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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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    Combination drug delivery with actively-targeted PLGA nanoparticles to overcome multidrug resistance in breast cancer
    (Elsevier, 2019) Tonbul, Hayrettin; Sahin, Adem; Tavukcuoglu, Ece; Esendagli, Gunes; Capan, Yilmaz
    Drug resistance is a major obstacle reducing the efficacy of cancer chemotherapy that decreases overall survival in breast cancer. P-glycoprotein (P-gp) inhibitors have potential to eliminate this problem whereas systemic usage of them such as elacridar is limited due to side effects and toxicity. This study aims to develop and evaluate paclitaxel and elacridar co-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles actively targeted to transferrin receptors to deliver anti-cancer drug and simultaneously overcome multi-drug resistance in breast cancer. In this study, PLGA nanoparticles were prepared by nanoprecipitation method and decorated with transferrin. Following characterization of the nanoparticles and drug release experiments, their efficacy was evaluated on breast cancer EMT6/AR1.0 cells which have high P-gp expression and resistance to paclitaxel. The average particle size and zeta potential of transferrin-decorated paclitaxel and elacridar co-loaded PLGA nanoparticles were 226.9 nm and - 3.9 mV, respectively. Their encapsulation efficiency was quite high (70-76%) and comparable for both paclitaxel and elacridar. Decoration with transferrin led to facilitated uptake of the nanoparticles by breast cancer cells and the combinatorial delivery of paclitaxel and elacridar through PLGA nanoparticles breached the resistance and enabled cytotoxicity. In conclusion, simultaneous and targeted delivery of nanoparticles co-loaded with P-gp inhibitors and anti-cancer drugs may be a promising approach for cancer therapy.
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    Development of curcumin and docetaxel co-loaded actively targeted PLGA nanoparticles to overcome blood brain barrier
    (Elsevier, 2021) Seko, Indrit; Tonbul, Hayrettin; Tavukcuoglu, Ece; Sahin, Adem; Akbas, Sedenay; Yanik, Hamdullah; Ozturk, Suleyman Can
    The aims of this study were to develop and characterize curcumin (CCM) and docetaxel (DTX) co-loaded poly lactide-co-glycolide (PLGA) nanoparticles (NPs) to overcome blood brain barrier. The cytotoxicity of the obtained curcumin and docetaxel co-loaded polysorbate 80 coated PLGA NPs were studied in U87 glioma cells and bEND.3 endothelial cells. The IC50 values are determined for both cell lines. In vitro release profile of the optimized formulation approximately 27% of DTX was released in the 1. hour and after a steady controlled release the DTX released percentages plateaued after 48. hour. In vitro curcumin release profile had a more controlled released by releasing less than 8% in the 1. hour and plateaued after 48. hour at approximately 78% curcumin released. Polysorbate 80 coated DTX-CCM-PLGA NPs showed no cytotoxicity and had better uptake in bEND.3 cells than uncoated DTX-CCM- PLGA NPs. The combination of CCM and DTX in PLGA nanoparticles showed a significant increased cytotoxic activity compared to CCM and DTX solutions, CCM loaded PLGA NPs and DTX loaded PLGA NPs. Moreover, in vivo biodistribution studies show that polysorbate 80 coating significantly improve brain penetration. Polysorbate 80 coated CCM and DTX loaded PLGA Nanoparticles can be potentially useful in the treatment of glioma by increasing the delivered quantity of drug in the brain through blood-brain barrier.
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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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    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 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.