Aytekin, Eren; Gözcü, Sefa; Polat, Heybet Kerem; Akşit, Hüseyin; Karakuyu, Nasıf Fatih; Kurt, Nihat; Sofu, Gülşah Usta; Akkaya, Züleyha Yalnız; Tebrizi, Behzat; Çalış, Sema

Corneal neovascularization (CV) is a vision-threatening condition characterized by the pathological ingrowth of blood vessels. While corticosteroids and anti-VEGF agents are standard treatments, their prolonged use is associated with significant ocular side effects. This study aimed to develop and optimize nanosuspensions of Apigenin (APG) and Apigenin-7-O-glucoside (APG 7) to enhance their ocular bioavailability and evaluate their efficacy in the treatment of CV. APG and APG 7 were isolated from Petroselinum crispum . Nanosuspensions were formulated using an anti-solvent precipitation method, optimized via a 23 factorial design considering PVA concentration, Span 80 concentration, and homogenization speed. The physical properties, including particle size, PDI, and zeta potential, were characterized. In vivo efficacy was assessed over a 7-day treatment period in an alkali-burn induced rat CV model through clinical scoring, histopathology, and immunohistochemical analysis of VEGFA and IL-6 expression. The optimized APG nanosuspensions exhibited a mean particle size of ∼166.9 nm with high stability. In vivo studies demonstrated that 0.05% APG nanosuspension significantly inhibited corneal angiogenesis, reduced stromal edema, and downregulated VEGFA and IL-6 expression compared to the untreated injury group (p < 0.05). Conversely, APG 7 formulations failed to show significant therapeutic efficacy, likely due to limited corneal permeability attributed to the glycoside moiety. The 0.05% APG nanosuspension presents a promising, non-invasive therapeutic alternative for CV management, offering effective anti-angiogenic activity with improved ocular delivery characteristics.

Ozdal, Zeliha Duygu; Recber, Tuba; Demirel, Murside Ayse; Gultekin, Yakup; Nemutlu, Emirhan; Vural, Imran; Takka, Sevgi

Chemotherapy-induced nausea and vomiting (CINV) typically occurs in two distinct phases: an acute phase, which arises within the first 24 h following chemotherapy, and a delayed phase, which develops between 24 and 120 h afterward. While acute CINV is now effectively controlled using 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, managing delayed CINV remains a significant clinical challenge. This study was aimed to develop Ondansetron hydrochloride (OND), loaded nanocarriers featuring high encapsulation efficiency (EE), to enable sustained drug release over several days. OND loaded sustained release liposome and lipid polymer hybrid polymeric nanoparticle (LPHNP) were prepared. The prepared formulations were characterized in terms of particle size and distribution, zeta potential, encapsulation efficiency and drug release in an in vitro study. The effects of the type of phospholipids, phospholipid/cholesterol molar ratio, and pH of hydration medium on liposome formulations were examined. In LPHNP formulations, the effect of external water phase volume, phospholipid type, preparation method, and pH of the aqueous phase was evaluated. In vitro cytotoxicity of the formulations was determined using L929 fibroblast cells. Optimum LPHNP formulation and the commercial product (Zofer®) were administered subcutaneously in a single dose to Wistar albino rats. It was found higher Cmax and MRT in LPHNP formulations than Zofer®. In this study, the effectiveness and safety of Ondansetron hydrochloride loaded LPHNP formulations were determined.

