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Öğe Assessing the In Vitro and In Vivo Performance of L-Carnitine-Loaded Nanoparticles in Combating Obesity(Mdpi, 2023) Uner, Burcu; Ergin, Ahmet Dogan; Ansari, Irfan Aamer; Macit-Celebi, Melahat Sedanur; Ansari, Siddique Akber; Kahtani, Hamad M. AlAddressing obesity is a critical health concern of the century, necessitating urgent attention. L-carnitine (LC), an essential water-soluble compound, plays a pivotal role in lipid breakdown via beta-oxidation and facilitates the transport of long-chain fatty acids across mitochondrial membranes. However, LC's high hydrophilicity poses challenges to its diffusion through bilayers, resulting in limited bioavailability, a short half-life, and a lack of storage within the body, mandating frequent dosing. In our research, we developed LC-loaded nanoparticle lipid carriers (LC-NLCs) using economically viable and tissue-localized nanostructured lipid carriers (NLCs) to address these limitations. Employing the central composite design model, we optimized the formulation, employing the high-pressure homogenization (HPH) method and incorporating Poloxamer (R) 407 (surfactant), Compritol (R) 888 ATO (solid lipid), and oleic acid (liquid oil). A comprehensive assessment of nanoparticle physical attributes was performed, and an open-field test (OFT) was conducted on rats. We employed immunofluorescence assays targeting CRP and PPAR-gamma, along with an in vivo rat study utilizing an isolated fat cell line to assess adipogenesis. The optimal formulation, with an average size of 76.4 +/- 3.4 nm, was selected due to its significant efficacy in activating the PPAR-gamma pathway. Our findings from the OFT revealed noteworthy impacts of LC-NLC formulations (0.1 mg/mL and 0.2 mg/mL) on adipocyte cells, surpassing regular L-carnitine formulations' effects (0.1 mg/mL and 0.2 mg/mL) by 169.26% and 156.63%, respectively (p < 0.05).Öğe Characterization, optimization, and in vitro evaluation of cholesterol-free liposomes(Elsevier, 2023) Ergin, Ahmet Dogan; Uner, BurcuObjectives: Alzheimer's disease (AD) is a neurological disorder that causes dementia and a progressive loss of thinking, social, and memory abilities. Afterwards, this worsening induces the person incapable of doing even the most fundamental duties. Recent research have proven that Coenzyme-q10 (CoQ10), one of the endogenous fatty acids, suppresses phosphorylated Tau protein which is GM1-ganglioside-bound amyloid beta-protein (GM1-A beta), and inhibiting the formation of amyloid plaques in Alzheimer's disease. Unfortunately, CoQ10 is poorly absorbed due to its high molecular weight (863.34 g/mol) and high lipophilicity, and its bioavailability is quite low. Therefore, we developed the CoQ10-loaded, cholesterol-free liposomes to get across the limitations.Material and methods: Liposomes were developed by ether injection method, and physicochemical characterization of the liposomes were evaluated in terms of particle size, size distribution (PDI), zeta potential, encapsulation efficiency (% EE), and process recovery as well. Release study, DSC analysis, morphological analysis, and cytotoxicity assay were performed with optimized formulations.Results: The particle size, PDI, zeta potential, EE%, and process recovery of the formulations ranged from 343.8 to 167.9 nm; 0.269 to 0.431; (-56) to (-31.7); 18.15-93.48%; 74.63 to 99.62, respectively. According to cytotoxicity tests, liposomes have no significant toxic effect on cells while having decreased p-tau 181 and p-tau 231 proteins (p > 0.05). Conclusions: As a result, the novel cholesterol-free liposome formulation were proved that it might be candidate of including the therapeutical guideline for the future alzheimer's disease treatment with these substantial results.