**2. Quantum dots in medical science**

Quantum dots (QDs) have aroused much interest in recent years, especially in view of their potential applications in biology and medicine [18]. This heterogeneous class of engineered nanoparticles that are both semiconductors and fluorophores is rapidly emerging as an important type of nanoparticles with numerous potential applications in medicine [19]. QDs are semiconductor inorganic nanomaterials ranging from 1–10 nm. They contain elements found in groups II–IV (e.g., CdSe, CdTe, CdS, and ZnSe) or III–V (eg, InP and InAs) of the periodic table. QDs have fluorescent properties that offer superior features to conventional organic dyes, including high quantum yield, broad absorption, and narrow emission spectra (Figure 1). QDs are more photostable than conventional fluorophores; e.g., it has been reported that, under the same excitation conditions, 90% of the fluorescence of a normal organic dye fades within 1 minute, whereas the fluorescence of QDs remains intact even after 30 minute or more [20].

times. It has been proposed that this feature of QDs could be suppressed by "passivating" the QDs' surface with thiol moieties, polymers, or by using the QDs in free suspension. A standard nomenclature is generally utilized to describe the component parts of various QDs: Core/Shell or Core/Shell-Conjugate. For example, a QD with a cadmium-sulfide core and a maltodextrin shell which has been protein conjugated would be designated as CdS/protein [23]. As fluorescent particles, quantum dots can be detected and tracked with the same approach developed for organic fluorophores. All the technical development has been directly transposed to QD imaging and tracking. Biomedical applications exploit the fluorescent properties of QDs, particularly their advantage over traditional organic dyes for both diagnostic and clinical applications. The *in vitro* biomedical and diagnostic applica‐ tions of QDs include such techniques as the multicolor fluorescent labeling of cell surface molecules and cellular proteins in microscopy and other applications, detection of patho‐ gens and toxins, DNA and RNA technologies, and fluorescence resonance energy transfer. QDs are also being explored for use in whole-body *in vivo* imaging of normal and tumor tissues. QDs may also find use in therapeutic applications such as targeted drug delivery,

**Figure 1.** Spectrum and basic structure of quantum dots. (a) Emission spectra of quantum dots; (b) Schematic struc‐

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photodynamic therapy, and drug discovery [24].

ture of quantum dots and conjugation to biomolecules.

In terms of their basic structure, QDs consist of an inorganic core, an inorganic shell and aqueous organic coating. The size of the inorganic core determines the wavelength (color) of light emitted following excitation (Figure 1). The inorganic shell is responsible for increas‐ ing the photostability and luminescent properties of the QDs [21]. The photo stability of the inorganic shell has allowed QDs to be used as probes for imaging cells and tissues over long spans of time. While there are many useful features to QDs, there are also a number of issues related to their structure and function [22]. One of the most problematic is a phenomenon known as "blinking". This is the term used to describe the alternation between the lightemitting and –non-emitting state of the QD. This factor limits the number of photons that can be detected in a given time period and it also contributes to unpredictable photon arrival

Pharmacokinetic Properties and Safety of Cadmium-Containing Quantum Dots as Drug Delivery Systems http://dx.doi.org/10.5772/58553 473

integration and the ability to generate microenvironment parts that are particularly conducive to tissue regeneration. The main difficulty lies in finding suitable materials that allow for the fabrication of structures that remain active while the affected organ regenerates the damaged area [17]. Some of the materials that are being used include carbon nanotubes, the nanoparticles as hydroxyapatite or zirconia particles, biodegradable polymer nanofibers, nanocomposites, etc. One of the greatest achievements is the development of biomaterials with the ability to mimic the extracellular matrix, forming a real support identical to what appears naturally in cells and on which stem cells can be grown for subsequent implant in patients to repair or

The enormous advances in nanotechnology during the past decades have allowed for sub‐ stantial developments in the field of health sciences. The systems and methods described are only selected examples of the enormous activity that is taking place in thousands of laborato‐ ries around the world to improve health and quality of life across the whole of society. In the present chapter, we discuss the pharmacokinetic properties and safety of cadmium-containing

