Nanotechnology for personalized medicine: cancer research, diagnosis, and therapy

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NANOTECHNOLOGY FOR PERSONALIZED MEDICINE: CANCER RESEARCH, DIAGNOSIS, AND THERAPY

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Delia Albulet,*, Denisa A. Florea*, Bianca Boarca*, Lia M. Ditu**, Mariana C. Chifiriuc**, Alexandru M. Grumezescu*, Ecaterina Andronescu* *University of Bucharest, Bucharest, Romania **Research Institute of the University of Bucharest (ICUB), Bucharest, Romania

CHAPTER OUTLINE 1 Introduction........................................................................................................................................ 1 2 Main Types of Cancer.......................................................................................................................... 4 3 Personalized Treatment of Cancer........................................................................................................ 6 3.1 Nanotechnology: Progress in Cancer Research.................................................................6 4 Nanotreatment of Cancer..................................................................................................................... 9 5 Nanodrugs and Nanocarriers.............................................................................................................10 5.1 Magnetic Nanoparticles...............................................................................................10 5.2 Noble Metal Nanoparticles..........................................................................................12 5.3 Upconversion Nanoparticles........................................................................................13 5.4 Quantum Dots............................................................................................................14 5.5 Carbon-Based Nanostructures......................................................................................14 5.6 Polymeric Nanoparticles..............................................................................................15 5.7 Liposomes.................................................................................................................16 6 Conclusions......................................................................................................................................16 Acknowledgments....................................................................................................................................17 References..............................................................................................................................................17

1 INTRODUCTION Cancer represents an important health problem at a global level being the second cause of death in the United States. The American Cancer Society provides each year relevant data about the number of deaths caused by cancer, and it is believed that cancer-related deaths could surpass the number of deaths caused by heart diseases in the next years (Siegel et al., 2015). Cancer is a multistep process and appears as a consequence to the loss of control of cell division, leading to uncontrolled cellular proliferation (Bashyam, 2002), and also appears as the ability of the abnormal cells to overwhelm other tissues (Aly, 2012). Nanostructures for Cancer Therapy Copyright © 2017 Elsevier Inc. All rights reserved.

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The EUROCOURSE project developed a special program known as the European Cancer Observatory (ECO) to collect all the information available on cancer incidence, survival, prevalence, and mortality in Europe from 40 European countries, estimated for 2012. Based on this data, more than 3.3 million new cancer cases have been estimated, apart from nonmelanoma skin cancer. The widespread cancers were those of lung, prostate, large bowel, and breast, representing 1.7 million cases. The cancer with the greatest number of deaths is lung cancer, while the cancer with the greatest number of prevalent and incident cases is breast cancer (Steliarova-Foucher et al., 2015). Normal cells become tumor cells through changes taking place in their DNA, under the pressure of the environmental factors that cause the initial mutation. Normally, when DNA sequences are injured, the cells activate their repair mechanism or, if the damages are too extensive, the cells die. The devel­ opment of tumors derives from single modified cells that begin to proliferate abnormally because of the unrepaired DNA mutations. Tumor progression is viewed as a multistep process involving mutation and selection of cells with progressively increasing capacity for proliferation, survival, and invasion. One of the hallmarks of cancer is represented by the rapid growth of tumors, which leads to low oxygen rates (hypoxic conditions) (Blazejczyk et al., 2015). Nowadays, the genomic alterations that lead to cancer are better understood and the connections between genes and the conditions of the human body have been studied to prevent cancer initiation. The genes that cause tumor development under the mutation process are usually grouped in two main categories: 1. Cancer-promoting oncogenes, also known as protooncogenes, which are frequently activated in cancer cells, giving new properties, such as hyperactive division and growth, ability to become recognized in new tissues, or protection against apoptosis (programmed cell death). 2. Tumor suppressor genes (antioncogenes or TSG), which are inactivated in cancer cells (Aly, 2012; Harrington, 2011). To develop a malign neoplasm, mutations in both types of genes are expected. Substances that can cause the DNA mutations (also known as carcinogens) are linked to specific types of cancer. For example, smoking is connected to lung cancer, and solar ultraviolet radiation may cause skin cancer. The ability of abnormal cells to grow or spread to other vital organs is called metastasis and it is the most common cause of death for patients with malign neoplasm. The metastasis process takes place when the abnormal cells access the body’s blood vessels to move to other parts of the human body where they can proliferate and develop new tumors (Le Dévédec et al., 2010). Certainly, about 90% of malign neoplasm deaths come from metastasis (Ganapathy et al., 2015). At the beginning of the metastasis process, abnormal cells activate the epithelial-to-mesenchymal transition, also known as EMT, which refers to the activation of the latent embryonic program by the cancer cells (Pietilä et al., 2016). Angiogenesis process involves the endothelial cells, which break free from the blood vessels and develop tubes during the proliferation process (Tsimberidou et al., 2015). The cancer cells located in tumors are an abundant resource of proangiogenic molecules that guide the activity of endothelial cells, promoting their migration and determination. The endothelial cells manage the activity of platelets and they have an antiinflammatory, anticoagulant, and antiadhesive phenotype. The structure of tumor vessels is correlated with the malignancy of the tumors because of the cancer cells that grow along the existing vessels (Blazejczyk et al., 2015). The platelets are well known for their main function: to stop hemorrhage after tissue damage and vascular injury, because they have the ability to release bioactive factors when they become

1 Introduction

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activated (when matrix is exposed or if inflammation appears and disturbs the endothelium) (Yan and Jurasz, 2015). Besides their function in hemostasis, activated platelets also contribute to tumor cell metastasis with an intense impact on circulating tumor cell survival, growth, and invasiveness. Their influence on abnormal cells is based on mechanisms such as the release of GFs (growth factors), proteins, and so on. The cancer cells have the ability to control the platelets function so as to improve their extravagation and development (Tesfamariam, 2016). Disorder prevention is built around the idea that several risk factors may be controlled, for example, decreasing exposure to notorious causes of cancer, such as sunlight exposure, cigarettes, alcoholic drinks, unhealthy meals, and so on, or promoting activities that are correlated with reduced cancer risks (Bashyam, 2002; White et al., 2013). In the past few years, the main role of numerous intracellular or extracellular biochemical signals in malign neoplasm cell proliferation, metastasis, and invasion has been revealed. The mechanical properties of the ECM (extracellular matrix) showed an important influence in the metastasis process. In vivo and in vitro tests showed that enhanced tissue rigidity has a functional role in controlling the malign character of a tumor and tumor invasion (Wei and Yang, 2015). Solid tumors are living units made of various complex cell types that may even surpass the healthy tissues. According to Jiang et al. (2015), a new theory about the malignant progression of cancer was developed indicating the idea that this evolution not only depends on abnormal cells genetic aberrations, but also on the bidirectional dynamic and complex connections between stroma and cancer cells within the tumor microenvironment. Breast, lung, and prostate cancer are among the most frequent forms of solid tumors. Cancerous cells found in solid tumors enroll inflammatory cells, producing inflammatory stroma. The invasiveness and the resistance of the metastatic breast cells are the result of the oncogenic epithelial to mesenchymal transition. In this case, cells undergoing EMT hit the nearby stroma causing the extravasations of cells in the blood, individually or as a mass (Subramanian et al., 2015). The epithelium is a well-established structure with a uniform layer formed by the epithelial cells. In the case of the breast, these types of cells develop the lining of canals, which are responsible for milk transport in the lactation process. The most common type of carcinoma in breast cancer is the ductal carcinoma appearing both in men and women, but its prevalence in men is uncommon (Videira et al., 2014). An important role in encouraging the proliferation process of both the neoplastic and the normal breast epithelium is given by estrogens (Russo and Russo, 2006). There are many types of physiologi­ cal estrogens, such as estrogen, progesterone, cortisol, and aldosterone, but the main physiological estrogen in mammals is estradiol (E2) (Baker, 2013). Estradiol is the most biologically active hormone located in the breast tissue and it stimulates the breast evolution at puberty and during sexual maturity. In vivo and in vitro tests revealed the idea that E2 has the ability to induce full neoplastic transformation of epithelial cells (Russo and Russo, 2006). A significant regulator in breast cancer is the extracellular matrix. It produces several modifications in organization and structure, in comparison to the mammary gland under homeostasis. A number of ECM elements play an important role in metastasis and progression of breast cancer, such as collagens, specific laminins, fibronectin, glycosaminoglycan, proteoglycans, and ECM remodeling enzymes. Other common cell types that take part in tumor development are CAFs (cancer-associated fibroblasts, neuroendocrine cells, adipocytes) and MSCs (human mesenchymal cells or blood stem cells). These cells are located in the tumor microenvironment (TME). Additionally to cellular components,

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the TME is composed of a network of secreted proteins (which can change the extracellular matrix structure and composition) and biomechanical properties of the stromal tissue (Pietilä et al., 2016). A sustaining TME permits stromal cells to develop with cancer cells, encouraging the initial spreading. In contrast to cancer cells, stromal cells located inside the tumor microenvironment are genetically stable and this denotes a therapeutic target with a decreased risk of drug resistance (Chen et al., 2015). Tissue regeneration and cancer are not restricted to ECM structure or composition, but also involves remodeling enzymes that can change the ECM in different ways. The remodeling enzymes can increase the cancer cell migration and invasion and can affect the biological function and properties of ECMs components. These factors contribute directly to the development of metastasis and progression of cancer (Insua-Rodríguez and Oskarsson, 2015).