Öğe Effects of arginine on coenzyme-Q10 micelle uptake for mitochondria-targeted nanotherapy in phenylketonuria(Springer Heidelberg, 2024) Uner, Burcu; Dwivedi, Pankaj; Ergin, Ahmet DoganPhenylketonuria (PKU) is a rare inherited metabolic disease characterized by phenylalanine hydroxylase enzyme deficiency. In PKU patients, coenzyme Q10 (CoQ10) levels were found low. Therefore, we focused on the modification of CoQ10 to load the micelles and increase entry of micelles into the cell and mitochondria, and it is taking a part in ATP turnover. Micelles had produced by comparing two different production methods (thin-film layer and direct-dissolution), and characterization studies were performed (zeta potential, size, and encapsulation efficiency). Then, l-arginine (LARG) and poly-arginine (PARG) were incorporated with the micelles for subsequential release and PKU cell studies. The effects of these components on intracellular uptake and their use in the cellular cycle were analyzed by ELISA, Western blot, membrane potential measurement, and flow cytometry methods. In addition, both effects of LARG and PARG micelles on pharmacokinetics at the cellular level and their cell binding rate were determined. The thin- film method was found superior in micelle preparation. PARG/LARG-modified micelles showed sustained release. In the cellular and mitochondrial uptake of CoQ10, CoQ10micelle + PARG > CoQ10-micelle + LARG > CoQ10-micelle > CoQ10 was found. This increased localization caused lowering of oxygen consumption rates, but maintaining mitochondrial membrane potential. The study results had showed that besides micelle formulation, PARG and LARG are effective in cellular and mitochondrial targeting.Öğe Enhanced Cytotoxic Activity of 6-Mercaptopurine-Loaded Solid Lipid Nanoparticles in Hepatic Cancer Treatment(Mary Ann Liebert, Inc, 2023) Ergin, Ahmet Dogan; Oltulu, Cagatay; Koc, Buesra6-Mercaptopurine (6-MCP) is an antiproliferative purine analog used in acute lymphoblastic leukemia, non-Hodgkin lymphoma, and inflammatory bowel disease (Crohn's disease, ulcerative colitis). Although 6-MCP has the great therapeutic potential for cancer and immunosuppressant-related diseases, 6-MCP is not readily soluble in water, presents a high first-pass effect, short half-life (0.5-1.5 h), and implies a low bioavailability (16%). On the contrary, solid lipid nanoparticles (SLNs) are prepared from solid lipids at room temperature and body temperature. In this study, SLNs were prepared w/o/w double emulsion-solvent evaporation method using Precirol ATO5 as matrix lipid. In the emulsion stabilization, surfactant (Tween 80) and polymeric stabilizer (polyvinyl alcohol [PVA]) were used. Two group formulations using Tween 80 and PVA were compared in terms of particle size, polydispersity index, zeta potential encapsulation efficiency%, and process yield%. Differential calorimetric analysis and release properties were examined for optimum formulation, and release kinetics were calculated. According to studies, sustained release was obtained with SLNs by the Korsmayer-Peppas kinetic model. The in vitro cytotoxicity studies were performed on the hepatocarcinoma (HEP3G) cell line. According to the results, successful SLN formulations were produced, and PVA was found best stabilizer. Optimum formulation exhibited significantly higher cytotoxic effects on HEP3G than on pure 6-MCP. These results demonstrated that solid lipid nanodrug delivery systems have great potential for formulation of 6-MCP.Öğe Enhanced mitochondrial co-localization of 8-escin micelle and pancreatic tumor accumulation relation(Elsevier, 2023) Uner, Burcu; Ergin, Ahmet Dogan8-escin, a triterpenoid saponin derived from plants, is a valuable natural product that possesses strong antiinflammatory, as well as the potential for anticancer effects. However, its limited water solubility restricts its application. The 8-escin was efficiently loaded into Pluronic F127 micelles using the thin film method to improve its solubility and effectiveness. The formulations underwent various tests, including particle size, encapsulation efficiency, and product yield. Human pluripotent fibroblast and AsPC-1 pancreatic cancer cell lines were subjected to MTT studies. Fluorescence-labeled micelles were used to analyze cellular and mitochondrial uptake, and the results were analyzed using flow cytometry. The micelle formulation was found to be optimal with a particle size of 94.8 +/- 6.35 nm, zeta potential of 43.2 +/- 2.62 mV, PDI of 0.13 +/- 0.01, and encapsulation efficiency of 93.20 +/- 0.09. It demonstrated sustained release in all mediums. The micelle formulation had a stronger impact on cancer cells than healthy cells, but when compared to a marketed anticancer drug, it showed less ROS activity on healthy cells. Overall, the fluorescence-labeled micelle had greater uptake by cellular and mitochondrial systems. Micelles show great potential as a drug delivery system for 8-escin and other similar anticancer candidates that operate through a mitochondria-mediated anticancer mechanism.