Quantum dots (QDs) have aroused much interest in recent years, especially in view of their potential applications in biology and medicine [18]. This heterogeneous class of engineered nanoparticles that are both semiconductors and fluorophores is rapidly emerging as an important type of nanoparticles with numerous potential applications in medicine [19]. QDs are semiconductor inorganic nanomaterials ranging from 1–10 nm. They contain elements found in groups II–IV (e.g., CdSe, CdTe, CdS, and ZnSe) or III–V (eg, InP and InAs) of the periodic table. QDs have fluorescent properties that offer superior features to conventional organic dyes, including high quantum yield, broad absorption, and narrow emission spectra (Figure 1). QDs are more photostable than conventional fluorophores; e.g., it has been reported that, under the same excitation conditions, 90% of the fluorescence of a normal organic dye fades within 1 minute, whereas the fluorescence of QDs remains intact even after 30 minute

In terms of their basic structure, QDs consist of an inorganic core, an inorganic shell and aqueous organic coating. The size of the inorganic core determines the wavelength (color) of light emitted following excitation (Figure 1). The inorganic shell is responsible for increas‐ ing the photostability and luminescent properties of the QDs [21]. The photo stability of the inorganic shell has allowed QDs to be used as probes for imaging cells and tissues over long spans of time. While there are many useful features to QDs, there are also a number of issues related to their structure and function [22]. One of the most problematic is a phenomenon known as "blinking". This is the term used to describe the alternation between the lightemitting and –non-emitting state of the QD. This factor limits the number of photons that can be detected in a given time period and it also contributes to unpredictable photon arrival

quantum dots as tools for diagnosis and drug delivery systems.

**2. Quantum dots in medical science**

replace damaged organs.

472 Application of Nanotechnology in Drug Delivery

or more [20].

**Figure 1.** Spectrum and basic structure of quantum dots. (a) Emission spectra of quantum dots; (b) Schematic struc‐ ture of quantum dots and conjugation to biomolecules.

times. It has been proposed that this feature of QDs could be suppressed by "passivating" the QDs' surface with thiol moieties, polymers, or by using the QDs in free suspension. A standard nomenclature is generally utilized to describe the component parts of various QDs: Core/Shell or Core/Shell-Conjugate. For example, a QD with a cadmium-sulfide core and a maltodextrin shell which has been protein conjugated would be designated as CdS/protein [23]. As fluorescent particles, quantum dots can be detected and tracked with the same approach developed for organic fluorophores. All the technical development has been directly transposed to QD imaging and tracking. Biomedical applications exploit the fluorescent properties of QDs, particularly their advantage over traditional organic dyes for both diagnostic and clinical applications. The *in vitro* biomedical and diagnostic applica‐ tions of QDs include such techniques as the multicolor fluorescent labeling of cell surface molecules and cellular proteins in microscopy and other applications, detection of patho‐ gens and toxins, DNA and RNA technologies, and fluorescence resonance energy transfer. QDs are also being explored for use in whole-body *in vivo* imaging of normal and tumor tissues. QDs may also find use in therapeutic applications such as targeted drug delivery, photodynamic therapy, and drug discovery [24].

### **3. Cadmium-containing quantum dots**

Different results by various research groups indicate that cadmium (in group III–V) is extremely toxic if allowed to leach into the environment and this material also has DNAdamaging properties [25]. Other studies have shown that using cadmium in the cellular environment may lead to the formation of reactive oxygen species, resulting in cell death [26, 27]. The stability of groups III–V is known to be due to the presence of covalent rather than ionic bonding. The most optically suitable emitting 'core' materials have been cadmium-based materials. Cadmium selenide, Cadmium sulfide or Cadmium telluride particles provided bright emission across the visible and near infrared regions of the electromagnetic spectrum [28]. Questions have arisen regarding the suitability of cadmium-containing materials as biological labels. Other problematic factors include the suitability of the capping agents, the retention of particles over a certain size, biological magnification and, importantly, the breakdown and decomposition products of these inorganic materials. QDs are notoriously labile and the identity and ultimate destination of the inorganic decomposition products remains unclear. Despite this, cadmium-containing quantum dots provide a genuine advance in medical imaging and the numerous problems involving these particles are almost imme‐ diately dispelled if one wishes to image and explore fixed cells [29, 30].

