Polymer- and Lipid-Based Cancer Nanotheranostics

TABLE OF CONTENTS

INTRODUCTION

1. Using Nanotechnology in Cancer Diagnosis and Treatment

2. Polymer-based Cancer Nanotheranostics

3. Lipid-based Cancer Nanotheranostics

REFERENCES

INTRODUCTION

Cancer is a worldwide threat and there is no efficient cure for many types of this disease which is caused by damage to genes that control cell growth and division. The most important definitive feature of cancer is abnormal cell divisions that occur in various parts of the body and can spread to other organs (Nayak KA.& Pal D., 2010). The abnormal cell division suppresses the tissue or organ that it surrounds, preventing the tissue or organ from functioning. Early diagnosis is an important consideration in cancer treatment. It is difficult to diagnose cancer in the early stages with traditional diagnostic methods. Advances in nanotechnology, which is a multidisciplinary science, offers important opportunities in terms of cancer diagnosis and treatment. Cancer-causing factors can be grouped into two groups, roughly genetically and environmentally. Only 1% of cancers are caused by genetic transport. Disorders in some genes acquired by heredity cause cancer especially in childhood. However, disorders in genes such as BRCA1 and BRCA2 can cause cancer in older ages. For example, in women with these mutated genes, the risk of breast cancer has been observed to increase by 80% compared to the normal population (Ephrat PE. & Sharon LL, 2003). The remaining 99% of cancers depend on people's eating habits, working conditions, living environments, natural or artificial radiation to which they are exposed, and carcinogenic chemicals. These are called environmental cancer risk factors.

In cancer treatments, non-invasively real-time monitoring is a very important issue to determine the progress of healing. And the chemicals used in the treatment have cytotoxic properties, but these drugs must only kill the cancer cells. Practically, we can observe the cytotoxic effects on the cells and show drug efficiency. Also, animals are useful models for these kinds of experiments. On the other hand, these drugs kill normal cells too. This is the situation that we don’t want to as cancer researchers. The cancer researchers try to improve the platforms with high efficiency for cancer treatment, which don’t kill healthy cells, carry the drug to the exact desired point (cancer tissue), and be monitored by the doctors.

In this book; we mention cancer treatment, diagnosis with nanotechnology relations, and polymer and lipid-based (LB) nanotheranostic platforms.

1. Using Nanotechnology in Cancer Diagnosis and Treatment

Cancer is a disease that takes a long time to develop. It provides convenience in the treatment of diagnosis in the early stages. If the cells can be intervened in the early stages of the mutation, cancer development can be stopped (Auyang YS., 2006). In classical methods used in cancer diagnosis, X-Ray and / or CT scans detect growths and changes in organs. In suspicious cases, the diagnosis of cancer is clarified by performing a biopsy. Early diagnosis is not possible with these methods. In most cases, they can be visualized when the tumor reaches a diameter of 1 cm or weight of about 1 g. In this case, the number of cancerous cells is approximately 108. 2/3 of cancer cases were diagnosed when the case became fatal (Wang X. et al., 2004). Various problems encountered in conventional diagnostic methods reduce the efficiency of these methods.

With the help of nanotechnology, tumors can be diagnosed early. The ability of nanostructures to enter a single tumor cell increases the limits of imaging techniques in this regard. For example, in order to make a clinical diagnosis of breast cancer by mammography, 1.000.000 tumor cells must have been formed. With the help of nanotechnology, it is possible to diagnose breast cancer even when less than 100 tumor cells are formed (Singh KK., 2005). For early cancer diagnosis, cancer-specific biomolecules and nanostructures capable of forming bioconjugation are also used.

Radiotherapy, chemotherapy, and surgery are the main methods used in cancer treatment. Surgical methods consist of resection (removal) of cancerous tissue. Disadvantages of these methods are loss of organs, risk of recurrence of cancer, and the inability to apply to all types of cancer. In radiotherapy, cancerous cells are burned in the specific frequency band and with specific intensity radiation. Disadvantages of this method are damage to healthy cells as well as cancerous cells, the radiation distribution is not of equal density to all cancer cells and loss of function in the tissue exposed to radiation. In chemotherapy, it is aimed to kill cancer cells with drugs that have toxic effects and to eliminate the mechanisms that cause cancer cells to divide (Nehru MR. & Singh PO., 2008).

Classical chemotherapy drugs do not act targeted in the body. The drugs used affect cancer cells as well as healthy cells. Also, cancer cells do not reach the required doses for treatment (Wang X., et al., 2009). Chemotherapy weakens the patient's immune system and the patient becomes more susceptible to other diseases. Another problem encountered is the state of MDR (Multi-Drug Resistance) developing against anticancer components. All these important side effects are caused by the fact that chemotherapy drugs do not have a tissue-specific effect. In cancer treatment, chemotherapy drugs need to target tumors as much as possible and have a limited effect on healthy tissues. This issue is also important in terms of increasing the life and quality of the patient. Advances in nano-oncology have brought important innovations in targeted drug delivery (Goel HC. et al., 2009). In this way, the intracellular concentrations of drugs in cancer cells can be increased, while the toxic effects on healthy cells can be minimized.