2  MAIN TYPES OF CANCER Nowadays, a top killer in both women and men in the USA is lung cancer, with an approximate number of 160,000 deaths and 225,000 new cases in 2014, causing more deaths each year than the next main causes of malign neoplasm deaths (rectal/colon, prostate) and it is constantly associated with a history of about 20 years of consuming tobacco-based products. The main causes of this type of cancer initiation are: smoking, different chemicals, such as asbestos, nickel, uranium, family history, or radon gas. There are two types of lung cancer: primary and secondary. The primary type refers to the mo­ment when the tumor starts to increase in the lung first, and the secondary type is when the tumor has spread to the lung from other places or tissues. Primary lung cancer is divided into two principal categories: nonsmall cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) (Karachaliou et al., 2015). The most common lung cancer is the NSCLC and it presents several symptoms including anemia, paraneoplastic syndrome, weight loss, headaches, or bone pain. The SCLC type is extremely sensitive to initial therapy and most people diagnosed with this type of lung cancer die of recurrent disease. For patients with an extensive-stage diagnosis, chemotherapy can alleviate symptoms and extend survival, but even so long-term survival is uncommon. A great number of SCLC cases are connected to cigarette smoking (Kalemkerian et al., 2013). The lung neoplasm is a rapidly metastasizing and prevalent cancer with a high potential of invasiveness. Numerous mechanisms take part in the cell transformation from normal to malignant, such as genetic and epigenetic alterations that promote the spread of cancer by clonal expansion. It is very important to detect and characterize these molecular changes to improve prevention, treatment, and early detection (Lemjabbar-Alaoui et al., 2015). The lung cancer presents variable signs or symptoms and around 70% of patients detected with lung cancer show an advanced stage III or IV (Travis et al., 2013). There are several tests that may be done to diagnose lung malign neoplasm, for example, chest X-ray, lung biopsy, computed tomography scan, or bronchoscopy. When patients are diagnosed with stage IV they are frequently candidates for systemic therapy (which involves targeted therapy, chemotherapy, or a combination), palliative treatment, or clinical trials. The purpose is to detect patients with stage IV metastatic disease before they begin any aggressive treatment (like combined therapy) (Ettinger et al., 2012). To reduce the risk of lung cancer initiation, there are a few things that may be done, such as quitting smoking, a rich fiber diet including fresh fruits and vegetables, and excluding fatty foods from the daily diet.

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Prostate cancer is a common disease around the world with a high rate of mortality: it is the secondmost common cause of male death in the United Kingdom and it is expected to kill around 27,000 men in the USA. A percentage of 70% of patients with metastatic prostate malign neoplasm die from their disease within 5 years (Witte, 2016). This disease is extremely heterogeneous and it can vary from low-volume that can be controlled with closely observation through high-volume metastatic disease, which is lethal. There are various risk factors involved in the initiation of this type of cancer such as: age, genetic factors, unhealthy diets, and so forth. The age is frequently correlated with this type of disease, which is proved by the fact that the development of prostate cancer increases with age. Early low-grade prostate cancer does not present any signs or symptoms unless the metastatic spread occurs. The local growth can produce irrigative urinary symptoms and the spread can cause bone pain, but it can also appear in the forms of anorexia, fatigue, or weight loss. There are many investigations used in the diagnosis of prostate cancer. Many of them are detected by the regular measurement of the prostate-specific antigen (also known as PSA), which is a glycoprotein made only by prostate cells. The increased total PSA and a small ratio of free PSA are frequently associated with the prostate malign neoplasm (Singer and DiPaola, 2013). Other possible investigations to detect prostate cancer are biopsies, which can be transperineal template biopsies or MRI-targeted biopsies (magnetic resonance imaging), but the best results are obtained using the MRI-targeted method. If the results are positive for adenocarcinoma, the patients must do additional investigation and treatment. In this situation, an important role is provided by the MRI, which can offer information about the local extension of cancer. This information is very useful when radiotherapy or a radical prostatectomy is planned. If the MRI is not recommended for the patient, the CT scan can be used. In case of bone metastases, the whole-body bone scintigraphy is recommended, and also the PET method may be used to detect the metastases with the advantage that a diversity of radioactive tracers can be applied. It is very important to understand the modifiable dietary and lifestyle factors that can initiate the prostate cancer progression and development. There is a research that upholds the ideas that prostate cancer prevention is possible by being physically active and a lifelong avoidance of obesity (Discacciati and Wolk, 2014). One of the most common and aggressive forms of cancer both in children and in adults is leukemia. According to the World Health Organization, leukemia is in the top 15 common forms of malign neoplasm (Kampen, 2012). Leukemia is a malign neoplasm that begins in blood stem cells found in the bone marrow, a spongy and soft material that fills the center of bones. Blood has three types of cells which are produced in the bone marrow: white blood cells that fight infections, red blood cells that carry oxygen and platelets that assist blood to clot. Normally, each day billions of blood cells are made in the bone marrow. As a rule, the red blood cells (erythrocytes) are the ones generated the most, but in the case of leukemia the human body begins to create more white cells than is necessary. In this case, the leukemic cells are not able to fight infection, affect the normal functions of the vital organs, and the number of erythrocytes is decreased so the supply of oxygen is modified. Patients diagnosed with leukemia become anemic and present a high risk of infections and bleeding. At the moment, the conventional treatment is not efficient because it can cause side effects. The side effects are the result of the lack of specificity of the anticancer drugs because they do not only kill the cancer cells but also obstruct the development of normal cells, occasionally causing the necrosis of normal

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cells. One of the best ways to reduce drugs’ toxicity and to maintain its concentration for the needed period of time to direct the drug to its target site, so a lot of research has been done to develop smart drug delivery systems for leukemia treatment (Soni and Yadav, 2015).

3  PERSONALIZED TREATMENT OF CANCER Personalized oncology is focused on the use of “personalized medicine” in cancer treatment, consider­ ing the fact that tumor cells are various and multifaceted. The risk of a different response to a certain therapy may appear because tumors clinically look like a specific type but the difference can be observed only at a molecular level. For example, tumors can contain cancer stem cells that have different metastatic abilities and therapy responsiveness and most of them can be identified in breast, lung, and colon cancer. It is impractical to develop a general drug that can be applied to all patients with a certain disease because of the cancer heterogeneity. The solution would be to improve a treatment based on the characteristics of individual patients and diseases to match the requirement with the treatment (Liu, 2012). To develop a personalized cancer treatment with new therapeutic agents, mechanisms such as cancer initiation and invasion must be analyzed at the molecular level. The multifunctionality of nanoparticles helps them incorporate biotargeting ligands such as antibodies, peptides, and small molecules or therapeutic drugs and transport them to the action site, as well as being useful in diagnosis and disease progress monitoring after chemotherapy. This technology facilitates early detection and a mixture of diagnostics with therapeutics. Personalized nanotechnology can also deliver cells or genes that are taken from the patient himself to improve the specific targeting of tumors and increasing the efficacy of treatment (Liu, 2012; Toy et al., 2014). For personalized therapies there can be used individual biomarkers because they recognize the tumor tissue of the patient. These markers are difficult to find, which is why nanoparticles can be used to uncover the diagnostic and prognostic markers monitoring the efficacy of the treatment in a noninvasive way. For example, magnetic nanoparticles can catch circulating cancerous cells in bloodstream, quantum dots can notice the initial signs of cancer, and biosensors can find cancer biomarkers by discovering multiple protein markers in clinical samples (Liu, 2012).