and CdSe/ZnS quantum dots, either coated with mercaptopropionic acid (MPA), embedded in a silica shell or embedded in an amphiphilic polymer shell [41]. They found that the majority of the nanoparticles were ingested into the cells and were stored in vesicles around the nucleus, irrespective of the surface coating. We have previously synthesized CdS nanoparticles coated with maltodextrin polymer, and our results revealed that CdS-MD nanoparticles produced distinct dose-dependent effects (Figure 2) [42]. It is clear from this and other studies that the surface coating is related to the toxicity experienced by cells, which affects the level of toxic material released from the nanoparticles. Other studies have shown that different cell types

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**Figure 2.** CdS/maltodextrin quantum dots. (a) Schematic structure of CdS/maltodextrin quantum dots; (b) Characteri‐ zation of different sized CdS/MD quantum dots using TEM; (c) Spectra of CdS/MD quantum dots, the maximum lumi‐ nescence of which is a wavelength of 520 nm (CdS/MD520); (d) HepG2 cells observed under fluorescent microscopy

Biocompatibility is a word that is used extensively in biomaterials science. The incorporation of QDs into biological systems often requires strategies for the manipulation of the ligands bound to the surface of the QDs surface in order to make them water-soluble and biocompat‐

**4. Biocompatibility and functionalization of cadmium-containing**

have varying thresholds for quantum dot-induced toxicity.

at (x40) magnification.

**quantum dots**

Cadmium, which is the main component in the majority of quantum dots, is known to be acutely and chronically toxic to cells and organisms. In cells, it is taken into calcium membrane channels, where it accumulates [31]. Cadmium inhibits the synthesis of DNA, RNA and proteins, as well as breaking up DNA strands and mutating chromosomes [32]. On a cellular level, cadmium induces oxidative stress by depletion of endogenous antioxidants such as glutathione [33], as well as mitochondrial damage [34]. Cadmium nanoparticles exposure can lead to disturbances in cellular homeostatic mechanisms, resulting either in adaptive cellular responses or cell death. Cell death can occur either through an abrupt process named necrosis or a tightly regulated or programmed process (apoptosis and autophagy) [35]. Its toxicity is mainly associated with liver and kidney injury, osteoporosis and neurological dysfunctions at the level of living organisms. The toxic ions are commonly thought to be released from quantum dots when the surface of the nanoparticle is oxidized and early reports on the inclusion of simple quantum dots in bacteria support this [36]

Protecting the core can, to some degree, control toxicity related to cadmium leakage. However, the change in the physicochemical and structural properties of engineered quantum dots could be responsible for a number of material interactions that could also have toxicological effects [37, 38]. However, encapsulation is not simple and it has been reported that quantum dots have displayed toxicity even with well-protected cores. Recently, polymers that can act as coordination sites for cadmium ion aggregation have protected semiconductor nanoparticles. CdS nanoparticles protected with starch and, in particular, amylose, form a wide range of inclusion complexes for numerous guest molecules [39]. Soluble starch added during the synthesis has been used as a capping agent in the synthesis of CdS and CdSe nanoparticles, resulting in well-controlled and uniform particle sizes of cadmium-rich nanoparticles [40]. Early studies attempted to quantitatively determine values for the onset of cytotoxicity in CdSe and CdSe/ZnS quantum dots, either coated with mercaptopropionic acid (MPA), embedded in a silica shell or embedded in an amphiphilic polymer shell [41]. They found that the majority of the nanoparticles were ingested into the cells and were stored in vesicles around the nucleus, irrespective of the surface coating. We have previously synthesized CdS nanoparticles coated with maltodextrin polymer, and our results revealed that CdS-MD nanoparticles produced distinct dose-dependent effects (Figure 2) [42]. It is clear from this and other studies that the surface coating is related to the toxicity experienced by cells, which affects the level of toxic material released from the nanoparticles. Other studies have shown that different cell types have varying thresholds for quantum dot-induced toxicity.