Polat, Heybet Kerem; Karakuyu, Nasıf Fatih; Ünal, Sedat; Turanlı, Yasin; Pezik, Esra; Sofu, Gülşah Usta; Sarman, Emine

Corneal neovascularization (CnV) is a significant ophthalmological condition often leading to discomfort and vision impairment. Due to the limitations and side effects associated with conventional drug therapies for CnV, innovative treatment strategies are being explored. In this study, the potential of alpha-lipoic acid and rutin-loaded thermosensitive in situ gels for the treatment of CnV was evaluated. The ocular in situ gel was formulated using the cold method and included chitosan, poloxamer 407, and poloxamer 188 as polymers. A design of experiments (DoE) approach was employed to investigate the effects of formulation variables on critical quality attributes, including pH, gelation temperature, and viscosity. The optimized drug-loaded gel exhibited a pH of 5.05 ± 0.1, pseudo-plastic flow behavior with a viscosity of 341 ± 26 cP at 25 °C, and gelation at 34 ± 0.4 °C. Drug release followed Weibull and first-order kinetics. Ocular safety was confirmed through in vitro cytotoxicity studies using L929 and ARPE-19 cell lines. In vivo studies in rats and histochemical analyses of the cornea demonstrated that the optimized formulation (Formulation K) was as effective as dexamethasone, a standard treatment for CnV, and further promoted epithelial cell regeneration. Histological evaluations of ocular tissues revealed reduced inflammation and neovascularization in the Formulation K group, supporting its therapeutic potential. Overall, our findings suggest that the developed in situ gel system offers sustained drug release and enhanced therapeutic efficacy for the treatment of corneal neovascularization.

Karakuş, Emir Ersel; Sert, Esra; Erol, Ayşe; Kalındemirtaş, Ferdane Danışman; Özbaş, Fatih; Karakuş, Selcan

The development of multifunctional nanoformulations with enhanced anticancer activity and drug delivery potential is of increasing scientific importance. In this study, we synthesized and characterized copper oxide nanoparticles mediated by oolong tea extract (OE-CuO/Cu2O NPs) using a variety of techniques, including TEM, XRD, FTIR, and UV–Vis spectroscopy, to assess their physical and chemical properties. Remarkably, the results revealed that OE/CuO NPs exhibited significantly enhanced anticancer activity compared to OE alone. The effects of OE and OE-CuO/Cu2O NPs were on cytotoxicity, apoptosis, and cell cycle progression. Furthermore, we assessed the impact of these nanostructures on CD44/24 antibodies, known as aggressive cell markers, following treatment. The green OE-CuO/Cu2O NPs displayed remarkable inhibitory effects on colon cancer HCT116 and breast cancer cells MCF-7 cells. It was shown that OE-CuO/Cu2O NPs reduced the production of the CD44 antibody, provided cell cycle arrest, and encouraged apoptosis. More specifically, it was discovered that these NPs caused MCF-7 cells to undergo apoptosis and G2/M phase cell cycle arrest. Additionally, drug delivery investigations were conducted to evaluate the potential of OE-CuO/Cu2O NPs as drug nanocarriers, further underscoring their promise in developing novel anticancer agents with significant cytotoxic, apoptotic, and drug delivery properties.

Gültekin, Yakup; Korkmaz, Çağla; Öztürk, Naile; Filazi, Ayhan; Deniz, Ahmet; Doğan, Osman; Pezik, Esra; Barin, Gözde; Vural, İmran

Albendazole sulfoxide (ALBSOX) and Praziquantel (PRZ) are broad-spectrum anthelmintic medications used in the treatment of both humans and animals that are challenging to manufacture for geriatric and pediatric populations and have poor oral bioavailability due to their low water solubility and high lipophilicity. To increase the solubility and bioavailability of the drugs, ALBSOX and PRZ-loaded nanofiber films were prepared using polyvinylpyrrolidone K90 (PVP), a non-toxic, inert polymer with high hydrophilic characteristics. SEM analysis of the produced ALBSOX and PRZ-loaded PVP nanofiber films revealed them to be uniform and smooth, with good uniformity and mechanical properties. The PVP nanofiber films of ALBSOX and PRZ disintegrated in phosphate buffer (pH 6.8) in less than 1 s and increased the solubility of ALBSOX and PRZ about five times compared to pure active ingredients. Furthermore, the prepared ALBSOX and PRZ-loaded PVP nanofiber films were found to have no cytotoxic effect in cell viability studies using L929 cells, and increased the protoscolicidal effect of the ALBSOX and PRZ combination approximately 2-fold in studies of Echinococcus granulosus protoscoleces. The findings of the present study reveal that the developed PVP nanofiber films have the potential to improve the dissolution profile and pharmacological efficacy of the ALBSOX and PRZ.