3.1  NANOTECHNOLOGY: PROGRESS IN CANCER RESEARCH Nanotechnology refers to the development of structures and systems with the purpose to control their size and shape on a nanometer scale. A nanometer is considered the 10−9th part of a meter (Stylios et al., 2005). At this scale appears a good biological interaction between nanometric systems and natural structures, like proteins that are about 3–10 nm in size and blood cells that are approximately 6000 nm (Boisseau and Loubaton, 2011). This type of technology has many applications in science, engineering, and especially medicine. Nanomedicine can be used for prevention, monitoring, diagnosis, control, and treatment, having an impact at the molecular level to achieve a medical benefit (Boisseau and Loubaton, 2011; Logothetidis, 2011; Stylios et al., 2005). The diagnosis is the first step in a medical process and it can be made in vitro, through nanoparticles or nanodevices that recognize, capture, and concentrate natural biomolecules and also in vivo

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through synthetic assemblies that have the role of contrast agent for imaging. The imaging techniques that involve contrast agents are X-ray imaging, ultrasound imaging, and other diagnostic methods like magnetic resonance imaging, spectroscopy, or nuclear imaging (Boisseau and Loubaton, 2011; Toy et al., 2014). The best diagnosis tool and image-guided therapy is the medical imaging as it helps in monitoring diseases and acting against them in vivo. A tissue disorder can be identified by a modification of its morphology or by using a contrast agent that assists in localizing a disease and obtaining a targeted treatment. This option helps in detecting the tumors’ localization and stage, inflammations, or drug accumulations that can be dangerous (De Souza et al., 2015). Cancer cells can be detected through imaging after they cause a defect to a tissue that indicates that a great number of cells have grown and metastasized. Even if the tumor is detected, it is necessary to make a biopsy to establish the tumors’ nature (malignant or benign) and also determine the facts that can help the development of a treatment and make the tumor responsive to it. It is very important to identify the cancerous cell and to make it visible; through nanotechnologies these things can be achieved. Metal oxide nanoparticles provide a signal with a high contrast on the images of Magnetic Resonance or Computed Tomography and can be loaded with antibodies that recognize specific receptors on tumor cells (Boisseau and Loubaton, 2011). Besides diagnostics and therapy, imaging can be useful also as an external stimulus for the activation of drug release from outside. The stimulus can be temperature, ultrasounds, or laser light. Biosensors have biological elements named enzymes that can recognize or signal the existence of a certain molecule and its activity. The biological signal is converted into a quantifiable signal through a transductor, to obtain a medical result (Boisseau and Loubaton, 2011). Nanotechnology involves various devices, such as pills that can be swallowed for imaging or instruments for endoscopy to provide an accurate in vivo diagnostic. Implantable devices are used as well for glucose measurement or infection markers. As these devices are miniaturized, they are less invasive and can be better accepted by the body. The diagnosis of brain cancer is very hard to obtain as a biopsy of the brain tissue because it is an invasive and dangerous technique. The alternative is a nanotechnology based on an endoscopic nanopatterned pen that can be used to collect cells and proteins by surface adhesion without affecting the brain tissue. Nanotechnology can be used for the development of intelligent, biomimetic biomaterials that can cause positive reactions of cells and stimulate a specific regeneration process to create a new healthy tissue (Boisseau and Loubaton, 2011). The possible applications of nanoscale technologies in the medical field are the following: controlled drug delivery systems for diagnosis and therapy, as they can provide a targeted delivery of active biological substances; cancer treatment by detecting and destroying the tumor; restoration of human organs and implants with higher biocompatibility (Logothetidis, 2011; Stylios et al., 2005). Nanotechnologies have applications in drug delivery systems and they refer to the dispersion of nanoobjects in the body, releasing active molecules in the biological fluids. The requirement of this type of nanotechnology is to combine the physicochemical characteristics of the delivery product with the biodistribution and pharmacokinetics of the active substance (Bazile, 2014). The nanocarriers have specific characteristics such as nanometric size, favorable physical and chemical proprieties, and a high surface-to-volume ratio. They are useful by increasing drugs’ stability in the biological fluids, extending the blood circulation time, and releasing a controlled dilution

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of drugs (Wicki et al., 2015). Multifunctional nanocarriers aim not only to combine radiotherapy and chemotherapy, but also to accelerate the diagnostic process (Alexis et al., 2008). As all the functions of the human body have daily variations and each organism has its own specific parameters, the normal drug administration does not always have a pharmacological effect. The best treatment should be closely connected to the biological pattern of each patient to deliver a certain drug at the right place, in the right moment, and with the right concentration. This idea can decrease the number of side effects of medical substances and minimize the medical crises (Stylios et al., 2005; Wicki et al., 2015). A normal administration means that the drug will be delivered in the whole body and it will have in the first period an increased effect until a maximum level, decreasing after that and requiring a new administration. The main disadvantage is that healthy cells may be affected. With a targeted delivery, a long-term administration can be achieved for a specific organ with the necessary delivery rate and concentration. To carry the drugs, nanocarriers or drug delivery systems in form of nanoparticles, nanospheres, nanocapsules, or complexes at a macromolecular scale can be used (Stylios et al., 2005). The option of such carriers assists in better drug distribution to targeted molecules in a diseased tissue, without affecting the healthy ones (Bazile, 2014; Boisseau and Loubaton, 2011). The normal chemotherapy involves drugs that are able to destroy cancer cells. The disadvantage is that these substances may also kill normal, healthy cells, leading to complications like tiredness, neuropathy, hair-loss, or an abnormal function of the immune system. To solve this problem, nanoparticles can be used to carry the chemotherapeutic drugs and release them in the tumor area, without disturbing healthy cells. They have the task to keep the substances protected from degradation by the body before they arrive in the interest zone, to release them inside the tumor and to keep control over them, in such way that they can be discharged at the right time and in the most suitable concentration and distribution (Boisseau and Loubaton, 2011; Kanapathipillai et al., 2014). Future developments in nanotechnology include the achieving of self-regulated and bioresponsive delivery systems (Alexis et al., 2008). Scientists have studied the development of drug nanoparticles as a powder that can be incorporated in a 3D polymer scaffold or in a biodegradable shell also made from a polymer. The aim is to keep the drug encapsulated during the blood transport to be released only in the moment when it approaches the interest zone. The morphology of the polymers is well controlled using the technology of phase separation to represent the basis for the drug encapsulation. These scaffolds are able to deliver precise rates of the pharmacological agent at precise time points for long time (Stylios et al., 2005). These systems can also use attached antibodies fragments that contribute to a very specific release of them in a specific tissue (Boisseau and Loubaton, 2011). Nanotechnologies based on polymers represent an alternative to the traditional formulations for drug delivery, administration, and targeting (Couvreur et al., 2006). Nowadays, researchers are studying new drug delivery systems that are represented through implantable microchips that release a specific drug electronically at the diseased sites and communicate with the patient or doctor wirelessly. These microchips have specific sensors and they have the ability to record parameters of the organism, such as heart rate, glucose rate, temperature, or cellular activities. These noninvasive microelectronic methods can improve the performance (precision, personalization, automation), producing less pain and a lower number of side effects (Gianchandani and Meng, 2012). Tissue regeneration is the process of renewal and growth to repair or replace tissue that is damaged or suffers from a disease (Boisseau and Loubaton, 2011). For the regeneration of a deceased tissue there are two options: the first one is to create a new tissue in vitro and then place it in the body through surgery and the second one is to stimulate in vivo the natural tissue repair using cultivated cells at the

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place of disease or damage. These two options may induce immune responses and they also have a risk of disease transmission, so the alternative consists in nanotechnologies that have the matching dimensions to reach the level of an interaction with proteins that influence cell adhesion and regeneration (Stylios et al., 2005). Living cells can be combined with biomaterials to obtain an optimal regeneration effect. The cells provide biological functionality and biomaterials act like a matrix that can support cell proliferation. These materials must interact with proteins and cells without disturbing their normal activity (Boisseau and Loubaton, 2011). The studies show that synthetic polymers, for example, are a good option to produce a three-dimensional scaffold that has no disease or side effect risk. The next idea is to develop synthetic complex organs (Stylios et al., 2005). Nanomaterials can also deliver genes that control stem cells in consideration of regenerating a tissue. Another option is the implantation of bioactive materials that induce a self-healing effect through the stems cells of the patient without activating an immune response or infection. These materials must be biocompatible and cytocompatible. Regenerative therapies can be developed for diseases of vascular, bone, cartilage, heart, muscle, or brain tissue (Boisseau and Loubaton, 2011). Nanotechnologies also include microelectromechanical systems (MEMS) using nanofibers, nanoparticles, nanospheres, microneedles, microcapsules, or implantable pumps. These devices are small in size which helps them interact with biological molecules and aids in noninvasiveness. Other research includes studies of microchips, microneedles, oral drug delivery platforms, pumping systems, miniaturized osmotic pumps, and additional structures such as tubes, sheets, or spirals (Gianchandani and Meng, 2012). As nanotechnology contains structures that are smaller than natural human cells, being similar to enzymes and receptors, these systems can be used to produce interactions on the cell surface and inside the cells. Once they penetrate the cell, these nanostructures have the ability to detect a certain disease and to cure it by delivering specific drugs to the zone of interest (Stylios et al., 2005).

