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    An all-in-one nanoparticle for overcoming drug resistance: doxorubicin and elacridar co-loaded folate receptor targeted PLGA/MSN hybrid nanoparticles
    (Taylor & Francis Ltd, 2024) Tonbul, Hayrettin; Sahin, Adem; Ozturk, Sueleyman Can; Ultav, Goezde; Tavukcuoglu, Ece; Akbas, Sedenay; Aktas, Yesim
    Overexpression of permeability-glycoprotein (P-gp) transporter leads to multidrug resistance (MDR) through cellular exclusion of chemotherapeutics. Co-administration of P-gp inhibitors and chemotherapeutics is a promising approach for improving the efficacy of therapy. Nevertheless, problems in pharmacokinetics, toxicity and solubility limit the application of P-gp inhibitors. Herein, we developed a novel all-in-one hybrid nanoparticle system to overcome MDR in doxorubicin (DOX)-resistant breast cancer. First, folic acid-modified DOX-loaded mesoporous silica nanoparticles (MSNs) were prepared and then loaded into PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles along with a P-gp inhibitor, elacridar. This hybrid nanoparticle system had high drug loading capacity, enabled both passive and active targeting of tumour tissues, and exhibited sequential and pH-triggered release of drugs. In vitro and in vivo studies in DOX-resistant breast cancer demonstrated the ability of the hybrid nanoparticles to reverse P-gp-mediated drug resistance. The nanoparticles were efficiently taken up by the breast cancer cells and delivered elacridar, in vitro. Biodistribution studies demonstrated substantial accumulation of the folate receptor-targeted PLGA/MSN hybrid nanoparticles in tumour-bearing mice. Moreover, deceleration of the tumour growth was remarkable in the animals administered with the DOX and elacridar co-loaded hybrid nanoparticles when compared to those treated with the marketed liposomal DOX (Caelyx (R)) or its combination with elacridar.
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    Development of a HPLC Method for the Determination of Cyclosporine A From Chitosan Nanoparticles
    (Colegio Farmaceuticos Provincia De Buenos Aires, 2012) Buyuktuncel, Ebru; Yucel, Cigdem; Kaynak, M. Sinan; Aktas, Yesim
    A reversed-phase high performance liquid chromatographic method was developed for the determination of cyclosporine A from chitosan nanoparticles. Ibuprofen was used as internal standard. The separation was achieved on a Phenomenex C18 column (150 x 4.6mm, 5 mu m) using 60: 20: 20, acetonitril: methanol: water mixture at pH 4 as mobile phase under isocratic conditions. The system was operated at 80 degrees C and the flow rate of mobile phase was adjusted to 1 mL/min. The detection wavelength was set at 205 nm. The calibration curve was linear from 2 to 150 mu g/mL with correlation coefficient values from 0.9994 to 0.9997. The lower limit of quantification 2 mu g/mL and limit of detection was 0.5 mu g/mL. Recovery was 99-101 % and the intra-and inter-day coefficients of variation were 0.94-2.32 and 2.52-3.45 %, respectively depending on the concentration. The method was found to be specific, accurate, precise and sensitive for the determination of cyclosporine A from chitosan based drug delivery systems.
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    Development of paclitaxel and flurbiprofen co-loaded PLGA nanoparticles: understanding critical formulation and process parameters using Plackett-Burman design
    (Istanbul Univ, Fac Pharmacy, 2019) Sahin, Adem; Caban-Toktas, Secil; Tonbul, Hayrettin; Yerlikaya, Firat; Aktas, Yesim; Capan, Yilmaz
    Nano drug co-delivery system is a popular strategy for combined application of two or more anticancer and/or synergistic drugs. Synergistic effects of nonsteroidal anti-inflammatory drugs and anti-cancer drugs in cancer treatment are shown in the literature. This study aimed to screen and understand the critical formulation and process parameters in the preparation of flurbiprofen and paclitaxel co-loaded nanoparticles to develop an anti-cancer nano co-delivery system. With this aim, critical parameters were determined using the Plackett-Burman experimental design (DoE). Flurbiprofen and paclitaxel drug loading amounts were considered as critical quality attributes to control the effective drug loading ratio. Furthermore, average particle size and zeta potential were also defined as critical quality attributes in order to optimize passive drug targeting and colloidal stability. Surfactant type was determined as the most significant factor for the average particle size and zeta potential. For flurbiprofen and paclitaxel drug loading into the nanoparticles, amounts of both flurbiprofen and paclitaxel were determined as critical factors. Consequently, paclitaxel and flurbiprofen were efficiently loaded into nanoparticles, and the impact of the formulation variables was successfully screened by a DoE. By controlling the determined parameters, the therapeutic efficacy of co-loaded drug nanoparticles could be maximized in further studies.
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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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    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.