**Pharmacokinetic Properties and Safety of Cadmium-Containing Quantum Dots as Drug Delivery Systems**

Lourdes Rodriguez-Fragoso, Ivonne Gutiérrez-Sancha, Patricia Rodríguez-Fragoso, Anahí Rodríguez-López and Jorge Reyes-Esparza

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/58553

**1. Introduction**

[27] Yadav JS, Lavanya MP, Das PP, Bag I, Krishnan A, Jagannadh B, Mohapatra DK, Bhadra MP, Bhadra U: 4-N-pyridin-2-yl-benzamide nanotubes compatible with mouse stem cell and oral delivery in Drosophila. Nanotechnology 2010; 21: 209802.

[28] Stuart L. Schreiber. Target-Oriented and Diversity-Oriented Organic Synthesis in

[29] Peer D, Park EJ, Morishita Y, Carman CV, Shimaoka M. Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science. 2008;

[30] Yadav JS, Das PP, Reddy TL, Bag I, Lavanya PM, Jagannadh B, Mohapatra DK, Bha‐ dra MP, Bhadra U: Sub-cellular internalization and organ specific oral delivery of PABA nanoparticles by side chain variation. J. Nanobiotechnology, 2011, 9, 10.

Drug Discovery. Science 2000; 287(5460): 1964-1969

319(5863): 627-30.

468 Application of Nanotechnology in Drug Delivery

The pharmaceutical industry's current challenge to serve public health needs by has become increasingly difficult due to obstacles that slow down the process of identifying and develop‐ ing new treatments of unmet medical diseases. There are many auspicious new therapies that have progressed into clinical trials in recent years; they include treatments for cancer, inflam‐ mation, neurodegenerative and psychiatric disorders, anti-infective respiratory and metabolic disorders, but their development has failed for a number of reasons. Overcoming these obstacles incurs tremendous costs and takes a lot of time; new therapies must then be identified get successfully issued into the marketplace. In response, government, academic and phar‐ maceutical industry researchers are looking for new ways to approach the discovery of new medicines and technologies that will not only combat illness but also improve the quality of life, a most important outcome of expensive new treatments. Counterbalancing this important goal are efforts to innovate in the face of increasing public pressure to control costs and increase the speed with which new medicines arrive on the marketplace.

For a few years now, nanotechnology has emerged as an area of science and technology that is leading us to a new industrial revolution. Nanotechnology is defined as scientific and technological development at the atomic and molecular levels, in the range of about 1-100 nm, to obtain a fundamental understanding of phenomena and materials on a nanoscale and to create and use structures, devices and systems that have novel properties and functions due

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

to their size. The most interesting aspect of nanotechnology is its ability to work with materials of small size that, however, can change radically on a physical and chemical level at this scale: electrical conductivity, color, resistance or elasticity, among other properties, behave differ‐ ently than they do in volumetric material. The emergence of nanotechnology in the health sciences has led to a new discipline called nanomedicine, the main objective of which is the development of tools to diagnose, prevent and treat diseases when they are still not very advanced or incipient [1].

administered therapeutic agents [9]. Nanotechnology can play an important role in the development of proper formulations that address the drug delivery issues related to NNMs with poor biopharmaceutical properties, such as poor solubility, poor permeability across the intestinal epithelium, enzymatic or nonenzymatic degradation/metabolism, complexation with chelating ligands or metal cations, intestinal efflux, and poor transport properties. Additionally, nanotechnology can also achieve desirable pharmacokinetic and toxicological properties that aid in the accelerated development of the NNM. Nanoparticulate drug delivery systems are being used to alter the drug's biopharmaceutics and pharmacokinetics such as drug absorption, distribution, metabolism, and elimination [10]. Examples of nanoscale delivery systems include polymeric nanoparticles, liposomes, nanoemulsions, micelles, and

Pharmacokinetic Properties and Safety of Cadmium-Containing Quantum Dots as Drug Delivery Systems

http://dx.doi.org/10.5772/58553

471

A number of nano-delivery systems are designed to encapsulate the drug in carriers (e.g., liposomes, micelles, polymeric nanoparticles, and dendrimers), which masks the unfavorable biopharmaceutical properties of the molecule and replaces them with the properties of the materials used to make the nano-delivery system. These approaches were used for a number of poorly soluble NNMs in aqueous phase or easily degraded and metabolized NNMs. Another approach involves the covalent conjugation of the molecules with carrier and targeting moieties (e.g., polymer-drug conjugate, antibody-drug conjugates, solubilizers-drug conjugates, etc.) that override the drug's poor biopharmaceutical properties and improve the pharmacokinetics and biodistribution. This approach was used for site-specific or targeted delivery to alter the pharmacokinetics of the drug by increasing the plasma elimination halflife, preventing degradation or metabolism of the drug in the systemic circulation, and possibly altering the organ and subcellular distribution of the drug, thus alleviating unwanted toxicity due to nonspecific distribution, improving patient compliance and providing favorable clinical outcomes [11]. Advances in nanomedicine are also applied for site-specific drug and gene delivery strategies, especially for the treatment of cancer and other life-threatening diseases [12, 13]. The nanotechnology approach, although expensive and time consuming, can signifi‐ cantly assist in the accelerated development of NNMs with adequate druglike properties and can assist the pharmaceutical companies in adding more lead molecules to their pipeline. One of the major challenges in this process is the development of "nanotherapies", specifically those targeting diseased tissues and organs while avoiding damage to surrounding healthy cells

