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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 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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    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.