4. developed by attachment of the RGD-peptides with a

4. Role RGD peptide in diagnosis and treatment of cancer:

4.1. Journey of RGD peptide: Introduction

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RGD peptide is present on several extracellular matrix and plasma proteins and help in cell adhesion (Figure 1) (Colombo and Bianchi, 2010). Firstly RGD was diagnosed as specific binding sites for fibronectin (FN) and the FN receptor (Pierschbacher and Ruoslahti, 1984). That is why it is an important area of interest various researches and successfully performed on various utilities of the peptide in different research areas. Different types of glycoproteins are present in extracellular matrix (ECM), such as von Willebrand factor (vWF), laminin, osteopontin, fibrinogen (Fg), vitronectin (VN), etc. (Kim et al., 2011), and they are functioned as RGD-adhesive proteins. RGD participates as crucial protein in cell adhesion and cell recognition process.

Figure 1. RGD peptide: Arginine-glycine-aspartic sequence

Hynes, 1987, had found that members of the adhesion receptors, were called integrins, which are the membrane proteins associated with ECM glycoprotein receptors on the cell surface (Hynes et al., 1987). The integrins binding to their specific ligands depend upon divalent cations which induce cell-cell and cell-matrix adhesion. Therefore, integrins comprise cell adhesion receptors not only for cell-matrix adhesion process but also for indicating movement of molecules across the cell membrane. The integrins receptors are present in different types of animal species from lower class animals (like sponges) to the highest class animals (like mammals) which may be expressed as a large heterodimeric type of receptors found on the cell surface (Yamada and Geiger, 1997). These receptors are helpful in various elementary cellular mechanisms like proliferation, differentiation, attachment migration, and survival. They also initiated and progressed a lot of diseases like osteoporosis neoplasia, inflammation, angiogenesis, tumor metastasis and thrombosis (Humphries et al., 2006). 

Nowadays, the development of RGD-based ligands is the major area of research of interest for theranostic purpose which means these systems may be used for the effective diagnosis and treatment of various diseases for example it is used to target tumor cells by identification followed by internalization. This system also used in the study of tissue engineering, i.e. the regenerating of transplanted tissue.

RGD tailored imaging agents and therapeutic agents have been investigated and developed by attachment of the RGD-peptides with a drug loaded carrier system. RGD-peptides and RGD-mimetics have also been applied to polymers, liposomes and peptides by chemical methods to enhance the pharmacological effects of drugs. In addition, RGD-peptides have been also developed in gene delivery by using of viral and non-viral vectors (Temming et al., 2005).

4.2. Types of the RGD peptide

RGD-peptides may be of two types i.e. linear and cyclic RGD on the basis of sequence and their structure. Cyclic peptides are more advantageous as compare to linear peptides because they are resistant to protease enzymes, more stable and also have better ability to interact towards integrin receptors with high affinity. Therefore, the cyclic RGD peptides exhibit a better activity compared to the linear RGD peptides (Verrier et al., 2002; Frochot et al., 2007). RGD peptides have wide range of applications in scientific and clinical research due to following characteristics (Hilgenbrink and Low, 2005; Bellis, 2011):

Ø  The size of RGD peptide is much smaller as compared to other biological moiety like monoclonal antibodies, so that the RGD modified carrier system can easily reach to the tumor site;

Ø  Easily translate to use in clinics due to relatively easy and inexpensive synthesis

Ø  The use of RGD shows low immunogenicity or pathogen transfer;

Ø  When compared with folic acid, the RGD peptides have various applications in tumor therapy, as well as can be coupled to material surfaces in controlled orientations and densities.

RGD peptide has a specific site for a number of extracellular matrix proteins which helps in cell recognition and attachment. RGD peptide also binds to angiogenic cells of newly formed blood vessels, which regulates cellular progress and development. RGD also helps in cell spreading, cell attachment, actin-skeleton formation, and focal-adhesion formation with integrins. These four co-related phenomenon are very essential for proper functioning of cell physiology and cell cycle (Hwang et al., 2007). 

Integrins glycoprotein receptors are heterodimeric in nature which may be of ?5?3 and ?v?3 type and responsible for control of cell-cell and cell-extracellular matrix interactions. At the early stage of angiogenesis integrin ?v?3 has important role. It is over-expressed at low levels on normal epithelial cells and endothelial cells, and also over-expressed on the stimulated endothelial cells of tumor neovasculature and other tumor cells, including melanomas, osteosarcomas, glioblastomas, neuroblastomas, breast cancer and lung carcinomas (Zitzmann et al., 2002). There are other types of integrins like ?3?1, ?v?5, ?v?1, ?8?1 and ?v?6 also present, which may also get recognized by the RGD peptides (Plow et al., 2000).

Efficient immobilization of the RGD peptide on the surface of biomaterial is very essential in tissue engineering. Cells interact with cell surface receptors with adhesion in the ECM. It has been already reported that the RGD peptide improved cell adhesion and also used as a synthetic ECM protein to stimulate specific cellular responses and to encourage new tissue formation (Liu, 2006).

4.3. Applicability of RGD Peptide in different fields

Peptides are broadly used in various types of physiological and pathological processes as discussed in previous sections. As other peptides, the RGD peptide may also be very useful in the designing and development of new antithrombotic drugs, anti-tumor drugs and tissue engineering along with diagnosis of tumors.

4.3.1 Theranostic Application: Radiolabelled RGD Peptides for Tumor Imaging and Diagnosis

Radiolabelled RGD peptide shows the high specificity and sensitivity for the tumor cells. This may be due to the relatively high and specific affinity for ?v?3 integrins which are over-expressed in tumor neovasculature.