4  NANOTREATMENT OF CANCER Classical cancer treatment is achieved nowadays through chemotherapy, radiotherapy, and surgery used only in the case of solid tumors. Unfortunately, all these methods involve the risk of side effects for some patients, due to the fact that they cause enhanced damage also for healthy cells. The use of a therapy that has a targeted impact on tumor cells without having an effect on normal cell function arouses particular interest. The treatment of cancer can also be made through epigenetic therapy, nuclear targeting, endoradiotherapy, immunotherapy by vaccination, and nanotechnological methods of drug delivery. Drug-delivery nanosystems can guarantee that the carried drug will arrive at the target and will act there preferentially. Active targeting means that the complex integrates a particular ligand for receptors of the targeted tissues such as small molecules, proteins, or peptides. Passive targeting represents the diffusion and accumulation of complexes in tumors or inflammations. Apoptosis can be used to kill tumors in a selective way while controlling the expression and function of molecules related to the apoptosis process. One way of treating the cancer is to destroy tumor cells from within through nanoshells that can absorb light at specific wavelengths and release heat to kill these cells. After the targeted incorporation

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of these nanoshells into the tumor cells they absorb near-infrared (NIR) light and eliminate intense heat that kill cancerous cells without affecting the normal ones (Aly, 2012). The physiopathological proprieties of cancer are used for passive targeting. The permeability and retention effect (EPR) increases the accumulation of nanoparticles conjugated with drugs in the tumor cells; it is grounded on the presence of permeable blood vessels of tumors that have gaps with sizes of 100–780 nm. This targeting can occur without the functionalization of the nanocarriers’ surface with specific ligands (Duhem et al., 2014; Kanapathipillai et al., 2014; Nichols and Bae, 2012).

5  NANODRUGS AND NANOCARRIERS For the active targeting, nanocarriers are functionalized with a high-affinity ligand that attaches to a specific receptor on a targeted tumor cell. Ligands are represented by small molecules such as carbohydrates or folic acid and macromolecules such as antibodies, peptides, proteins, and oligonucleotides. The efficiency of the targeting requires the stability of the nanocarriers to prevent the early release and degradation of the drug in the bloodstream (Kim et al., 2014; Wicki et al., 2015).

5.1  MAGNETIC NANOPARTICLES Magnetic nanoparticles can be used in biomedicine because of their small size, optical proprieties, stability, and easy functionalization. They can help in applications such as diagnosis, drug delivery, and radiotherapy (Ouvinha de Oliveira et al., 2014). In biomedicine, MNPs are often used in drug delivery, noninvasive tumor imaging and early malignant growth detection, on the strength of optical and magnetic properties (Quyen Chau et al., 2015). MNPs are proven to be a suitable choice for hyperthermia treatment, having the possibility to apply an external magnetic field that could guide these nanoparticles to an exact area (tissues and/or organs) (Rivas et al., 2013). Moreover, an organic/inorganic molecule shell could be linked to the surface of the MNPs to allow a special bonding to target a specific location. These kinds of nonmagnetic attached particles that are functionalized play specific roles in preserving the magnetic properties of the core. By protecting the MNPs, it increases not only the biocompatibility, but also the nontoxicity properties and therefore future functionalization methods (Rivas et al., 2012). Hyperthermia represents an abnormal increase of the body temperature and can appear in infections as a response of the immune system. High temperatures can be used to destroy cancer cells to achieve tumor regression. Cancer cells are sensitive to hyperthermia therefore the apoptosis process will occur at 42–45°C in comparison to healthy cells. As this heating may produce side effects to the surrounding tissues, magnetic nanoparticles (MNPs) can be used for the magnetic fluid hyperthermia (MFH). A suspension of MNPs is injected at the tumor zone and these can induce an active or passive accumulation. The active one means using ligands on the nanoparticles’ surface that are specific for receptors present on the surface of tumor cells and the passive one refers to the enhanced permeability and retention effect (EPR) of MNPs. MNPs inside the tumor can change electromagnetic energy into heat with the aid of an external magnetic field (Lima-Tenório et al., 2015). In this way, nanoparticles will help generating local temperature without disturbing the cells in surrounding tissues. This type of therapy makes the difference from traditional methods to being noninvasive as the small size of the injected particles permit them to pass through biological barriers and by decreasing the toxicity level (Johannsen et al., 2007; Lima-Tenório et al., 2015).

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Iron oxide-based nanoparticles that are properly coated have the main in vivo application in hyperthermia, because of their biocompatibility and nontoxicity. They are also used in other biomedical applications, for example, drug delivery, cell and/or tissue targeting, and resonance imaging (Rivas et al., 2012). A good example of this kind of nanoparticles would be superparamagnetic iron oxide nanoparticles (SPIONs). SPIONs are, presently, an innovative type of MNPs, due to their particular magnetic properties and small size (Agiotis et al., 2016). SPIONs are nanoparticles that are effective at targeting tumor-based cells because of the enhancement of permeability, their biocompatibility, and the retention effect (EPR) on the grounds of damaged vascular architecture of cancerous tissue and by averting reticuloendothelial system (RES), in reaching the target. Alongside from their unique particles, they should be hydrophilic to reduce the endorsement of macrophages and have longer circulation times to reach the site of interest with a strong effect (Brannon-Peppas and Blanchette, 2004). By conjugation with chitosan, which is an encouraging carrier for therapy and also therapeutic agents in cancer, the SPIONs can be delivered to a specific tumor site. In addition, ligands attached covalently to SPIONs can actively target, and radiolabeled antibodies attached to the nanoparticles enhance tumor theranostics strategies. Doxorubicin (DOX), an antibiotic used as an anticancer drug, improves the chemotherapy efficacy by restraining the synthesis of nucleic acids inside the tumor cells. To sum up, this aggregation activates the signal of apoptosis supported intrinsic and extrinsic paths (Zolata et al., 2014). Magnetite (Fe3O4) nanoparticles’ applications are vast, because they are biocompatible and chemically stable, but the most useful application is drug delivery for anticancer purposes (Ansar et al., 2015). Yu and coworkers conducted research on a magnetite nanoparticle, coated with silica, modified the surface group, and combined it with a polymer and eventually adjusted it by an imidazole group. Finally, DOX was loaded into the compound. Results showed superparamagnetic properties and pH-responsible release of the drug, in vitro, making this kind of particle an ideal candidate for tumor targeting (Yu et al., 2013). A new type of therapy called sonodynamic therapy (SDT), using ultrasound (US) that has good penetration and activates sonosensitizers, giving rise to reactive oxygen species (ROS), is being used for large tumors embedded in deep tissue. This type of therapy has many advantages, like being applied directly to the tumor and raising the drug intake by amplifying the toxicity of the chemotherapeutic agents. One of the most promising sonosensitizers explored for the treatment of cancer is TiO2, which does not present any cytotoxicity: it is biocompatible, it has an easy preparation method, and it has a stable structure when interacting with biological systems. The most important advantage of TiO2 is the fact that it has the power to generate oxidative radicals through ultraviolet (UV). To attain a therapeutic effect, the titanium dioxide-encapsulated Fe3O4 nanoparticles were functionalized with DOX, resulting in compounds appropriate for codelivering the targeted sonosensitizer and great anticancer drug for the treatment of cancer. Shen et al. (2015) conducted their research on applying an external magnetic field to the administered Fe3O4@TiO2-DOX, and they concluded that the compound is specifically delivered to the cancer cells and absorbed for a long period of time. Gao and coworkers combined a noble metal with a magnetic nanoparticle in the form of Au-Fe2O3 to induce cancer cell–specific apoptosis, but also imaging of the apoptotic process in real time. They combined Au with γ-Fe2O3 because both of them preserved their great optical and catalytic properties. The result was coupled with two peptides: RGD (Arg-Gly-Asp sequence) and FITC-DEVD (fluorescein isothiocyanate-conjugated DEVD peptide). Functionalizing the Au-Fe2O3 compound with peptides led to a targeting therapy and also imaging in a simultaneous way; moreover, it is an excellent choice for applications in cancer diagnosis and therapy (Gao et al., 2012).

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Magnetic nanoparticles such as iron oxides (magnetite and hematite) represent the first choice in cancer treatment and diagnosis, especially hyperthermia, due to their superparamagnetic properties. Further studies are being conducted to develop a new compound that will have a specific target and not harm normal cells.