Pezik, Esra; Gulsun, Tuğba; Gündüz, Miyase Gözde; Sahin, Selma; Öztürk, Naile; Vural, İmran

M3, a condensed 1,4-dihydropyridine (DHP) derivative, targets both L- and T-type calcium channels and therefore, stands as a promising antihypertensive drug candidate. This study aims to improve the poor solubility of M3 using nanocrystal technology (a combination of precipitation and ultrasonication methods) to enhance its oral bioavailability. Pre-formulation studies were performed and M3 nanosuspensions were prepared using different stabilizers (polyvinyl pyrrolidone K30, polyvinyl alcohol, SoluPlus®) and surfactants (poloxamer 188, poloxamer 407, sodium deoxycholate, sodium lauryl sulfate) at different concentrations (0.05, 0.1, 0.5, 1.0, 2.0%, w/v). The optimum nanosuspension formulation was freeze-dried using different cryoprotectants (mannitol, trehalose, glucose, sucrose, dextran) at different ratios (1.25, 2.5, 5.0%, w/v). It was determined that the most suitable cryoprotectant and ratio was 5.0% trehalose, resulting in nanocrystals with a size of 320.2 ± 15.3 nm and a zeta potential of −27.4 ± 0.1 mV. The physicochemical properties of M3, poloxamer 188, physical mixture and freeze-dried nanocrystals were evaluated by XRD, DSC and FT-IR analyses. Characterization studies showed amorphization of M3 in the freeze-dried nanocrystals prepared with poloxamer 188. The result of equilibrium solubility and permeability studies results indicated that M3 could be a BCS class 4 compound. Cell culture studies using Caco-2 cells showed that M3 had no significant toxic effect on the cells and had a Papp value of 2.2 × 10−7 cm/s. Compared to coarse M3 powder freeze-dried M3 nanocrystals showed a 200-fold increase in solubility and a 28.6-fold increase in apparent permeability. The cytotoxic effect of M3 was also reduced by using poloxamers as stabilizers in the formulation. M3 nanosuspensions were found to be a promising candidate for the oral administration of M3 for the potential treatment of hypertension due to the increase in solubility and permeability which could enhance its oral bioavailability.

Karahan, Gizem; Tan, Ezgi; Danışman-Kalındemirtaş, Ferdane; Erdem-Kuruca, Serap; Karakuş, Selcan

Within the field of pharmaceutical technology, the design of green and multifunctional nanocarriers has received significant attention due to their excellent synergistic anticancer and antimicrobial properties. In this study, a novel kappa carrageenan/polyethylene glycol-halloysite nanocomposite (κCA-PEG-Hal NC) was prepared as a part of the development of the cisplatin (Cis) delivery nanosystem in pancreatic cancer treatment. The prepared nanostructure was characterized by SEM, TEM, XRD, and FTIR techniques. The spherical κCA-PEG-Hal NC was outperformed by a smaller particle size of 65 ± 1 nm. The prepared nanostructure exhibited a high Cis release percentage of 90.44 ± 0.5%. The experimental results showed that the prepared κCA-PEG-Hal NC had a high cytotoxic effect on HepG2 hepatocellular carcinoma and MIA PaCa-2 pancreatic cancer cells, while having low cytotoxicity against HUVEC human umbilical vein endothelial cells. Furthermore, the κCA-PEG-Hal NC had robust antimicrobial effects against different pathogenic microorganisms. Due to the multifunctional nature of κCA-PEG-Hal NC, it is proposed as an effective nanocarrier for delivery of anticancer drug (Cis) and an antimicrobial agent with excellent surface and biological properties.