**3. Cadmium-containing quantum dots**

474 Application of Nanotechnology in Drug Delivery

Different results by various research groups indicate that cadmium (in group III–V) is extremely toxic if allowed to leach into the environment and this material also has DNAdamaging properties [25]. Other studies have shown that using cadmium in the cellular environment may lead to the formation of reactive oxygen species, resulting in cell death [26, 27]. The stability of groups III–V is known to be due to the presence of covalent rather than ionic bonding. The most optically suitable emitting 'core' materials have been cadmium-based materials. Cadmium selenide, Cadmium sulfide or Cadmium telluride particles provided bright emission across the visible and near infrared regions of the electromagnetic spectrum [28]. Questions have arisen regarding the suitability of cadmium-containing materials as biological labels. Other problematic factors include the suitability of the capping agents, the retention of particles over a certain size, biological magnification and, importantly, the breakdown and decomposition products of these inorganic materials. QDs are notoriously labile and the identity and ultimate destination of the inorganic decomposition products remains unclear. Despite this, cadmium-containing quantum dots provide a genuine advance in medical imaging and the numerous problems involving these particles are almost imme‐

Cadmium, which is the main component in the majority of quantum dots, is known to be acutely and chronically toxic to cells and organisms. In cells, it is taken into calcium membrane channels, where it accumulates [31]. Cadmium inhibits the synthesis of DNA, RNA and proteins, as well as breaking up DNA strands and mutating chromosomes [32]. On a cellular level, cadmium induces oxidative stress by depletion of endogenous antioxidants such as glutathione [33], as well as mitochondrial damage [34]. Cadmium nanoparticles exposure can lead to disturbances in cellular homeostatic mechanisms, resulting either in adaptive cellular responses or cell death. Cell death can occur either through an abrupt process named necrosis or a tightly regulated or programmed process (apoptosis and autophagy) [35]. Its toxicity is mainly associated with liver and kidney injury, osteoporosis and neurological dysfunctions at the level of living organisms. The toxic ions are commonly thought to be released from quantum dots when the surface of the nanoparticle is oxidized and early reports on the

Protecting the core can, to some degree, control toxicity related to cadmium leakage. However, the change in the physicochemical and structural properties of engineered quantum dots could be responsible for a number of material interactions that could also have toxicological effects [37, 38]. However, encapsulation is not simple and it has been reported that quantum dots have displayed toxicity even with well-protected cores. Recently, polymers that can act as coordination sites for cadmium ion aggregation have protected semiconductor nanoparticles. CdS nanoparticles protected with starch and, in particular, amylose, form a wide range of inclusion complexes for numerous guest molecules [39]. Soluble starch added during the synthesis has been used as a capping agent in the synthesis of CdS and CdSe nanoparticles, resulting in well-controlled and uniform particle sizes of cadmium-rich nanoparticles [40]. Early studies attempted to quantitatively determine values for the onset of cytotoxicity in CdSe

diately dispelled if one wishes to image and explore fixed cells [29, 30].

inclusion of simple quantum dots in bacteria support this [36]

**Figure 2.** CdS/maltodextrin quantum dots. (a) Schematic structure of CdS/maltodextrin quantum dots; (b) Characteri‐ zation of different sized CdS/MD quantum dots using TEM; (c) Spectra of CdS/MD quantum dots, the maximum lumi‐ nescence of which is a wavelength of 520 nm (CdS/MD520); (d) HepG2 cells observed under fluorescent microscopy at (x40) magnification.