5.2  NOBLE METAL NANOPARTICLES Noble metal nanoparticles, such as gold nanoparticles and silver nanoparticles present excellent properties for the use of drug delivery for antitumor applications. Both of them have to be functionalized and doped to improve their unique properties. Silver nanoparticles have good characteristics for cancer treatment besides their antimicrobial proprieties. They have the ability to inhibit the proliferation of tumor cells by constraining the angiogenesis. Studies show also that these nanoparticles are cytotoxic for cancer cells and induce apoptosis having a significant effect on prostate tumor cells (Ouvinha de Oliveira et al., 2014). AgNPs represent a suitable choice for cancer applications. The properties that make them stand out are the following: stability in aqueous solutions, small size, precise distribution, high area negative charge, biocompatibility, and have the power to enter the cancerous cells and inhibit their viability through induction of apoptosis (Guo et al., 2015). However, there are some concerns about the toxicity of metallic nanoparticles on healthy cells because of the metallic ions derived from them. These ions can produce reactive oxygen species (ROS) that can damage DNA molecules or lead to intracellular calcium homeostasis and lipid peroxidation disturbing the normal cell cycle (Ouvinha de Oliveira et al., 2014; Sullivan and Chandel, 2014). The nanoparticles can form aggregates that can induce inflammatory damage to the microcirculation, especially to capillary vessels. Investigating the aggregation tendency is an important step in analyzing metallic nanoparticles, particularly when agents are administered at a high particle concentration (Chapman et al., 2013). AuNPs (gold nanoparticles) are particles that are clustered or colloidal, having a diameter of a few to hundreds of nm, with core or surface coating. These nanoparticles present a number of advantages, the most outstanding being its synthetic versatility, which can allow the modification of the properties of size, surface, or shape. Either size or shape control can efficiently achieve AuNPs with a size between 1 and 150 nm, with various morphologies that can offer different properties, such as chemical, electrical, and/or optical (Personick and Mirkin, 2013). AuNPs have a coating around the core that is not only protective, but can also be modified to control the stability of the particle, its solubility, and its interactions with the biological environment. This kind of nanoparticle has the potential to be utilized as targeting, labeling, and therapeutic agents. One of the most relevant applications of AuNPs is radiosintetization (RT), which has been studied over the past decades and is currently under research for its clinical purposes (Her et al., 2015). Due to AuNPs capacity to absorb the light, by using a local surface plasmon resonance (LSPR), they represent an ideal candidate for applications in biomedicine. By modifying the AuNPs’ size and shape, the LSPR wavelength can vary from ultraviolet (UV) spectra to near-infrared (NIR) spectra. Antitumor effects can be reached directly by photothermal ablation or by inducing a hyperthermia of the AuNPs. These effects sensitize the cells to RT on the direction of increasing blood flow to reduce the hypoxia of the tumor, activating immunological responses and inflecting heat-related genes that influence the damage responses of DNA (Her et al., 2015).

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A good way to transport and unload pharmaceutical substances is by using gold nanoparticles because they have special and unique chemical and physical properties. Basically, gold nanoparticles are nontoxic, inert, and they have sizes between 1 and 150 nm. The composition consists of a central part made of gold atoms that can be functionalized by adding a monolayer of thiol fragments. Gold nanoparticles can be used together with anticancer drugs as they show a decrease of tumor cell proliferation. Studies show that these particles used in combination with drugs have a higher effect than the simple drugs or the simple particles (Aly, 2012). Because of their impressive properties, gold nanoparticles are useful for the delivery of drugs with high toxicity by modifying their surface chemistry. For example, cytokine TNF-α (tumor necrosis factor alpha) is an antitumor and highly toxic element that can be incorporated in PEG-coated gold nanoparticles, decreasing the systemic toxicity and having a positive impact on tumor damage. Experiments were made to check the accumulation of these complexes in healthy organs such as liver, spleen, and lungs, and the results showed that such aggregates are absent. Many substances were studied by bounding them to gold nanoparticles for different types of cancers like osteosarcoma, prostate cancer, breast cancer, cervical cancer, or lung carcinoma. The antitumor properties were proved by the fast accumulation of these particles in tumor cells with an increased tumor toxicity compared to the substances used alone (Nazir et al., 2014). Gold nanoparticles show a cytotoxic effect on prostate cancer cell lines because of their size, shape, surface functionalization, and thermal diffusion. The local hyperthermia generated by gold nanoparticles cause cancer cell death (Ouvinha de Oliveira et al., 2014). A comparative study on Au and Ag nanoparticles showed that AgNPs exhibit a higher potential of photodynamic effect, by reducing the viability of the tumor cells and their proliferation (El-Hussein et al., 2015). A joint study on silver and gold nanoparticles used in cancer therapy was conducted by Petra and coworkers to determine if they have potential in this field. Both of them, biosynthesized b-Au-500 and b-Ag-750, were functionalized with leaf extract from Butea monosperma (BM), which acts like a reducing agent and stabilizing/capping agent. These nanoparticles were functionalized with Doxorubicin (DOX), an anticancer drug that is well known and approved by the FDA (Food and Drug Administration). The results were promising, these drug delivery systems (DDS) show great therapeutic efficacy against cancer cells and biocompatibility in relation to normal cells. To sum up, in vitro testing shows great potential in being a drug delivery vehicle for the therapy of cancer (Patra et al., 2015).

5.3  UPCONVERSION NANOPARTICLES Upconversion nanoparticles (UCNPs) represent the basis of a unique category of nanomaterials, for instance lanthanide (Ln3+) in the form of lanthanide-doped nanocrystals. These kinds of nanoparticles are currently used in biomedicine, for the treatment of tumor cells. UCNPs proved that their flexibility and facile properties in nanotechnology make them an exquisite solution not only for cancer therapy but also imaging (Wang et al., 2011). According to Hu et al, the UCNPs fused with fluorescein (FITC) dyes and linked with folic acid (FA) represent a good solution for targeted imaging of cancerous cells (Hu et al., 2009). Apart from this research, Xiong et al. (2009) conjugated UCNPs to FA and arginine-glycerin-aspartic acid (RGD) peptide, with good in vivo results for tumor targeting and also imaging. Furthermore, another study on polyethylene glycol (PEG) linked with UCNPs and loaded with doxorubicin (DOX) reveals that this

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material complex has a promising future in varying the pH value, drug delivering, and controlling the release to tumor cells (Wang et al., 2011). Photodynamic therapy (PDT) is currently being treated by near-infrared-to-visible upconversion technology and is a new type of noninvasive treatment used for cancer therapy. NaYF4: Yb/Er nanocrystals are the upconversion nanoparticles of choice in this research, due to being efficient. Mesoporoussilica-coated NaYF4: Yb/Er (sodium yttrium fluoride, ytterbium, and erbium) are the choice for PDT use. Vitamin B12 (VB12), a water-soluble vitamin that is easy to obtain and also biocompatible is incorporated inside the shell of the mesoporous silica and as a PDT drug. Results showed that this nanocomposite induced apoptosis of the cancer cells, by producing ROS and killing the cancerous cells only when exposed to the near-infrared radiation light (Xu et al., 2016). Upconversion nanoparticles represent a revolutionary type of nanomaterials. Lanthanide and sodium yttrium fluoride, ytterbium, and erbium are the best choices for imaging, but also used in drug delivery with anticancer purposes.

5.4  QUANTUM DOTS Quantum dots are nanocrystals composed of heavy metals that emit light and have sizes in the range of 1–10 nm. They have superior properties compared to other fluorescent particles because of their photostability and long-term fluorescence intensity (Alivisatos, 2004). The application of the quantum dots is to track in real time the dynamics of cellular components. These nanoparticles do not show adverse effects on the proliferation, differentiation, morphology, and viability of healthy cells (Ferreira et al., 2008; Retèl et al., 2009). Quantum dots (QDs) can be used in cancer treatment as they have application in bioimaging and biodiagnostics. A significant tool in the study of cancer biology and efficiency of therapies is the molecular imaging of viable cells. Light in different colors is emitted when QDs of different sizes are excited at specific wavelengths. The detection of cancer markers or antigens can be made with QDs, as their signal intensity is brighter and the photosensibility is better than for classical fluorescent molecules. The nanocrystals can be coated with targeting peptides to determine the localization and accumulation of the probes after the injection is made intravenous. They can help in studying the metastatic activity and potential of tumor cells in vivo. The particles can be secured against the in vivo degradation through a coating with polyethylene glycol (PEG) molecules that also increases the biocompatibility. This complex can incorporate monoclonal antibodies to recognize the prostate tumor antigens. Quantum dots are multifunctional as they can be used in drug delivery, diagnosis, and therapy, obtaining outstanding results (Kawasaki and Player, 2005).

5.5  CARBON-BASED NANOSTRUCTURES Carbon nanomaterials such as graphene oxide and carbon nanotubes, either single wall or multiwall, are a safe choice for applications in cancer. These types of nanomaterials gained attention in the past decade and are currently used as drug delivery carriers for anticancer therapy. Recently, carbon nanomaterials (CNMs), such as graphene and carbon nanotubes, are widely approached in multiple fields, including biomedicine. These nanomaterials present various qualities due to their morphology and physicochemical properties: their large surface area allows efficient drug loading and forms a stable covalent link between two molecules, making them desirable platforms for decoration with magnetic nanoparticles (MNPs) (Quyen Chau et al., 2015).

