2000 chitosan oligosaccharide polymer (COS) using (sulfo-SMCC) bifunctional linker.

2000 characterized the therapeutic properties of RGD peptides and monoclonal antibody (MAb) in vivo (Mitjans et al., 2000). The Cyclic RGD peptide targeted MAb could successfully inhibit ?v integrin–mediated cellular adhesion and induce detachment of previously substrate-attached tumor cells. On the basis of above studies it can be suggested that RGD peptide used as ?v antagonists for inhibiting human melanoma tumor growth.

In other case the drug loaded, cyclo(Arg-Gly-Asp-D-Phe-Lys) (c(RGDfK)) peptide modified poly lactic co-glycolic acid (PLGA) nanoparticles were prepared. The histopathological evaluations of these nanoparticles demonstrated that the advanced drug delivery system which could majorly inhibit the growth of tumor therefore offer a effective strategy for safe cancer therapy (Shen et al., 2013).

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In another study, the COS-SMCC-GGRGDSK conjugate was prepared by conjugating integrin-binding ligand (GGRGDSK) peptide with chitosan oligosaccharide polymer (COS) using (sulfo-SMCC) bifunctional linker. The conjugate was evaluated for its ability to enhance the cellular uptake of cell-impermeable materials in human ovarian carcinoma (SK-OV-3) cancer cell lines. Treatment with RGD targeted COS NPs showed a spectacular reduction in the cancer cell viability in comparison to paclitaxel (PTX) free drug, and PTX-loaded COS NPs (El-Sayed et al., 2016).

For the effective treatment of prostate cancer, a liposomal drug delivery system conjugated with cyclic arginine-glycine-aspartic acid-tyrosine-lysine peptide (cRGDyk) was developed (Wang et al., 2014). In vitro studies suggested that cRGDyk conjugated liposomes showed signi?cantly higher cellular uptake of cisplatin and higher cytotoxicity. In vivo results revealed that cRGDyk-liposomal drug system showed higher accumulation at the tumor sites with prolonged blood circulation time. cRGDyk conjugated liposomal drug system could suppress osteoclastic and osteoblastic bone lesions, relieve from pain, and improve overall survival. So these systems could serve as an effective drug system for targeted and synergistic therapy of bone metastases due to their enhanced therapeutic ef?cacy and low organ toxicity (Wang et al., 2014).

Huang et al., 2016 developed doxorubicin (DOX) and paclitaxel (PTX)-loaded pluronic micelles decorated with cyclic arginine-glycine-aspartic acid peptide (c(RGDyK)) for glioma cell targeting. These micellar systems were increase drug penetration across the blood–brain barrier via integrin-mediated transcytosis/endocytosis. The in-vitro study in U87 malignant glioblastoma cells suggested that RGD-micelles showed higher cellular uptake and cytotoxity when compared with non-RGD-micelles. In vivo fluorescence imaging demonstrated the specificity and higher efficacy of drugs to the glioma cells. RGD-micelles showed an extended median survival time of 39 days, without acute toxicity to major organs (Huang et al., 2016).

RGD peptide also activates caspase-3 which leads to damage of DNA molecule and causes tumor cell apoptosis as a result cell death occurs (Anuradha et al., 2000). Chen et al., 2001 discovered that TSU prostate cancer cells, B16 melanoma cells and endothelial cells growth could be inhibited by the synthetic RGD-tachyplesin in a dose-dependent manner in vitro and also helpful in in vivo tumor reduction (Chen et al., 2001).

The ?v-integrins (?v?3, ?v?5) maintain the existence of endothelial cells through controlling tumor angiogenesis by the interaction between the activated endothelial cells to extracellular matrix proteins. A methylated derivative of cyclic RGD-peptide was developed as an integrin antagonist, had a devastating effect on microcirculation, angiogenesis, growth and metastasis of a solid tumor in vivo (Eliceiri and Cheresh, 1999).  Chavakis et al., 2002, established that at even a low dose the RGD peptide could attain therapeutic ability by complete inhibition of early vascular endothelial growth factor (VEGF), which participates in angiogenesis of tumor cells (Chavakis et al., 2002). RGD peptide with radioactive agent has also been used in the determination of antiangiogenic effect of drug in ovarian cancer-bearing mice with a new drug agent ?avopiridol. The study suggested that ?avopiridol treatment has a dual-effect, i.e. reducing integrin ?V?3 expression on endothelial cells due to the reduction of tumor microvessel density (MVD) and up-regulating the integrin ?V?3 expression on tumor cells (Yang et al., 2014).

4.3.3. Carrier Application: RGD-Modified Carriers for cancer treament RGD-Modified Drugs for Targeted Drug Therapy

The RGD-modified therapeutic proteins, peptides and drugs can be used to regulate drug pharmacokinetics, their biodistribution and become a carrier for cell targeting and endosomal delivery (Meyer et al., 2006). Acid-sensitive cis-aconityl linkage has been used for the linking of RGD-modified PEGylated polyamidoamine (PAMAM) dendrimer loaded with doxorubicin (DOX). This RGD-mediated drug complex system may enhanced doxorubicin delivery on tumor cells due to overexpression of integrin receptors. The DOX is released in controlled manner in acidic lysosomes. This modified conjugated system also showed extended half-life and enhanced drug concentration in brain tumor as compared to normal cells (Zhu et al., 2011).  Dextran based cRGDfK conjugate was also developed by Wang et al., 2012, with the help of oleate linkage. Their in vitro estimation results verified that this conjugate system showed higher tumor targeting efficiency in MDA-MB-231 cells by effective cell internalization (Wang et al., 2012). Some more examples of RGD-modified drugs complexes with other details are summarized in Table 2.



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