c) Regenerative medicine aims to repair or replace damaged tissues and organs using nano‐ technology tools [14]. Regenerative nanomedicine deals with the repair or replacement of damaged or diseased tissues and organs by applying methods derived from gene therapy, cell therapy, chemical dosage and bio-regenerative tissue engineering, stimulating the human body's very own repair mechanisms [15]. The main contributions of nanotechnology to regenerative medicine are related to the production of new materials and support systems, the use of embryonic and adult stem cells, and the production of bioactive molecules that serve as signals for cell differentiation [16]. Nanotechnology can play a dominant role in tissue engineering by facilitating new materials and techniques that allow fro more efficient tissue

and, thus, the dreaded side effects of current treatments.

dendrimers.

Nanomedicine includes three main areas: nanodiagnosis, nanotherapy and regenerative medicine [2]. Their main goals are explained in the following paragraphs:

a) The purpose of nanodiagnosis is to identify diseases in their initial stages at the cellular or molecular level and, ideally, down to the level of a single cell, using contrast nanodevices and systems [3]. Early identification would lead to immediate application of appropriate treatment, increasing the probability of healing. Nanosystem diagnostics can be used *in vitro* or *in vivo*. *In vivo* diagnosis normally requires that devices penetrate the human body to identify and (ideally) quantify the presence of specific pathogen or cancer cells, for example. This entails a number of problems associated with the biocompatibility of the material of the device, as well as sophisticated design to ensure effectiveness and minimize side effects. Meanwhile, the *in vitro* diagnosis provides greater design flexibility of design because it can be applied to very small samples of body fluids or tissue from which specific detection can be performed (pathogens or genetic defects, for example) in a very short time with high precision and sensitivity [4]. Because of these fundamental differences, *in vitro* detection using nanoscale devices is expected to reach the market faster and consolidate more easily than *in vivo* methods. There are two main areas of work: images and nanosystems and biosensors. These systems rely on the use of nanoparticles, semiconductors, or magnetic metals, such as contrast agents for *in vivo* labeling. These new systems can increase sensitivity and give better contrast in imaging techniques. One of the first proposed nanoparticle systems was the identification of tumor cells. In the case of nanodiagnostics, the main testing devices being developed are nanobiosensors, devices capable of detecting in real time without the need for fluorescent or radioactive markers and with high sensitivity and selectivity all kinds of chemical and biological substances [5].

b) The aim of nanotherapy is to drive nanosystems containing recognition elements to act or transport and release drugs exclusively in cells or affected areas in order to achieve a more effective treatment, minimizing side effects [6]. Approximately 40% of the novel new molecules (NNMs) selected for full-scale development based on their safety and efficacy data fail to reach the clinical development phase due to poor biopharmaceutical properties, which translate into poor bioavailability and undesirable pharmacokinetic properties. Several nanotechnologybased products, including Doxil® (doxorubicin HCl liposome injection) and Abraxane® (paclitaxel protein-bound particles for injectable suspension) are already on the market [7, 8]. In addition, Baxter and Elan are promoting Nanoedge® dispersion technology and Nano‐ Crystal® technologies respectively, so as to improve the biopharmaceutical properties of orally administered therapeutic agents [9]. Nanotechnology can play an important role in the development of proper formulations that address the drug delivery issues related to NNMs with poor biopharmaceutical properties, such as poor solubility, poor permeability across the intestinal epithelium, enzymatic or nonenzymatic degradation/metabolism, complexation with chelating ligands or metal cations, intestinal efflux, and poor transport properties. Additionally, nanotechnology can also achieve desirable pharmacokinetic and toxicological properties that aid in the accelerated development of the NNM. Nanoparticulate drug delivery systems are being used to alter the drug's biopharmaceutics and pharmacokinetics such as drug absorption, distribution, metabolism, and elimination [10]. Examples of nanoscale delivery systems include polymeric nanoparticles, liposomes, nanoemulsions, micelles, and dendrimers.

to their size. The most interesting aspect of nanotechnology is its ability to work with materials of small size that, however, can change radically on a physical and chemical level at this scale: electrical conductivity, color, resistance or elasticity, among other properties, behave differ‐ ently than they do in volumetric material. The emergence of nanotechnology in the health sciences has led to a new discipline called nanomedicine, the main objective of which is the development of tools to diagnose, prevent and treat diseases when they are still not very