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Carbon nanotubes (CNTs) represent seamless cylindrical shells of graphitic carbon; each shell is made of trivalent carbon atoms that form a hexagonal network without any edges. CNTs have mechanical and electronic properties that suggest strength and flexibility (Ebbesen, 1996). CNTs are the first choice of the approach in chemistry, because they present controllable functional groups, biocompatibility, and biodegradability (Quyen Chau et al., 2015). Graphene-based materials, such as graphene oxide, on the other hand look not only safer, but also much less biopersistant (Jasim et al., 2015). Single-walled carbon nanotubes (SWCNTs) conjugated with one coupling point to distearoylphosphatidylethanolamine-hyaluronic acid (DSPE-HA) have improved biocompatibility and cancer cells targeting. Epirubicin (EPI) represents the model drug of choice, because of its efficiency, for SWCNTs functionalized by DSPE-HA, resulting in the drug delivery compound EPI-SWCNTs-DSPE-HA. Multidrug resistance (MDR) has the potential to be overcome by this carrier; EPI-SWCNTs-DSPE-HA enhanced the retention and also eased the intracellular aggregation of EPI in the MDR cancerous cells (Yao et al., 2016). Graphene oxide (GO) in the form of reduced graphene oxide (rGO) classified with the polil-lysine (PLL), which is a cationic polymer that penetrates the cells and membranes with ease and subsequently with the antibodies anti-HER2, used to bind with HER2, which is a receptor found in breast cancer in 25%–30% of the cases. Anti-HER2-rGO-PLL system is a great carrier for drug delivery in anticancer therapy, due to specific targeting, effective colloidal stability, and synergistic effect (Zheng et al., 2016). CNM/MNP (carbon nanomaterials/magnetic nanomaterials) hybrids provide the possibility of superior performances. Different types of MNPs can be conjugated to CNMs for MNPs for magnetic targeting, magnetic manipulation, capture, and separation of cells toward development of magnetic carbon-based devices (Quyen Chau et al., 2015). MNPs are utilized in treating hypothermia, killing the cancerous cells of the bones by heating the infected parts through appliance of alternating magnetic field (Afroze et al., 2016). A material that is compatible with the bone, hydroxyapatite (HA) is used because it presents properties such as osteo-conductivity, biodegradability, biocompatibility, and resembles the inorganic component found in the matrix of the bone, showing a great attraction for hosting the hard tissues (Zhou and Lee, 2011). Multiwalled carbon nanotubes (MWCNTs) have good electric, magnetic, and thermal properties and are thus considered a perfect candidate for reinforcing HA (Yang et al., 2016). By combining MWCNTs and HA results, a nanocomposite that is improved with magnetic properties to induce apoptosis in cancer cells by inducing hyperthermia magnetically at temperatures higher than 43°C. Results demonstrated that HA/f-MWCNTs nanocomposites show ferromagnetic properties and are expected to selectively target the cancer cells in bone tissues (Afroze et al., 2016).

5.6  POLYMERIC NANOPARTICLES Polymeric nanoparticles have great potential in the treatment and therapy of cancer, being used in detection and diagnosis of tumors. Polymers that have such properties are used for the release of an encapsulated drug for an extensive period of time (Soni and Yadav, 2015). Poly(d,l-lactic-co-glycolic) acid (PLGA) is among the preferred polymers, due to its biodegradability and biocompatibility (Soni and Yadav, 2015). Polyethylene glycol (PEG) produces nanoparticles that are biocompatible, highly hydrophilic, easy to modify, and possess an antifouling performance (Cui et al., 2016). PEG/PLGA copolymers are the subject of various studies, such as drug release for cancer treatment. Being approved by FDA, PEG/PLGA presents biocompatibility, biodegradability, being nontoxic even after hydrolysis. The micellar system sustains drug release, increases the stability,

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and extends the circulation time. A new trend is developed for the codelivery of therapeutic and also diagnostic agents to achieve more information about the cancer tissues (Zhang et al., 2014). Poly(3,4-ethylenedioxythiophene) (PEDOT) has a narrow structure, great conductivity, and stability, and it is highly utilized in various fields, the most promising one being electrochemistry, with applications in biomedicine as not only biosensors, but also biointerfaces. Doping PEG with PEDOT resulted in a PEDOT/PEG compound and was thereafter immobilized with AuNPs and alphafetoprotein (AFP) antibody and antigen. AuNPs/PEDOT/PEG-based AFP is a biosensor that possesses excellent properties, for example, sensitivity, selectivity, and ultralow detection limit, showing it has the potential to be used in cancer diagnosis (Cui et al., 2016). Polymeric nanoparticles, in the form of PEG, PLGA, or PEDOT show promising characteristics for being used not only as biosensors, but also as biointerfaces and therapeutic and diagnostic agents in the treatment of cancer. As albumin is an abundant protein in the body, nanocomplexes based on albumin avoid the risk of the generation of an immunological response or hemolytic problems, and they have exceptional drugdelivery proprieties (Nigam et al., 2014). For the delivery of lipophilic drugs, albumin nanoparticles allow their transportation, avoiding the need of toxic solvents and premedication against hypersensitivity reactions. The advantages are that drugs are delivered selectively in the right concentration and there is no risk of inert particle accumulation in tissues (Fanciullino et al., 2013).

5.7 LIPOSOMES The liposomes contain either natural or synthetic phospholipids. Liposomes can incorporate drugs if they are created in a liquid solution with soluble drug, by using lipophilic drugs, organic solvents, or pH-gradient methods. These structures can reach the interest zone by the extravasation from the blood vessel into the interstitial space; the tissue targeting can be active or passive. Liposomes can be functionalized by adding molecules to their lipid bilayer surface (Aly, 2012; Kim et al., 2014). Drug delivery systems based on liposomal nanoparticles are biocompatible because they are comparable with the phospholipidic bilayer of the cell membrane and they do not cause any toxicity. They can integrate hydrophobic and hydrophilic drugs, keeping them away from degradation. Current studies show that doxorubicin, curcumin, or resveratrol incorporated in liposome systems inhibits the toxicity of healthy cells even if the drug concentration gets higher. This method can be used in the treatment of prostate cancer as the liposomal formulations can target the prostate tumor cells and they inhibit the cell proliferation more than regular drugs. The issues of liposomes are instability and short half-life; these problems can be solved only by an optimal functionalization (Ouvinha de Oliveira et al., 2014), thus developing stable and pH-sensitive liposomes that are able to deliver the drug in acidic conditions (Alexis et al., 2008).

6 CONCLUSIONS The need for cancer treatment and curing, the second leading cause of death after heart diseases, is rising, especially in economically developed countries. Therefore, the need to study new materials or improve existing ones is continuous and necessary.

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Over the past decades, extensive efforts and investments have been made to diminish and eliminate the effects of cancer. Although at the moment there is no exact antidote on the market, scientists are optimistic that in the near future a new treatment will emerge. Ongoing researches are expected to make a breakthrough and revolutionize the present cancer technologies and treatment agenda. Nanotechnologies such as targeted drug delivery, smart imaging, tissue engineering, biosensors, and diagnostics represent the main tool of cancer treatment. Each and every one of them is equally important and in combination, they could improve their effectiveness. In the treatment of cancer, a wide range of nanomaterials has been used over the years. Some of them proved to be unsuited for medical purposes due to the appearance of side effects. Others confirmed they are ideal not only because of their biocompatibility in regard to human tissues, but also because they present unique properties that improve the whole complex in its interaction with the biological system of the human body. Moreover, an improvement of the properties of the material in use can be attained from surface functionalizing, doping, and colinking two or more nanospheres, nanocapsules, or macromolecular scale complexes. Future prospects are expected to change the way scientists and doctors think and come up with a better solution for cancer treatment, and in this respect personalized medicine gains appreciation, since recent findings support the relevance of differential treatment in severe and multifactorial diseases, such as cancer.

ACKNOWLEDGMENTS This work has been funded by University Politehnica of Bucharest, through the “Excellence Research Grants” Program, UPB—GEX. Identifier: UPB–EXCELENŢĂ–2016 Research project “Suprafete nanobiostructurate antimicrobiene utilizate pentru stimularea fixarii la interfata os-implant,” Contract number: 554.