Öğe Improving the Bioavailability and Efficacy of Coenzyme Q10 on Alzheimer's Disease Through the Arginine Based Proniosomes(Elsevier Science Inc, 2023) Ergin, Ahmet Dogan; Uner, Burcu; Balcib, Sencan; Demirbag, Caglar; Benetti, Camillo; Oltulu, CagatayCoenzyme Q10 (CoQ10) is a fat-soluble vitamin-with a benzoquinone-like structure. CoQ10 plays a role in membrane stability, energy conversion, and ATP production. It is also one of the important antioxidants in the body. The bioavailability of exogenous CoQ10 is extremely low due to its poor aqueous solubility and large molecular mass.In this study, mixed proniosomal drug delivery systems have been used to increase solubility and bioavailability of CoQ10. Arginine (semi-essential amino acid) was incorporated in the formulation composition to achieve higher efficacy by boosting nitric oxide presence, endothelial dysfunction, and cellular uptake.Proniosomes were investigated in terms of particle size, polydispersity index, zeta potential, encapsulation efficiency, and process yield, and optimization studies were carried on by utilizing STATISTICA 8.0 software considering dependent factors (carrier amount, drug amount, and surfactant ratio). Optimum proniosome formulation (particle size 187.5 +/- 16.35 nm, zeta potential: -44.7 +/- 12.8 mV, encapsulation efficiency 99.05 +/- 0.30%, and product yield: 90.55%) was evaluated for thermal analysis, in-vitro drug release using microcentrifuge method. In-vitro cytotoxicity studies of proniosomes were performed on intestinal Epithelial Cells (Cellartis (R), ChiPSC18) and no cytotoxic effects was seen during the 72 h. Besides, anti Alzheimer effect was investigated on APPSL-GFP lentivirus-infected human neural cells (APPSL-GFP-l-HNC) and Alzheimer biomarkers (p-tau181 and p-tau217).While CoQ10's relative bioavailability was statistically increased by proniosome compared to CoQ10 suspension (p<0.01, Grubb test). PK parameters of proniosome formulation, obtained with non-compartmental modeling, were fitting to the data (R-2=0.956 +/- 0.026).The study results proved that proniosomal formulation has a high potential drug delivery system for both increasing bioavailability and anti-Alzheimer effect of CoQ10.(c) 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.Öğe In vitro hepatotoxicity evaluation of methotrexate-loaded niosome formulation: fabrication, characterization and cell culture studies(Tubitak Scientific & Technological Research Council Turkey, 2023) Ergin, Ahmet Dogan; Oltulu, Cagatay; Turker, Nebiye Pelin; Demirbolat, Gulen MelikeBackground/aim: Methotrexate (MTX) is a folic acid antagonist that is widely used to treat osteosarcoma, leukemia, breast cancer, and autoimmune and inflammatory diseases. The most important concerns with MTX are its poor solubility and high toxicity, particularly in liver cells. To enhance its solubility and to minimize its toxicity, we encapsulated MTX in niosomes and investigated its hepatotoxicity mechanisms using genetic biomarkers. Materials and methods: Niosomes were successfully prepared using a modified thin film method, and the prepared monodisperse smallsized formulation was subsequently characterized. In vitro cytotoxicity studies were performed both in hepatocarcinoma (HEP3G) and healthy liver (AML12) cell lines. Specifically, immunofluorescence assay and evaluation of the expression levels of apoptotic, antioxidant, heat shock protein, and oxidative stress genes were performed. Results: The formulation had a particle size of 117.1 +/- 33 nm, a surface charge of -38.41 +/- 0.7 mV, and an encapsulation efficiency of 59.7% +/- 2.3%. The results showed that the niosomal formulation exhibited significantly higher cytotoxic effects in HEP3G than in AML12. The immunofluorescence and genetic analyses showed that the increased cytotoxicity of niosomes resulted mainly from oxidative stress and slight apoptosis. Conclusion: These results demonstrated that niosomal drug delivery systems could be a new potential formulation for minimizing MTX-related hepatotoxicity.