Master Degree / Yüksek Lisans Tezleri

Permanent URI for this collectionhttps://hdl.handle.net/11147/3008

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2016 - 20192

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Subject: search.filters.subject.mPEG-peptideWoS Q: search.filters.wosQuartile.N/A

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  • Master Thesis
    Development of Endosome Disruptive Peptide and Peg Conjugate Based Doxorubicin Delivery System
    (Izmir Institute of Technology, 2019) Özkıyıcı, Selin; Top, Ayben
    In this study, it was aimed to develop a drug carrier system including a TAT-derived cell penetrating peptide in order to provide fast transport of anticancer drugs from endosomal compartments to nucleus. The drug delivery system, denoted as mPEGpeptide- oxime-DOX, was based on polyethylene glycol, endosome disruptive peptide (G2RQR3QR3G2S), and doxorubicin (DOX) conjugate. Control drug delivery system, lack of the peptide (mPEG-oxime-DOX) was also synthesized to assess the effect of the peptide on the physiochemical and drug release properties of the drug carrier. As the first synthesis step, mPEG-OH was converted to mPEG-aldehyde form using DMSO-acetic anhydride oxidation reaction and aldehyde functionalization was determined by using FTIR and NMR spectroscopy. The peptide and mPEG-peptide were synthesized using solid phase synthesis protocol, and their purities were confirmed using HPLC and MALDI-TOF mass spectroscopy analyses. Prior to DOX conjugation, hydroxyl group of serine residue in the mPEG-peptide system was oxidized to aldehyde. The anticancer drug was attached to the carrier molecules via amine-aldehyde reaction forming an acid cleavable oxime bond. Drug release, size distribution, and stability of the PEG-peptideoxime- DOX system were evaluated and compared with those results of the control drug delivery system. For mPEG-oxime-DOX, a pH programmed DOX release with the respective % DOX release values of ~68 % and ~28 % at pH 5.0 and pH 7.4 was observed. For mPEG-peptide-oxime-DOX, on the other hand, quite low DOX release (~10-15 %) was obtained for both pH values suggesting possible interaction between DOX and the peptide. Mean size value of the mPEG-oxime-DOX was measured as ~24 nm. However, mPEG-peptide-oxime-DOX, had quite lower hydrodynamic diameter values (~3nm and ~6 nm at pH 5.0 and pH 7.4, respectively) possibly due to repulsions between the arginines in the peptide domain. Observation of the morphology and evaluation of the cytotoxicity of these drug delivery systems are underway.
  • Master Thesis
    Development of Peg and Peg-Peptide Based Drug Delivery Systems
    (Izmir Institute of Technology, 2016) Balcı, Beste; Top, Ayben
    In this study, two types of drug delivery systems (DDS) were prepared; mPEG (methoxy polyethylene glycol)-HYD (hydrazide)-DOX and mPEG-peptide-(HYD)-DOX. In the design of the conjugates, mPEG was used to increase the blood circulation time. HYD provided an acid cleavable bond between the carrier molecule and DOX, whereas peptide containing histidines imparted pH responsiveness of the molecule. Doxorubicin (DOX) was selected as a model anti-cancer drug. DDS were synthesized using two steps; hydrazide functionalization of carboxylic acid of the carrier molecule followed by DOX conjugation. Hydrazide form of the carrier molecules denoted as HYD1 and HYD2 were obtained using adipic acid dihydrazide (AADH) and carbohydrazide (CH), respectively. To increase DOX conjugation, trifluoroacetic acid (TFA) and DOX amounts were changed and the reactions were carried out at the conditions giving the highest DOX conjugation (mPEG-HYD:DOX:TFA= 2.5mg:2mg:20μL per 1 mL of DMSO). The peptide (AT1=CGGGHHHHHHGGGE) was synthesized using solid phase peptide synthesis (SPPS) and PEGylated using mPEG-maleimide to obtain mPEG-AT1 conjugate. The purity of AT1 and mPEG-AT1 were confirmed using mass spectroscopy and high performance liquid chromatography (HPLC). DOX conjugation percentages were obtained as 62  7, 60  3 and 35 + 3 for mPEG-HYD1-DOX, mPEG-HYD2-DOX and mPEG-AT1-HYD1-DOX, respectively. Drug release studies indicated modest pH responsiveness of the carrier molecules obtained using AADH. On the other hand, mPEG-HYD2-DOX released  13% of drug at the end of the 72h independent of pH. For mPEG-AT1-DOX, drug release percentage values were obtained as  15% and  30% at pH 7.4 and 5.0 respectively. Cytotoxicity of the conjugates of DDS was determined using lung cancer (A-549) cell lines. DOX equivalent IC50 values were determined as 20, 40 and 5 for mPEG-HYD1-DOX, mPEG-HYD2-DOX and mPEG-AT1-DOX respectively.