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  • L Sneddon R Talamini D Trichopoulos A Znaor P

    2020-08-18

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    215 Chemistry and Physics of Lipids xxx (xxxx) xxx–xxx
    Contents lists available at ScienceDirect
    Chemistry and Physics of Lipids
    journal homepage: www.elsevier.com/locate/chemphyslip
    Bombesin conjugated solid lipid nanoparticles for improved delivery of epigallocatechin gallate for breast cancer treatment
    Rasika Radhakrishnana,b,c, Deep Poojaa,b,c, , Hitesh Kulharid, Sagarika Gudema, Halley Gora Ravuria, Suresh Bhargavab,c, , Sistla Ramakrishnaa,b,
    a Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
    b IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
    c Centre for Advanced Materials and Industrial Chemistry, School of Science, RMIT University, Melbourne, Australia
    d School of Nano Sciences, Central University of Gujarat, Gandhinagar, India
    Keywords:
    Epigallocatechin gallate (EGCG)
    Solid lipid nanoparticles
    Breast cancer
    Bombesin
    Drug targeting
    Survival rate 
    Epigallocatechin-gallate (EGCG) is a potent anti-cancer therapeutic which effectively controls the growth of cancerous 1462249-75-7 through a variety of different pathways. However, its molecular structure is susceptible to modifications due to cellular enzymes affecting its stability, bioavailability and hence, overall efficiency. In this study, we have initially encapsulated EGCG in the matrix of solid lipid nanoparticles to provide a stable drug carrier. To confer additional specificity towards gastrin releasing peptide receptors (GRPR) overexpressed in breast cancer, EGCG loaded nanoparticles were conjugated with a GRPR-specific peptide. In-vitro cytotoxicity studies showed that the peptide-conjugated formulations possessed greater cytotoxicity to cancer cell lines compared to the non-conjugated formulations. Further, in-vivo studies performed on C57/BL6 mice showed greater survivability and reduction in tumour volume in mice treated with peptide-conjugated formulation as compared to the mice treated with non-conjugated formulation or with plain EGCG. These results warrant the potential of the system designed in this study as a novel and effective drug delivery system in breast cancer therapy.
    1. Introduction
    Nanoparticle-based delivery systems have shown highly significant potential in the delivery of a wide range of therapeutic agents (Goethals et al., 2013; Pecorelli et al., 2010; Zhang et al., 2008). These nano-systems are not only able to deliver the therapeutic moieties effectively in the biological systems but also improve their physicochemical properties. Furthermore, they can be modified with one or more tar-geting ligands which direct them to the desired target-site. Therefore, these targeted nanosystems can increase the drug concentration in the diseased cells or tissues, which improves the efficacy of the therapeutic agent while simultaneously restricting unwanted circulation and accu-mulation of the therapeutic agent in healthy cells or tissues.
    Catechins, one of the constituents found abundantly in green tea, have been known for their anti-oxidative, anti-bacterial, anti-in-flammatory, anti-cancer and anti-viral activities (Cabrera et al., 2006). Epigallocatechin gallate (EGCG) is one of the most studied catechins owing to its extensive pharmacological activities (Lee et al., 2009; Tachibana, 2009; Tedeschi et al., 2002). It shows anti-cancer activity
    against many cancer cell lines by inhibiting tumorigenesis, proliferation and angiogenesis (Braicu et al., 2013). Besides, it has been seen that using EGCG in combination with traditional chemotherapy drugs leads to an increase in cytotoxic potential when compared to that of the drug alone (Pons-Fuster López et al., 2019). The structure of EGCG consists of 4 heterocyclic rings with 8 free hydroxyl groups. These hydroxyl groups are found to be susceptible to easy glucuronidation, sulphation and o-methylation (Dufresne and Farnworth, 2001) in physiological systems. These modifications interfere with the therapeutic efficiency of EGCG, as the presence and action of the free hydroxyl groups on the molecule are commonly linked with its efficacy (Tachibana, 2009). In our previous study we have addressed this issue of stability by en-capsulating EGCG within solid lipid nanoparticles (SLNs) and studied the increase in cytotoxicity against various cancer cell lines (Rasika Radhakrishnan et al., 2016). The encapsulation enhanced the cyto-toxicity of EGCG in cancer cell lines by up to 8 times. Solid lipid na-noparticles possess advantages including an improvement in drug sta-bility, drug entrapment and biocompatibility, as they are composed of easily biodegradable excipients (Schwarz et al., 1994). SLNs can be