Öğe A novel delivery system for enhancing bioavailability of S-adenosyl-L-methionine: Pectin nanoparticles-in-microparticles and their in vitro - in vivo evaluation'(Elsevier, 2021) Ergin, Ahmet Dogan; Bayindir, Zerrin Sezgin; Ozcelikay, Arif Tanju; Yuksel, NiluferNanoparticles-in-microparticles (NIMs) are novel drug delivery systems, which combine the benefits of nano-, and micro-sized drug carriers within one system to improve the bioavailability of drugs or provide site specific drug delivery. The goal of this work was to study the in vitro and in vivo characteristics of a new pectin nanoparticle based NIM formulation for colon targeted delivery of S-adenosyl-L-methionine (SAMe). The effects of different formulation parameters on physicochemical characteristics of pectin nanoparticles prepared by ionicgelation method were estimated by a factorial design. The studied formulation variables were different amounts of drug, pectin and crosslinking agent. NIMs were prepared using fluidized bed technology by coating the optimum nanoparticle formulation (particle size 301.5 +/- 20.3 nm, zeta potential: -16.3 +/- 1.7 mV, entrapment efficiency: 74.80 +/- 3.75%, product yield: 69.61%) on inert pellets via subcoating and pH- sensitive functional coating materials. NIMs were characterized by particle size, surface charge, morphology, entrapment efficiency, DSC, XRPD, in vitro drug release in the presence and absence of enzymes (pepsin and pectinase) in simulated gastric and colonic fluids. The in vitro drug release studies suggested retarded drug release, which was interpreted as an advantage for improving oral bioavailability of SAMe via colonic absorption. Comparative bioavailability of SAMe was determined after oral administration of pure SAMe solution, SAMe loaded pectin nanoparticles and NIMs to Wistar rats. Although inter-subject variability was observed, the relative bioavailability of SAMe (260%) increased via oral NIMs administration. This outcome should be supported with further bioavailability studies in larger groups. Overall, this study suggests that developed fluidized bed coating technique can be used to construct solid microparticular systems for colonic delivery of nanoparticles and overcome the difficulties in processing nanoparticles.Öğe Properties of Pluronic F68 and F127 micelles interacting furosemide from coarse-grained molecular simulations as validated by experiments(Elsevier, 2023) Dalgakiran, Erdal Anil; Ergin, Ahmet Dogan; Kacar, GokhanUnderstanding properties of the drug delivery nanoparticles is of utmost importance to investigate the properties of the currently used systems and/or to design new drug delivery materials. Therefore, in this work we strive to study particular FDA approved drug delivery materials, namely Pluronics, to understand micellization properties and drug encapsulation behaviour at the molecular-level. Our main approach is to employ molecular simulations, which are confirmed by experiments performed within the scope of this work. To that aim, dissipative particle dynamics (DPD) simulations are employed. We quantify the encapsulation efficiency properties of Pluronics, namely F68 and F127, where furosemide as the drug. The DPD simulations predict the encapsulation efficiency of the F68 system higher than F127 system due to a shorter hydrophobic section. Moreover, the micelle properties of Pluronics are quantified by means of the number of micelles, aggregation number, surface area to volume ratio, micelle sizes; and polymer chain properties such as, chain end-to-end distance, radius of gyration prop-erties. We observe similar number of micelles for both systems and the aggregation numbers are rather higher for the F127 system. Moreover, both systems adopt alike end-to-end distance and radius-of-gyration values, and the micelle sizes agree with the experimental data in literature. Furthermore, the interactions of hydrophilic and hydrophobic groups with furosemide and water are analysed by computing the radial distribution functions.