**Chapter 1** Toxicity of Quantum Dots

*Gerardo González De la Cruz, Lourdes Rodríguez-Fragoso, Patricia Rodríguez-Fragoso and Anahi Rodríguez-López*

### **Abstract**

Quantum dots (QD) have been deeply studied due to their physicochemical and optical properties with important advantages of a wide range biomedical applications. Nevertheless, concern prevails about its toxic effects, mainly in those QD whose core contains cadmium. Therefore, there are reports about the toxicity caused by the release of ions of cadmium and the effects related to its tiny nanometric size. The aim of this chapter is to show the evaluations about the toxicity of QD, which include studies on viability, proliferation, uptake, and distribution *in vitro* and *in vivo* models. What are the worrying toxic effects of QD? There are reports about some mechanisms of toxicity caused by QD, such as immunological toxicity, cell death (apoptosis and necrosis), genotoxicity, among others. In addition, we discuss how coating QD with passivating agents that improve their biocompatibility. Likewise, this coating modifies their size and surface charge, which are fundamental aspects of the interaction with other biomolecules. We consider highlighting information about more precise techniques and methodologies that help us to understand how QD induce damage in several biological systems.

**Keywords:** quantum dots, cytotoxicity, cadmium, nanotoxicity, biocompatibility

### **1. Introduction**

In recent decades, there have been countless publications on the use of nanomaterials, particularly in the biomedical area. The main use of semiconductor nanoparticles (NPs) lies in the development of formulations for the delivery of anticancer therapies, specifically targeting diseased tissues and organs. Moreover, quantum dots (QDs) provide remarkable specificity while avoiding damage to surrounding healthy cells and thus avoiding the dreaded side and adverse effects of current treatments. However, among the great applications and their attractive physicochemical and optical properties are a myriad of toxicological effects in biological systems [1]. QDs are inorganic semiconductors with a size range of 1–10 nm. Unlike other types of nanomaterials (NMs), QDs possess a unique and exceptional luminescent property. QDs have become the focus of a study by many researchers [2]. So far, QDs are the most promising option that have exhibited potential for applications in bioimaging (luminescence detection) [3, 4].

Quantum dots have properties, such as luminescent intensity, broad emission spectrum, tight size control, and selectivity, based on their composition. In addition, quantum dots have high resistance to photobleaching, physicochemical robustness, and better half-life than other conventional fluorochromes [5–9]. These nanomaterials are constituted by central semiconductor core consisting of elements from groups II, VI, III-V, or IV-VI of the periodic table and mostly can be composed of heavy metals and toxic materials (e.g., Cd, Te and Hg, CdS, CdTe, CdSe, among others) [10, 11]. Because their main component is cadmium and because of their tiny size they imply a potential hazard, especially for medical applications. There are different types of cadmium-free quantum dots, such as InP/ZnS, CuInS2/ZnS, AgInS2/ZnS, silicon, and graphene. Although they are cadmium-free in their composition, they are still subject to rigorous toxicological studies [12].

In order to reduce the cytotoxicity of quantum dots, there are some strategies such as the use of some shells composed of ZnS, CdS, ZnSe, or even CdS/ZnS multishells. By covering the core not only improved luminescent effect but also reducing the toxicity by avoiding the release of heavy metal ions [13, 14]. Achieving functionalization of the QD core shell with a polymeric shell can give the desired biocompatibility and decrease its cytotoxic effects [15, 16]. Among some functionalized QDs, there are those coated with polymers such as dextrin or maltodextrin, which make the semiconductor able to target organs and can even be taken up by cellular organelles [17–19]. This advantage allows QD to be more specific and selective for applications for disease diagnosis and treatment purposes. However, the negative effects that QDs may have on cells are difficult to assess. QDs have higher fluorescence intensity, prolonged lifetime, specificity, and possess optical stability compared to conventional fluorochromes. In addition, the wavelength at which they emit is given by tight control of the core size. **Figure 1** shows the characteristic image of QDs emitting photoluminescence.

The characteristics of QDs include size, which is what determines the wavelength at which they emit, although in some cases it does not depend on their composition. Thus, QDs of smaller size (2 nm) emit in blue, QDs of 3–5 nm in green, 6–8 nm in orange, and sizes of approximately 8–10 nm in red [10]. The controversial mechanisms by which QDs are introduced into cells are of great interest among the scientific community and thus the molecular and physiological basis of cytotoxicity. These cytotoxic effects have been classified into *in vivo* and *in vitro*. Thus, cell culture-based tests have become the first choice for bioassessment of QD toxicity [20]. However, *in vitro* studies include assessments of cell membrane integrity, morphological changes, organelle dysfunction, and in some cases quantification of viable cells. Nevertheless,

#### **Figure 1.**

*Fluorescence image of cadmium QD. La emisión de fluorescencia es dependiente del tamaño de los QD. Por lo que, la fotoluminiscencia va del Azul Para aquellos QD más pequeños y hasta el rojo Para los de un núcleo mayor.*

information on the behavior of quantum dots in a biological system is still scarce and does not emphasize the cell type-dependent toxicity induced by quantum dots. In this review, we have summarized the efforts in achieving a less toxic design, its advantages and disadvantages in the synthesis of single and bioconjugated quantum dots for application as nanovehicles.
