**1. Introduction**

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#### **1.1. Nanomedicine for cancer**

Cancer is one of the leading causes of death worldwide, occupying the second place in developing countries, and showing a growing incidence over time [1]. Current cancer therapy strategies are based in surgery, radiotherapy and chemotherapy, being the chemotherapy the one that shows the greater efficiency for cancer treatment, mainly in more advanced stages [2, 3]. Despite of this great response, anticancer agents are administrated at higher amounts in order to provide a final suitable concentration to the target tissues or organs, and this procedure is repeated in each cycle of chemotherapy [4]. Introduction of new agents to cancer therapy has greatly improved patient survival but still there are several biological barriers that antagonize drug delivery to target cells and tissues, namely unfavorable blood half-life and physiologic behavior with high off-target effects and effective clearance from the human organism [2, 5, 6]. Moreover, in cancer, there is a small subset of cancer cells-cancer stem cells (CSC)-that, like normal stem cells, can self-renew, give rise to heterogeneous populations of daughter cells, and proliferate extensively [7, 8]. Standard chemotherapy is directed against rapidly dividing cells, the bulk of non-stem cells of a tumor, and thus CSC often appear relatively refractory to those agents [7-9]. The development of side effects in normal tissues (e.g. nephrotoxicity, neurotoxicity, cardiotoxicity, etc) and multidrug resistance (MDR) mechanisms by cancer cells leads to a reduction in drug concentration at target location, a poor accumulation in the tumor with consequent reduction of efficacy that may associate to patient relapse [9-13]. To overcome these issues and still improve the efficiency of chemotherapeutic agents there is a demand for less toxic and more target specific therapies towards cancer cells, i.e. novel drugs, drug delivery systems (DDSs) and also gene delivery systems [3, 4, 14-17].

© 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.

Introduction

1. Nanomedicine for cancer

Nanotechnology is the manipulation of matter on an atomic, molecular, and supramolecular scale involving the design, production, characterization and application of different nanoscale materials in several key areas providing novel technological advances mainly in the field of medicine (so called Nanomedicine) [6, 18-20]. The development and optimization of drug delivery approaches based in nanoparticles concerns the early detection of cancer cells and/or specific tumor biomarkers, and the enhancement of the efficacy of the treatments applied [21]. The most important biomedical applications of nanoscale materials can be organized as shown in Figure 1. demand for less toxic and more target specific therapies towards cancer cells, i.e. novel drugs, drug delivery systems (DDSs) and also gene delivery systems [3, 4, 14-17]. Nanotechnology is the manipulation of matter on an atomic, molecular, and supramolecular scale involving the design, production, characterization and application of different nanoscale materials in several key areas providing novel technological advances mainly in the field of medicine (so called Nanomedicine) [6, 18-20]. The development and optimization of drug delivery approaches based in nanoparticles concerns the early detection of cancer cells and/or specific tumor biomarkers, and the enhancement of the efficacy of the treatments applied [21]. The most important biomedical applications of nanoscale materials can be organized as shown in Figure 1.

To overcome these issues and still improve the efficiency of chemotherapeutic agents there is a

Cancer is one of the leading causes of death worldwide, occupying the second place in developing countries, and showing a growing incidence over time [1]. Current cancer therapy strategies are based in surgery, radiotherapy and chemotherapy, being the chemotherapy the one that shows the greater efficiency for cancer treatment, mainly in more advanced stages [2, 3]. Despite of this great response, anticancer agents are administrated at higher amounts in order to provide a final suitable concentration to the target tissues or organs, and this procedure is repeated in each cycle of chemotherapy [4]. Introduction of new agents to cancer therapy has greatly improved patient survival but still there are several biological barriers that antagonize drug delivery to target cells and tissues, namely unfavorable blood half-life and physiologic behavior with high off-target effects and effective clearance from the human organism [2, 5, 6]. Moreover, in cancer, there is a small subset of cancer cells - cancer stem cells (CSC) - that, like normal stem cells, can self-renew, give rise to heterogeneous populations of daughter cells, and proliferate extensively [7, 8]. Standard chemotherapy is directed against rapidly dividing cells, the bulk of non-stem cells of a tumor, and thus CSC often appear relatively refractory to those agents [7-9]. The development of side effects in normal tissues (e.g. nephrotoxicity, neurotoxicity, cardiotoxicity, etc) and multidrug resistance (MDR) mechanisms by