Öğe Solubilization Effect of Anionic, Cationic and Nonionic Surfactants on Coenzyme Q10 Solid Dispersion(Marmara Univ, 2023) Ergin, Ahmet DoganCoenzyme Q10 (CoQ10) is an oil-soluble vitamin-like benzoquinone compound. Coenzyme Q10 plays a role in providing membrane stability, energy conversion and ATP production. It is also one of the important antioxidants in the body. The bioavailability of coenzyme Q10 is very low due to its low solubility in water and its large molecular mass. Among the solubility enhancement approaches, solid dispersions (SDs) are one of the most promising strategies. The use of suitable carrier and methodology plays a significant role in the biological response. In terms of a carrier, solid dispersions are classified broadly the third group. Surfactant-based SDs are called third-generation solid dispersions. To evaluate the surfactant effect on solubilization of CoQ10, three different surfactants of varying ratios between 1:1, 1:3 and 1:5 (w/w) were used namely sodium dodecylsulfate (SDS) (anionic), cetyl trimethyl ammonium bromide (CTAB) (cationic) and Pluronic F127 (non-ionic). CoQ10 solid dispersions were characterized in terms of particle size, polydispersity index, zeta potential, FTIR spectroscopy, DSC analysis, saturation solubility and in vitro dissolution studies. To compare dissolution rate, area under the dissolution curve (AUC), Mean Dissolution Time (MDT), mean residence time of the drug substance molecules in the dosage form (MRT), and dissolutio nefficiency % (DE%) were calculated. All the formulations showed improvement in the aqueous solubility, while the dissolution rate was increased only by Pluronic F127 (p<0.05). Among the surfactants, Pluronic F127-based SDs were found superior to other surfactants. The results revealed that surfactant-based SDs offered great success in improving the therapeutic efficacy of CoQ10.Öğe A study to enhance the oral bioavailability of s-adenosyl-L-methionine (SAMe): SLN and SLN nanocomposite particles(Elsevier Ireland Ltd, 2021) Amasya, Gulin; Ergin, Ahmet Dogan; Cakirci, Ozge Erkan; Ozcelikay, Arif Tanju; Bayindir, Zerrin Sezgin; Yuksel, NiluferThe endogenous molecule, S-adenosyl-L-methionine (SAMe) is a key factor due to its role in the methylation cycle and modulation of monoaminergic neurotransmission. Since many mental disorders have linked to the monoaminergic system, the level of SAMe in blood and cerebrospinal fluid is important in the treatment of major depression. In this study, solid lipid nanoparticles (SLN) were prepared in order to increase the limited oral bioavailability of SAMe, and SLN based nanocomposite particles (SAMe-SLN-NC) were further developed using an enteric polymer for passive targeting of intestinal lymphatic system. In this manner, it was also aimed to protect SAMe loaded SLN from harsh gastric environment as well as hepatic first-pass metabolism. Dynamic light scattering (DLS) analysis of SLN was performed, drug content was measured, SAMe release patterns were examined and the permeation ability of SAMe was investigated by the Parallel Artificial Membrane Permeability Assay (PAMPA) to characterize SAMe loaded SLN formulation. According to the PAMPA results, SAMe-SLN with the average particle size of 242 nm showed enhanced SAMe permeability in comparison to pure drug. Delayed drug release obtained by SLN nanocomposite particles indicated the protection of drug-loaded SLN in the acidic gastric medium and their intact presence in the intestine. SAMe solution or particle suspensions were prepared using 0.45 (w/v) hydroxypropyl methylcellulose aqueous solution to be applied to groups of animals for pharmacokinetic studies. In vivo pharmacokinetic parameters revealed enhancement in relative bioavailability of SAMe upon oral administration of SLN based formulations. This was attributed to intact absorption of lipid matrix through lymphatic path. A statistically significant increase in SAMe plasma levels was obtained at 15th and 30th minutes with SAMe-SLN and at 2nd and 4th hours with SAMe-SLN-NC. Overall results suggest that SLN is a promising carrier to passive lymphatic targeting of SAMe and novel SLN nanocomposite particles which presented efficient oral bioavailability is a potential way for oral delivery of SAMe and treatment of major depression.
