Cieˆncias, Instituto Nacional de Cieˆncia e Tecnologia de Fotoˆnica (INCT-INFo), and the Universidade Federal de Pernambuco (UFPE).

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