REFERENCES Afroze, J.D., Abden, M.J., Alam, M.S., Bahadur, N.M., Gafur, M.A., 2016. Development of functionalized carbon nanotube reinforced hydroxyapatite magnetic nanocomposites. Mater. Lett. 169, 24–27. Agiotis, L., Theodorakos, I., Samothrakitis, S., Papazoglou, S., Zergioti, I., Raptis, Y.S., 2016. Magnetic manipulation of superparamagnetic nanoparticles in a microfluidic system for drug delivery applications. J. Magn. Magn. Mater. 401, 956–964. Alexis, F., Rhee, J.-W., Richie, J.P., Radovic-Moreno, A.F., Langer, R., Farokhzad, O.C., 2008. New frontiers in nanotechnology for cancer treatment. Urol. Oncol. 26, 74–85. Alivisatos, P., 2004. The use of nanocrystals in biological detection. Nat. Biotechnol. 22, 47–52. Aly, H.A., 2012. Cancer therapy and vaccination. J. Immunol. Methods 382, 1–23. Ansar, M.Z., Atiq, S., Riaz, S., Naseem, S., 2015. Magnetite nano-crystallites for anti-cancer drug delivery. Mater. Today 2, 5410–5414. Baker, M.E., 2013. What are the physiological estrogens? Steroids 78, 337–340. Bashyam, M.D., 2002. Understanding cancer metastasis. Cancer 94, 1821–1829. Bazile, D., 2014. Nanotechnologies in drug delivery: an industrial perspective. J. Drug Deliv. Sci. Technol. 24, 12–21. Blazejczyk, A., Papiernik, D., Porshneva, K., Sadowska, J., Wietrzyk, J., 2015. Endothelium and cancer metastasis: perspectives for antimetastatic therapy. Pharmacol. Rep. 67, 711–718.

18

CHAPTER 1  NANOTECHNOLOGY FOR PERSONALIZED MEDICINE

Boisseau, P., Loubaton, B., 2011. Nanomedicine, nanotechnology in medicine. C. R. Phys. 12, 620–636. Brannon-Peppas, L., Blanchette, J.O., 2004. Nanoparticle and targeted systems for cancer therapy. Adv. Drug Deliv. Rev. 56, 1649–1659. Chapman, S., Dobrovolskaia, M., Farahani, K., Goodwin, A., Joshi, A., Lee, H., Meade, T., Pomper, M., Ptak, K., Rao, J., Singh, R., Sridhar, S., Stern, S., Wang, A., Weaver, J.B., Woloschak, G., Yang, L., 2013. Nanoparticles for cancer imaging: the good, the bad, and the promise. Nano Today 8, 454–460. Chen, F., Zhuang, X., Lin, L., Yu, P., Wang, Y., Shi, Y., Hu, G., Sun, Y., 2015. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med. 13, 45. Couvreur, P., Gref, R., Andrieux, K., Malvy, C., 2006. Nanotechnologies for drug delivery: application to cancer and autoimmune diseases. Prog. Solid State Chem. 34, 231–235. Cui, M., Song, Z., Wu, Y., Guo, B., Fan, X., Luo, X., 2016. A highly sensitive biosensor for tumor maker alpha fetoprotein based on poly(ethylene glycol)-doped conducting polymer PEDOT. Biosens. Bioelectron. 79, 736–741. De Souza, R., Spence, T., Huang, H., Allen, C., 2015. Preclinical imaging and translational animal models of cancer for accelerated clinical implementation of nanotechnologies and macromolecular agents. J. Control. Release 219, 313–330. Discacciati, A., Wolk, A., 2014. Lifestyle and dietary factors in prostate cancer prevention. Springer-Verlag, Berlin-Heidelberg. Duhem, N., Danhier, F., Préat, V., 2014. Vitamin E-based nanomedicines for anticancer drug delivery. J. Control. Release 182, 33–44. Ebbesen, T.W., 1996. Carbon nanotubes. Phys. Today. El-Hussein, A., Mfouo-Tynga, I., Abdel-Harith, M., Abrahamse, H., 2015. Comparative study between the photodynamic ability of gold and silver nanoparticles in mediating cell death in breast and lung cancer cell lines. J. Photochem. Photobiol. 153, 67–75. Ettinger, D.S., Akerley, W., Borghaei, H., Chang, A.C., Cheney, R.T., Chirieac, L.R., D’amico, T.A., Demmy, T.L., Ganti, A.K.P., Govindan, R., 2012. Non-small cell lung cancer. J. Natl. Compr. Cancer Netw. 10, 1236–1271. Fanciullino, R., Ciccolini, J., Milano, G., 2013. Challenges, expectations and limits for nanoparticles-based therapeutics in cancer: a focus on nano-albumin-bound drugs. Crit. Rev. Oncol. Hematol. 88, 504–513. Ferreira, L., Karp, J.M., Nobre, L., Langer, R., 2008. New opportunities: the use of nanotechnologies to manipulate and track stem cells. Cell Stem Cell 3, 136–146. Ganapathy, V., Moghe, P.V., Roth, C.M., 2015. Targeting tumor metastases: drug delivery mechanisms and technologies. J. Control. Release 219, 215–223. Gao, W., Ji, L., Li, L., Cui, G., Xu, K., Li, P., Tang, B., 2012. Bifunctional combined Au-Fe2O3 nanoparticles for induction of cancer cell-specific apoptosis and real-time imaging. Biomaterials 33, 3710–3718. Gianchandani, Y., Meng, E., 2012. Emerging micro- and nanotechnologies at the interface of engineering, science, and medicine for the development of novel drug delivery devices and systems. Adv. Drug Deliv. Rev. 64, 1545–1546. Guo, D., Dou, D., Ge, L., Huang, Z., Wang, L., Gu, N., 2015. A caffeic acid mediated facile synthesis of silver nanoparticles with powerful anticancer activity. Colloids Surf. B Biointerfaces 134, 229–234. Harrington, K.J., 2011. Biology of cancer. Medicine 39, 689–692. Her, S., Jaffray, D.A., Allen, C., 2015. Gold nanoparticles for applications in cancer radiotherapy: mechanisms and recent advancements. Adv. Drug Deliv. Rev. Hu, H., Xiong, L., Zhou, J., Li, F., Cao, T., Huang, C., 2009. Multimodal-luminescence core-shell nanocomposites for targeted imaging of tumor cells. Chemistry 15, 3577–3584. Insua-Rodríguez, J., Oskarsson, T., 2015. The extracellular matrix in breast cancer. Adv. Drug Deliv. Rev. Jasim, D.A., Menard-Moyon, C., Begin, D., Bianco, A., Kostarelos, K., 2015. Tissue distribution and urinary excretion of intravenously administered chemically functionalized graphene oxide sheets. Chem. Sci. 6, 3952–3964.

REFERENCES

19

Jiang, W., Sanders, A., Katoh, M., Ungefroren, H., Gieseler, F., Prince, M., Thompson, S., Zollo, M., Spano, D., Dhawan, P., 2015. Tissue invasion and metastasis: molecular, biological, and clinical perspectives. Semin. Cancer Biol. 35, S244–S275. Johannsen, M., Gneveckow, U., Thiesen, B., Taymoorian, K., Cho, C.H., Waldöfner, N., Scholz, R., Jordan, A., Loening, S.A., Wust, P., 2007. Thermotherapy of prostate cancer using magnetic nanoparticles: feasibility, imaging, and three-dimensional temperature distribution. Eur. Urol. 52, 1653–1662. Kalemkerian, G.P., Akerley, W., Bogner, P., Borghaei, H., Chow, L.Q., Downey, R.J., Gandhi, L., Ganti, A.K.P., Govindan, R., Grecula, J.C., 2013. Small-cell lung cancer. J. Natl. Compr. Cancer Netw. 11, 78–98. Kampen, K.R., 2012. The discovery and early understanding of leukemia. Leuk. Res. 36, 6–13. Kanapathipillai, M., Brock, A., Ingber, D.E., 2014. Nanoparticle targeting of anticancer drugs that alter intracellular signaling or influence the tumor microenvironment. Adv. Drug Deliv. Rev. 79–80, 107–118. Karachaliou, N., Cao, M.G., Teixidó, C., Viteri, S., Morales-Espinosa, D., Santarpia, M., Rosell, R., 2015. Understanding the function and dysfunction of the immune system in lung cancer: the role of immune checkpoints. Cancer Biol. Med. 12, 79. Kawasaki, E.S., Player, A., 2005. Nanotechnology, nanomedicine, and the development of new, effective therapies for cancer. Nanomedicine 1, 101–109. Kim, P.S., Djazayeri, S., Zeineldin, R., 2014. Novel nanotechnology approaches to diagnosis and therapy of ovarian cancer. Gynecol. Oncol. 120, 393–403. Le Dévédec, S.E., Yan, K., De Bont, H., Ghotra, V., Truong, H., Danen, E.H., Verbeek, F., Van De Water, B., 2010. Systems microscopy approaches to understand cancer cell migration and metastasis. Cell. Mol. Life Sci. 67, 3219–3240. Lemjabbar-Alaoui, H., Hassan, O.U., Yang, Y.-W., Buchanan, P., 2015. Lung cancer: biology and treatment options. Biochim. Biophys. Acta 1856, 189–210. Lima-Tenório, M.K., Gómez Pineda, E.A., Ahmad, N.M., Fessi, H., Elaissari, A., 2015. Magnetic nanoparticles: in vivo cancer diagnosis and therapy. Int. J. Pharm. 493, 313–327. Liu, S., 2012. Epigenetics advancing personalized nanomedicine in cancer therapy. Adv. Drug Deliv. Rev. 64, 1532–1543. Logothetidis, S., 2011. Focus on the multidisciplinarity of nanosciences and nanotechnologies. Mater. Sci. Eng. B 176, 1547. Nazir, S., Hussain, T., Ayub, A., Rashid, U., Macrobert, A.J., 2014. Nanomaterials in combating cancer: therapeutic applications and developments. Nanomedicine 10, 19–34. Nichols, J.W., Bae, Y.H., 2012. Odyssey of a cancer nanoparticle: from injection site to site of action. Nano Today 7, 606–618. Nigam, P., Waghmode, S., Louis, M., Wangnoo, S., Chavan, P., Sarkar, D., 2014. Graphene quantum dots conjugated albumin nanoparticles for targeted drug delivery and imaging of pancreatic cancer. J. Mater. Chem. B 2, 3190–3195. Ouvinha de Oliveira, R., de Santa Maria, L.C., Barratt, G., 2014. Nanomedicine and its applications to the treatment of prostate cancer. Ann. Pharm. Fr. 72, 303–316. Patra, S., Mukherjee, S., Barui, A.K., Ganguly, A., Sreedhar, B., Patra, C.R., 2015. Green synthesis, characterization of gold and silver nanoparticles and their potential application for cancer therapeutics. Mater. Sci. Eng. C 53, 298–309. Personick, M.L., Mirkin, C.A., 2013. Making sense of the mayhem behind shape control in the synthesis of gold nanoparticles. J. Am. Chem. Soc. 135, 18238–18247. Pietilä, M., Ivaska, J., Mani, S., 2016. Whom to blame for metastasis, the epithelial-mesenchymal transition or the tumor microenvironment? Cancer Lett. 380 (1). Quyen Chau, N.D., Ménard-Moyon, C., Kostarelos, K., Bianco, A., 2015. Multifunctional carbon nanomaterial hybrids for magnetic manipulation and targeting. Biochem. Biophys. Res. Commun. 468, 454–462.