**Figure 1.** Biomedical application of nanotherapeutics (adapted from [6]).

These nanotherapeutics' potential in cancer relies on i) passive targeting due to the enhance of the permeability and retention (EPR) effect promoted by angiogenic vessels with defective vasculature and improper lymphatic flow surrounding the tumor [18] that can be reinforced by ii) specific targeting based on multifunctional nanomaterials that bypass the biological barriers and reach cancer cells [4]. Nanotechnology for drug vectorization provides for new and more specific drug targeting and delivery platforms that can reduce toxicity and other side effects and also maintain or improve the therapeutic index [9, 22, 23]. In fact, the devel‐ opment of targeting delivery systems is the ultimate goal in cancer therapy, which has been taking the lead in what concerns overcoming the MDR problem [9, 13, 24, 25].

2

**2. Nanoparticles as delivery systems**

healthy tissues in living organisms [35, 36].

with (bio)molecules of interest.

be efficient [18, 22, 37, 38].

review see [40-42].

the treatment of cancer (for a review see [6]).

Nanoparticles have been developed as effective target specific strategies for cancer treatment, acting as nanocarriers and also as active agents [4, 6, 5, 26]. Over the last decades, different types of nanoparticles have been developed based on various components, including carbon, silica oxides, metal oxides, nanocrystals, lipids, polymers, dendrimers, and quantum dots, together with increasing variety of newly developed materials [4, 27-34]. These nanomaterials are capable to provide a high degree of biocompatibility before and after conjugation to biomolecules for specific function so as to translate into nanomedicines and clinical practice. Nanomaterials provide for a favorable blood half-life and physiologic behavior with minimal off-target effects, effective clearance from the human organism, and minimal or no toxicity to

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In fact, the protection from adsorption to plasma proteins and/or degradation by circulating nucleases allows for an increased availability of effector molecule at site of interest. This is further enhanced by the considerable decrease to clearance from the organism that conjugation to nanoparticles confers. The modulation of pharmacokinetic and pharmacodynamics parameter constitutes a key factor when modifying the mode of administration (and vehicle and route of administration associated) that is usually neglected when compared to the ability of therapeutic nanoconjugates to offer the possibility of enhanced targeting (active and/or passive) and cell uptake. When considering nanoparticles for therapeutics one should also evaluate the effect on cellular metabolism and fate that can be attained via optimal conjugation

DDSs can improve the properties of free drugs by increase their *in vivo* stability and biodis‐ tribution, solubility and even by modulation of pharmacokinetics, promoting the transport and even more important the release of higher doses of the drug in the target site in order to

DDSs can be constructed by direct conjugation with the drugs and further surface modifica‐ tions can lead to a better delivery for such systems, promoting a targeted delivery to specific types of cells and reaching cell compartments such as nucleus and mitochondria [15, 39]. As far as drug delivery is concerned, the most important nanoparticle platforms are liposomes, polymer conjugates, metallic nanoparticles (for example AuNPs), polymeric micelles, den‐ drimers, nanoshells, and protein and nucleic acid-based nanoparticles (for a more complete

Among a wide variety of nanosystems, only a few nanomedicines, such as Doxil® (Janssen Biotech Inc., Horsham, PA, USA), DaunoXome® (Galen US Inc., Souderton, PA, USA), Depocyt® (Pacira Pharmaceuticals Inc., San Diego, CA, USA), Genexol-PM® (Samyang Biopharmaceuticals Corporation, Jongno-gu, Seoul, Korea), Abraxane® (Celgene Corporation, Inc., Berkeley Heights, NJ, USA), Myocet® (Sopherion Therapeutics Inc., Princeton, NJ, USA) and Oncaspar® (Enzon Pharmaceuticals Inc., Bridgewater, NJ, USA), are approved for use in

Here, we will discuss recent applications on AuNPs as platforms for anticancer therapy, emphasizing strategies for targeted delivery for gene silencing focusing on the optimal pathways to test these therapeutics *in vitro* and *in vivo*. Also, an overview of the toxicological aspects of these materials will be provided.