The term “Theranostics” means combining diagnosis and treatment for a variety of diseases on a single platform. Nanotherapy systems, which combine diagnosis, targeted therapy, and monitoring of treatment response, are defined as theranostic nano-medicine (Sumer B.& Gao J., 2008). Theranostic is the name given to the combination of the treatment agent and the diagnostic method used to define the effect of this agent ( Kelkar SS.& Reineke TM., 2011 ). This diagnosis/treatment hybridization matches target-specific therapy with diagnostic information. This method is especially used in personalized medicine applications. This method makes it possible to classify the diseases according to the molecular phenotype, to observe the biodistribution of the molecule, and to monitor the response to treatment (Lee DY. &Li KC., 2011 ). Many diagnosis and treatment procedures in nuclear medicine are also included in the scope of theranostic. Iodine-131 (I-131) treatment and scintigraphy, which is the most commonly used diagnosis/treatment method, is the best example of the theranostic practice. By combining diagnosis and treatment on a single platform, cellular phenotypes in each tumor are first characterized and then targeted therapy can be applied. In this way, the effectiveness of treatments can be increased by applying personalized treatments instead of general treatments (Sumer B. & Gao J., 2008). Theranostic platforms can be created by adding chemotherapy drugs to nanoparticles currently used as imaging agents.

2. Polymer-based Cancer Nanotheranostics

Cancer nanotheranostics are the nanoplatforms that provide real-time monitoring non-invasively, desired functions using standard procedures in nanotechnology, controlled encapsulated or linked drug loading/releasing, individualized cancer therapy (Bhojani, Van Dort, Rehemtulla, & Ross, 2010; Chen, Zhang, Zhu, Xie, & Chen, 2017). A conventional nanotheranostic platform has two parts which are diagnostic [magnetic resonance imaging (MRI), single-photon emission computed tomography, ultrasound imaging agents, etc.] and therapeutic agents (chemotherapy, radiation therapy agents, etc.) (Chen et al., 2017). Also, the therapeutic part can act as an imaging agent because of its inherent fluorescence property (Luk & Zhang, 2014) (Figure 1). A polymeric nanotheranostic platform must have stability, targeting ability, and effective biodistribution capabilities (Afshar, 2015).

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Figure 1. A simple drawing of a nanotheranostic platform.

Any nanotheranostic particle should have three parts: A targeting agent that is generally inside of the particle for targeting the specific location, an imaging agent, and a drug molecule.

The parts of the nanotheranostic platform can be modified by lipids, polymers, and other natural or synthetic structures. Some polymers are preferable to improve the cancer nanotheranostic system because of biocompatibility, versatility, changeable physicochemical properties by adding different functional groups, controllable sizes, and degradation rates (Gopinath, 2015; Sisay, 2014). In the past few decades, the widely thought aim for cancer researchers is to send a cytotoxic agent into the cancerous tissue without sticking to the biological barriers; and in the theranostic area, to monitor the treatment which is using a single nanomedicine. Biological barriers are the main disadvantage of all cancer treatment studies. Successful polymer-, lipid- or any material-based cancer nanotheranostic agents should be prepared to reach exactly into the cancerous target and bypass all barriers on its way. This is one of the important features we call “effectiveness” in cancer treatment. Biological barriers may be separated into two different topics: Immune system, liver, kidneys, blood, spleen, and blood-brain barrier. When a foreign material goes into the body, all these systems cross it with their ways (Kievit & Zhang, 2011).

Reaching the tumor site without structural degradation and not causing an immunogenic effect is a very important issue for any cancer drug after in vivo injection. Frank Davis found the idea of PEGylation for a protein in the 1960s (Hoffman, 2016) but nowadays it is a very advantageous way for improving pharmaceutics and Food and Drug Administration (FDA)-approved PEGylated nanomedicines are commercially selling in the market (Bobo, Robinson, Islam, Thurecht, & Corrie, 2016). PEG is a commonly used polymer for drug modification. Covalent, non-covalent conjunction or coating with PEG (all of them are PEGylation) is a good strategy to target cells and tissues, to enhance the pharmacokinetic profile, to improve physicochemically (such as increasing hydrophilicity) and biocompatibility properties, to decrease immunogenicity, to reduce the rate of glomerular filtration, to prolong the blood circulation of the drug half-life in the body. (Kim, Lee, & Chen, 2013; P. Mishra, Nayak, & Dey, 2016; Suk, Xu, Kim, Hanes, & Ensign, 2016; Vllasaliu, Fowler, & Stolnik, 2014). Also, PEG coating can be resistant to aggregation, opsonization, and phagocytosis (Suk et al., 2016) that are all of the unwanted conditions. PEGylation is adaptable for both passive, active, and stimuli-responsive targeting (P. Mishra et al., 2016). 2000, 3400, 5000, 10.000, and 20.000 Da molecular weights of PEG are common in some reported studies (Jokerst, Lobovkina, Zare, & Gambhir, 2011).

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