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    An effective VEGF-siRNA delivery via folic acid decorated and pegylated silica nanoparticles
    (Elsevier, 2022) Ultav, Gozde; Tonbul, Hayrettin; Salva, Emine
    Limitation of tumor vascularization can be helpful for cancer treatment. Silica nanoparticles can be produced in small diameters with good reproducibility, stability, and biocompatibility. Also, silica nanoparticles (SNPs) can be easily modified to carry negatively-charged oligonucleotides such as DNA or RNA and can be targeted to the tumor site by active targeting. In this study, we aimed to develop a gene delivery system exploiting the high amounts of folic acid receptors on breast cancer cells. Small-sized SNPs were synthesized and surface modifi-cations were performed by amination, PEGylation and folic acid conjugation (about 30 nm in diameter). Folic -acid conjugated SNPs (SNP-FA) complexed with VEGF-siRNA. Folic acid conjugation increased the cellular up-take by cancer cells (MDA-MB-231 and HeLa) according to the flow cytometer and fluorescence microscopy results. The VEGF gene silencing efficiency was determined by an ELISA and SNP-FA showed 73% and 50% gene silencing efficiency at HeLa and MDA-MB-231 cell lines, respectively. The results showed that SNPs with a suitable surface modification can be a good candidate for gene delivery.
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    Folic acid decoration of mesoporous silica nanoparticles to increase cellular uptake and cytotoxic activity of doxorubicin in human breast cancer cells
    (Elsevier, 2021) Tonbul, Hayrettin; Sahin, Adem; Tavukcuoglu, Ece; Ultav, Gozde; Akbas, Sedenay; Aktas, Yesim; Esendagli, Gunes
    Breast cancer is the most frequent cancer among women and impacts over two million women each year. Although many different types of anticancer agents are available for breast cancer treatment, doxorubicin is one of the most widely used drug. However, doxorubicin related side effects such as heart failure and arrhythmia limit its usage. To overcome this limitation and improve doxorubicin effectiveness, pegylated liposomal doxorubicin formulation Doxil (R)/Caelyx (R) was developed. Although cardiotoxicity related side effects were reduced with liposomal doxorubicin formulations, a superior effect was not obtained and better approaches are still needed. In this study, it was aimed to develop a more effective doxorubicin formulation than Doxil (R) and to evaluate its anticancer activity. In order to achieve this goal, small sized mesoporous silica nanoparticles (MSNs) (similar to 50 nm) were obtained, actively targeted with folic acid conjugation and loaded with doxorubicin. The obtained nanoparticles were fully characterized, conjugation was verified, and pH dependent drug release profile was shown. The nanoparticles' anticancer activity was investigated in detail on the ZR-75-1 and T47-D breast cancer cell lines. Fluorescence microscope and flow cytometry studies revealed that the cellular uptake of doxorubicin could be enhanced with small sized MSNs. Moreover, folic acid conjugation made a tangible contribution to this effect. Additionally, similar results were also obtained in cytotoxicity studies on both cell lines. In conclusion, actively targeted small sized MSNs may be a promising approach to potentiate the anticancer effect of doxorubicin.
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    Silica nanoparticle synthesis by experimental design for drug and gene delivery applications
    (Marmara Univ, 2023) Ultav, Gozde; Tonbul, Hayrettin; Sahin, Adem; Capan, Yilmaz
    Silica nanoparticles (SNPs) are one of the most researched drug/gene delivery platforms due to their easy and cheap production. Their toxicity depends on the nanoparticle characteristics like particle size or shape. It is well known that the smaller nanoparticles have a better cellular uptake potential. For this reason, in this study, we synthesized SNPs with a particle size of around 100 nm via an experimental design method that combines Technique for Order Preference by Similarity to the Ideal Solution (TOPSIS) with Taguchi design to optimize more than one response. After the optimization, average particle size, particle size distribution, zeta potential, and particle morphology of validated SNPs were analyzed. The cytotoxicity studies were performed on fibroblast cells (L929) for 48 and 72 hours. Results show that obtained nanoparticles were spherical-shaped with a size of around 100 nm and had good biocompatibility.
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    SYNTHESIS AND STRUCTURAL CHARACTERIZATION OF NOVEL 2-PYRAZOLINE DERIVATIVES: EVALUATION OF THEIR ANTIPROLIFERATIVE ACTIVITY AND FLUORESCENCE PROPERTIES
    (Polskie Towarzystwo Farmaceutyczne, 2022) Ugras, Zefine; Tok, Fatih; Salva, Emine; Ultav, Gozde; Kocyigit-kaymakcioglu, Bedia
    In this study, a series of novel 2-pyrazoline derivatives were synthesized and their structures were established by using spectral methods. The antiproliferative activities of compounds were investigated against human cell lines A-549 and MCF-7 by MTT assay and L-929 (mouse normal fibroblast) cell cytotoxicity was also examined. Apoptotic effects of the compounds in breast and lung cancer cells were assessed by Annexin V-FITC apoptosis assay using flow cytometry. The antiproliferative effect on lung carcinoma of the synthesized compounds was higher than breast carcinoma. Moreover, it was observed that none of the synthesized compounds have cytotoxic activity in healthy cells. Flow cytometry studies have shown that compounds induced apoptosis at high concentrations. Additionally, fluorescence cell imaging studies were performed for the first time in A-549 and MCF-7 cancer cell lines to determine the potential of the biosensor compounds by fluorescence microscopy. Compounds 4b, 4d, 4e, and 4f showed fluorescence properties by considering microscopic imaging.
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    Synthesis of Small-Sized Mesoporous Silica Nanoparticles by Experimental Design and Characterization for Further Drug Delivery
    (Colegio Farmaceuticos Provincia De Buenos Aires, 2019) Tonbul, Hayrettin; Ultav, Gozde; Akbas, Sedenay; Sahin, Adem; Aktas, Yesim; Capan, Yilmaz
    Studies on the use of mesoporous silica nanoparticles (MSNs) as a drug delivery system are increasing every year. The present study focused on the synthesis of small-sized MSNs for future drug delivery application. The MSNs with an approximate size of 50 nm with low polydispersity index (PDI) and high synthesis yield were obtained using the technique for order preference by similarity to ideal solution (TOPSIS) based in Taguchi design. The optimized MSN formulation was fully characterized and biocompatibility of this formulation was evaluated. The results demonstrated that optimized MSNs' average particle size was 53.2 nm, PDI was 0.125 and the synthesis yield was 84%. Moreover, obtained nanoparticles had a spherical shape and offer quite high drug loading area. Biocompatibility data also show that obtained MSN's were not reducing cell viability below 80% up to 32 mu g/mL concentration. Results indicated that obtained MSNs might be a promising approach for further drug delivery application.