Nanomedicine includes three main areas: nanodiagnosis, nanotherapy and regenerative

a) The purpose of nanodiagnosis is to identify diseases in their initial stages at the cellular or molecular level and, ideally, down to the level of a single cell, using contrast nanodevices and systems [3]. Early identification would lead to immediate application of appropriate treatment, increasing the probability of healing. Nanosystem diagnostics can be used *in vitro* or *in vivo*. *In vivo* diagnosis normally requires that devices penetrate the human body to identify and (ideally) quantify the presence of specific pathogen or cancer cells, for example. This entails a number of problems associated with the biocompatibility of the material of the device, as well as sophisticated design to ensure effectiveness and minimize side effects. Meanwhile, the *in vitro* diagnosis provides greater design flexibility of design because it can be applied to very small samples of body fluids or tissue from which specific detection can be performed (pathogens or genetic defects, for example) in a very short time with high precision and sensitivity [4]. Because of these fundamental differences, *in vitro* detection using nanoscale devices is expected to reach the market faster and consolidate more easily than *in vivo* methods. There are two main areas of work: images and nanosystems and biosensors. These systems rely on the use of nanoparticles, semiconductors, or magnetic metals, such as contrast agents for *in vivo* labeling. These new systems can increase sensitivity and give better contrast in imaging techniques. One of the first proposed nanoparticle systems was the identification of tumor cells. In the case of nanodiagnostics, the main testing devices being developed are nanobiosensors, devices capable of detecting in real time without the need for fluorescent or radioactive markers and with high sensitivity and selectivity all kinds of chemical and

b) The aim of nanotherapy is to drive nanosystems containing recognition elements to act or transport and release drugs exclusively in cells or affected areas in order to achieve a more effective treatment, minimizing side effects [6]. Approximately 40% of the novel new molecules (NNMs) selected for full-scale development based on their safety and efficacy data fail to reach the clinical development phase due to poor biopharmaceutical properties, which translate into poor bioavailability and undesirable pharmacokinetic properties. Several nanotechnologybased products, including Doxil® (doxorubicin HCl liposome injection) and Abraxane® (paclitaxel protein-bound particles for injectable suspension) are already on the market [7, 8]. In addition, Baxter and Elan are promoting Nanoedge® dispersion technology and Nano‐ Crystal® technologies respectively, so as to improve the biopharmaceutical properties of orally

medicine [2]. Their main goals are explained in the following paragraphs:

advanced or incipient [1].

470 Application of Nanotechnology in Drug Delivery

biological substances [5].

A number of nano-delivery systems are designed to encapsulate the drug in carriers (e.g., liposomes, micelles, polymeric nanoparticles, and dendrimers), which masks the unfavorable biopharmaceutical properties of the molecule and replaces them with the properties of the materials used to make the nano-delivery system. These approaches were used for a number of poorly soluble NNMs in aqueous phase or easily degraded and metabolized NNMs. Another approach involves the covalent conjugation of the molecules with carrier and targeting moieties (e.g., polymer-drug conjugate, antibody-drug conjugates, solubilizers-drug conjugates, etc.) that override the drug's poor biopharmaceutical properties and improve the pharmacokinetics and biodistribution. This approach was used for site-specific or targeted delivery to alter the pharmacokinetics of the drug by increasing the plasma elimination halflife, preventing degradation or metabolism of the drug in the systemic circulation, and possibly altering the organ and subcellular distribution of the drug, thus alleviating unwanted toxicity due to nonspecific distribution, improving patient compliance and providing favorable clinical outcomes [11]. Advances in nanomedicine are also applied for site-specific drug and gene delivery strategies, especially for the treatment of cancer and other life-threatening diseases [12, 13]. The nanotechnology approach, although expensive and time consuming, can signifi‐ cantly assist in the accelerated development of NNMs with adequate druglike properties and can assist the pharmaceutical companies in adding more lead molecules to their pipeline. One of the major challenges in this process is the development of "nanotherapies", specifically those targeting diseased tissues and organs while avoiding damage to surrounding healthy cells and, thus, the dreaded side effects of current treatments.

c) Regenerative medicine aims to repair or replace damaged tissues and organs using nano‐ technology tools [14]. Regenerative nanomedicine deals with the repair or replacement of damaged or diseased tissues and organs by applying methods derived from gene therapy, cell therapy, chemical dosage and bio-regenerative tissue engineering, stimulating the human body's very own repair mechanisms [15]. The main contributions of nanotechnology to regenerative medicine are related to the production of new materials and support systems, the use of embryonic and adult stem cells, and the production of bioactive molecules that serve as signals for cell differentiation [16]. Nanotechnology can play a dominant role in tissue engineering by facilitating new materials and techniques that allow fro more efficient tissue 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 replace damaged organs.

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 as tools for diagnosis and drug delivery systems.