20

CHAPTER 1  NANOTECHNOLOGY FOR PERSONALIZED MEDICINE

Retèl, V.P., Hummel, M.J., Van Harten, W.H., 2009. Review on early technology assessments of nanotechnologies in oncology. Mol. Oncol. 3, 394–401. Rivas, J., Bañobre-López, M., Piñeiro-Redondo, Y., Rivas, B., López-Quintela, M.A., 2012. Magnetic nanoparticles for application in cancer therapy. J. Magn. Magn. Mater. 324, 3499–3502. Rivas, J., Redondo, Y.P., Iglesias-Silva, E., Vilas-Vilela, J.M., León, L.M., López-Quintela, M.A., 2013. Air-stable Fe@Au nanoparticles synthesized by the microemulsion’s methods. J. Korean Phys. Soc. 62, 1376–1381. Russo, J., Russo, I.H., 2006. The role of estrogen in the initiation of breast cancer. J. Steroid Biochem. Mol. Biol. 102, 89–96. Shen, S., Wu, L., Liu, J., Xie, M., Shen, H., Qi, X., Yan, Y., Ge, Y., Jin, Y., 2015. Core–shell structured Fe3O4@ TiO2-doxorubicin nanoparticles for targeted chemo-sonodynamic therapy of cancer. Int. J. Pharm. 486, 380–388. Siegel, R.L., Miller, K.D., Jemal, A., 2015. Cancer statistics, 2015. CA Cancer J. Clin. 65, 5–29. Singer, E.A., Dipaola, R.S., 2013. Our shifting understanding of factors influencing prostate-specific antigen. J. Natl. Cancer Inst. 105, 1264–1265. Soni, G., Yadav, K.S., 2015. Applications of nanoparticles in treatment and diagnosis of leukemia. Mater. Sci. Eng. C 47, 156–164. Steliarova-Foucher, E., O’callaghan, M., Ferlay, J., Masuyer, E., Rosso, S., Forman, D., Bray, F., Comber, H., 2015. The European cancer observatory: a new data resource. Eur. J. Cancer 51, 1131–1143. Stylios, G.K., Giannoudis, P.V., Wan, T., 2005. Applications of nanotechnologies in medical practice. Injury 36, S6–S13. Subramanian, A., Manigandan, A., Sivashankari, P., Sethuraman, S., 2015. Development of nanotheranostics against metastatic breast cancer: a focus on the biology and mechanistic approaches. Biotechnol. Adv. 33, 1897–1911. Sullivan, L.B., Chandel, N.S., 2014. Mitochondrial reactive oxygen species and cancer. Cancer Metab. 2, 17. Tesfamariam, B., 2016. Involvement of platelets in tumor cell metastasis. Pharmacol. Ther. 157, 112–119. Toy, R., Bauer, L., Hoimes, C., Ghaghada, K.B., Karathanasis, E., 2014. Targeted nanotechnology for cancer imaging. Adv. Drug Deliv. Rev. 76, 79–97. Travis, W.D., Brambilla, E., Riely, G.J., 2013. New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. J. Clin. Oncol. 31, 992–1001. Tsimberidou, A.M., Kurzrock, R., Anderson, K.C., Bast, R.C., Markman, M., Hawk, E., 2015. Targeted Therapy in Translational Cancer Research. Wiley, United States. Videira, M., Reis, R.L., Brito, M.A., 2014. Deconstructing breast cancer cell biology and the mechanisms of multidrug resistance. Biochim. Biophys. Acta 1846, 312–325. Wang, C., Cheng, L., Liu, Z., 2011. Drug delivery with upconversion nanoparticles for multifunctional targeted cancer cell imaging and therapy. Biomaterials 32, 1110–1120. Wei, S.C., Yang, J., 2015. Forcing through tumor metastasis: the interplay between tissue rigidity and epithelial– mesenchymal transition. Trends Cell Biol. White, M.C., Peipins, L.A., Watson, M., Trivers, K.F., Holman, D.M., Rodriguez, J.L., 2013. Cancer prevention for the next generation. J. Adolesc. Health 52, S1–S7. Wicki, A., Witzigmann, D., Balasubramanian, V., Huwyler, J., 2015. Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. J. Control. Release 200, 138–157. Witte, J.S., 2016. Prostate cancer: a closer look at risk factors. Clin. OMICs 3, 21–22. Xiong, L.Q., Chen, Z.G., Yu, M.X., Li, F.Y., Liu, C., Huang, C.H., 2009. Synthesis, characterization, and in vivo targeted imaging of amine-functionalized rare-earth up-converting nanophosphors. Biomaterials 30, 5592–5600. Xu, F., Ding, L., Tao, W., Yang, X.-Z., Qian, H.-S., Yao, R.-S., 2016. Mesoporous-silica-coated upconversion nanoparticles loaded with vitamin B12 for near-infrared-light mediated photodynamic therapy. Mater. Lett. 167, 205–208.

REFERENCES

21

Yan, M., Jurasz, P., 2015. The role of platelets in the tumor microenvironment: from solid tumors to leukemia. Biochim. Biophys. Acta. Yang, G., Lee, S.C., Lee, J.K., 2016. Reinforcement of norbornene-based nanocomposites with norbornene functionalized multiwalled carbon nanotubes. Chem. Eng. J. 288, 9–18. Yao, H.J., Sun, L., Liu, Y., Jiang, S., Pu, Y., Li, J., Zhang, Y., 2016. Monodistearoylphosphatidylethanolaminehyaluronic acid functionalization of single-walled carbon nanotubes for targeting intracellular drug delivery to overcome multidrug resistance of cancer cells. Carbon 96, 362–376. Yu, S., Wu, G., Gu, X., Wang, J., Wang, Y., Gao, H., Ma, J., 2013. Magnetic and pH-sensitive nanoparticles for antitumor drug delivery. Colloids Surf. B Biointerfaces 103, 15–22. Zhang, K., Tang, X., Zhang, J., Lu, W., Lin, X., Zhang, Y., Tian, B., Yang, H., He, H., 2014. PEG–PLGA copolymers: their structure and structure-influenced drug delivery applications. J. Control. Release 183, 77–86. Zheng, X.T., Ma, X.Q., Li, C.M., 2016. Highly efficient nuclear delivery of anticancer drugs using a biofunctionalized reduced graphene oxide. J. Colloid Interface Sci. 467, 35–42. Zhou, H., Lee, J., 2011. Nanoscale hydroxyapatite particles for bone tissue engineering. Acta Biomater. 7, 2769–2781. Zolata, H., Afarideh, H., Abbasi-Davani, F., 2014. Radio-immunoconjugated, Dox-loaded, surface-modified superparamagnetic iron oxide nanoparticles (SPIONs) as a bioprobe for breast cancer tumor theranostics. J. Radioanal. Nucl. Chem. 301, 451–460.