Yazar "Karaca, Ezgi" seçeneğine göre listele

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    Development of EPPT1 targeted biocompatible drug delivery system and investigation of its anticancer activity
    (İstanbul Medipol Üniversitesi Fen Bilimleri Enstitüsü, 2020) Karaca, Ezgi; Yüksel Durmaz, Yasemin
    Recently, the superior properties of graphene to other biomaterials have made graphene an indispensable and unique material for anticancer drug delivery research, gene and peptide transport. On the other hand, the undeniable beneficial effects of graphene provided by a wide surface area could be limited by toxic effects. Oxidized formation of graphene (G) is a graphene oxide (GO) that comprises a lot of oxygen functional groups which make it hydrophilic. Unfortunately, despite GO with an excellent functionalization ability and good solubility in water conditions, defected areas hamper sp3 hybridized carbon surface area. Partially reduction of some oxygen functionality on GO generates reduced graphene oxide (rGO) with less solubility but better graphene properties. Therefore, reduced graphene oxide is chosen due to a wider surface area and less toxicity associated with functional groups for several biological applications. Covering the wide surface area of rGO is a common strategy to have better water solubility and biocompatibility. Poly(ethylene glycol) is a commonly used polymer that provides an ability to nanoparticle prolonged circulation time with covering the unknown nanomaterial from immune cells and decreases the uptake by the spleen and liver-resident phagocyte. This thesis study focuses on the development of an EPPT1 targeted, biocompatible graphene-based drug delivery system that can address the biocompatibility problem of rGO and show the potential of selective drug delivery into the target cell. The surface of the graphene oxide was coated with a functional copolymer poly[(ethylene glycol methacrylate)-co-(methyl methacrylate)-co-(1-pyrene methacrylate)-co-(3-azido propyl methacrylate)] P[PEGMA-co-MMA-co-PMA-co-AzPMA] that enhances the biocompatibility and water dispersibility via its PEG brushes. The copolymer also contains the multiple pyrene units to enhance the ?-? interactions with graphene surface and azide groups to do further targeting agent functionalization of the coated surface which ensures the recognition of uMUC1 receptors that is highly expressed on the membrane of breast cancer cells. Doxorubicin (Dox) as anticancer drug loading and releasing profile of the targeted, biocompatible graphene platform were deeply investigated by showing the effect of PEG brush length (500 g/mol and 2000 g/mol), the effect of having ionic azide groups on the surface, the effect of the order of drug loading and targeting agent conjugation on drug release rate. Anticancer activity was tested in two different breast-cancer cells of MCF-7 and MDA-MB-231 using MTS and Resazurin Assay. Once the drug release profiles of the carriers with the 95% drug loading capacity were investigated at acidic (pH:5.5) and the physiological conditions (pH:7.4), the results showed that longer PEG brushes slow down the drug release however it ensures the biocompatibility and aqueous medium solubility. Azide group containing carrier has a faster drug release profile because of the ionic interaction between positively charged Doxorubicin at acidic pH. EPPT1 peptide showed the charge balancing effect and slowed down the release even in the azide group containing carriers in both PEG brush molecular weights (500, 2000 g/mol). After the investigation of the drug release profile of the nanocarriers system in a different copolymer and synthesis order variety, in-vitro experiments have been done. MTS and Resazurin assay have been performed with the empty carrier, non-targeted, and targeted Dox loaded carriers with negative and positive controls on MCF-7 and MDA-MB-231 breast cancer fibroblast secondary cell lines. Resazurin has chosen as the most reliable assay to work with Dox loaded therapeutics. The results showed that 7.5 ?g/ml targeted, Dox loaded, PAMP coated rGO nanocarrier with PEG2000 brushes gives 24 % cell viability, while free Dox gives 25 % cell viability after 48h interaction with MDA-MB231 cells. Finally, the selective cellular uptake ability of the compositions was investigated qualitatively and quantitively by confocal microscopy and flow cytometry analysis and it is shown that EPPT1 targeted a graphene-based drug delivery system selectively can accumulate more into breast cancer cell lines.
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    Effective PEGylation method to improve biocompatibility of graphene derivatives
    (Elsevier, 2020) Demirel, Erhan; Karaca, Ezgi; Yüksel Durmaz, Yasemin
    The research on the use of graphene (G) in the biological applications has increased exponentially with emerging concerns regarding its biosafety and potential cytotoxicity. The modification of the surface with biocompatible polymers is a promising approach where poly(ethylene glycol) (PEG) have been extensively used. However, increasing water solubility may not be enough to make G biocompatible since it has different cytotoxicity mechanisms like absorbing cell nutrition on its wide surface area and creating reactive oxygen species through its functional groups. A PEGylation method that uses surface area of graphene oxide (GO) by taking advantage of its solubility in aqueous medium and simultaneously producing reduced GO (rGO) to eliminate the cytotoxicity that comes from functional groups might be a solution to improve biocompatibility and solubility of rGO which is an optimum graphene derivative for biological applications. To have surface PEGylated rGO instead of having edge PEGylated GO; P(PEGMA-co-MMA-co-PMA) copolymers were synthesized and coated on GO via ?-? interactions through multiple pyrene units in the copolymer. Healed conjugated surface of rGO was used as an advantage to increase the efficiency of PEGylation by in-situ reduction of GO to rGO in the presence of copolymer to obtain biocompatible, water dispersible, highly PEGylated rGO.