Search Results (9)

Background: Dysregulation in phosphoinositide-3-kinase alpha (PI3Kα) signaling is implicated in the development of various cancers, including triple-negative breast cancer (TNBC). We have previously synthesized a series of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides as targeted inhibitors against PI3Kα. Herein, two drug candidates, R7 and R11, were selected to be further investigated as a nanoparticle (NP) formulation against TNBC. Methods: R7 and R11 were entrapped in D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) polymeric NPs by nanoprecipitation. Following their physicochemical characterization, the anticancer activity of the compounds and their NP formulations was evaluated in the TNBC cell line MDA-MB-231 by conducting viability, uptake, and apoptosis assays, as well as penetration assays in a multicellular tumor spheroid model. Results: The NPs exhibited a particle size of 100–200 nm, excellent drug loading efficiencies, and sustained release under physiologic conditions. Viability assays revealed superior potency for the NP formulations, with IC₅₀ values of 20 µM and 30 µM for R7- and R11-loaded NPs, respectively, compared to the free compounds, which exhibited IC₅₀ values of 280 µM and 290 µM for R7 and R11, respectively. These results were attributed to the inherent antiproliferative activity of TPGS, as evidenced by the cytotoxicity of the drug-free NPs, as well as the enhanced cellular uptake enabled by the NP vehicle, as demonstrated by fluorescence microscopy imaging and flow cytometry measurements. Further investigations showed that the NPs promoted apoptosis via a mitochondrial-dependent pathway that involved the activation of proapoptotic caspases. Moreover, the NP formulations enhanced the penetration ability of the free compounds in multicellular tumor spheroids, causing a time- and concentration-dependent disruption of the spheroids. Conclusions: Our findings highlight the important role nanotechnology can play in improving the biopharmaceutical properties of new drug candidates and facilitating their in vivo translation. Full article

Cleaning represents an important and challenging operation in the conservation of cultural heritage, and at present, a key issue consists in the development of more sustainable, “green” materials and methods to perform it. In the present work, a novel xylene-in-water microemulsion based on nonionic surfactants with low toxicity was obtained, designed as low-impact cleaning agent for metallic historic objects. Phase diagram of the mixtures containing polyoxyethylene-polyoxypropilene triblock copolymer Pluronic P84 and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) as surfactants, water, ethanol and xylene was studied, and a microemulsion with low surfactant content was selected as suitable cleaning nanosystem. Essential oils (EOs) from thyme and cinnamon leaf were added to the selected microemulsion in order to include other beneficial properties such as anticorrosive and antifungal protection. The microemulsions with or without EOs were characterized by size, size distribution and zeta potential. The cleaning efficacy of the tested microemulsions was assessed based on their ability to remove two types of artificial dirt by using X-ray energy dispersion spectrometry (EDX), scanning electron microscopy (SEM), contact angle measurements and color analysis. Microemulsions exhibit high capacity to remove artificial dirt from model copper coupons in spite of very low content of the organic solvent. Both thyme and cinnamon oil loading microemulsions prove to significantly reduce the corrosion rate of treated metallic plates compared to those of bare copper. The antifungal activity of the novel type of microemulsion was evaluated against Aspergillus niger, reported as main treat in biocorrosion of historic copper artifacts. Application of microemulsion with small amounts of EOs on Cu plates inhibits the growth of fungi, providing a good fungicidal effect. Full article

The treatment of several ocular inflammatory conditions affecting different areas of the ocular globe involves the administration of topical ophthalmic formulations containing corticosteroids. This research was aimed at evaluating the solubilising efficacy of 5.0% w/w of different binary mixtures of commercial amphiphilic polymeric surfactants with the purpose of obtaining nanomicellar solutions containing a high amount of loteprednol etabonate (LE). The selected LE-TPGS/HS nanomicelles, containing 0.253 mg/mL of the drug, had a small size (=13.57 nm) and uniform distribution (Polydispersity Index = 0.271), appeared completely transparent and perfectly filterable through 0.2 μm membrane filter, and remained stable up to 30 days at 4 °C. The critical micellar concentration (CMC_TPGS/HS) was 0.0983 mM and the negative value of the interaction parameter between the polymeric-surfactant-building unit (β_TPGS/HS = −0.1322) confirmed the ability of the polymeric surfactants to interact, favouring the dissolution of LE into nanomicelles. The disappearance of the endothermic peak of LE in the DSC analysis confirmed the interactions of LE with the polymeric surfactants. LE-TPGS/HS produced in vitro LE which sustained diffusion for 44 h (more than 40% of encapsulated LE). Furthermore, the lack of a significant cytotoxic effect on a sensitive corneal epithelial cell line makes it a candidate for further biological studies. Full article

N-(2-fluorphenyl)-6-chloro-4-hydroxy-2-quinolone-3-carboxamide (R19) is a newly synthesized phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor with promising activity against cancer cells. The purpose of this study was to develop a polymeric nanoparticle (NP) formulation for R19 to address its poor aqueous solubility and to facilitate its future administration in preclinical and clinical settings. NPs were prepared by nanoprecipitation using two polymers: D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and the poloxamer Pluronic P123 in different ratios. Physicochemical characterization of the NPs revealed them to be around 100 nm in size with high monodispersity, a spherical morphology, and an almost neutral surface charge. The NPs achieved ~60% drug loading efficiency and sustained release of R19 for up to 96 h, with excellent colloidal stability in serum-containing cell culture media. NPs containing TPGS enhanced R19’s potency against MCF-7 and MDA-MB-231 breast cancer cells in vitro, with half-maximal inhibitory concentrations (IC₅₀) ranging between 1.8 and 4.3 µM compared to free R19, which had an IC₅₀ of 14.7–17.0 µM. The NPs also demonstrated low cytotoxicity against human dermal fibroblasts and more significant induction of apoptosis compared to the free drug, which was correlated with their cellular uptake efficiency. Our findings present a biocompatible NP formulation for the delivery of a cancer-targeted PI3Kα inhibitor, R19, which can further enhance its potency for the treatment of breast cancer and potentially other cancer types. Full article

Manganese-zinc ferrite (MZF) is known as high-performance magnetic material and has been used in many fields and development. In the biomedical applications, the biocompatible MZF formulation attracted much attention. In this study, water-soluble amphiphilic vitamin E (TPGS, d-alpha-tocopheryl poly(ethylene glycol 1000) succinate) formulated MZF nanoparticles were synthesized to serve as both a magnetic resonance imaging (MRI) contrast agent and a vehicle for creating magnetically induced hyperthermia against cancer. The MZF nanoparticles were synthesized from a metallic acetylacetonate in an organic phase and further modified with TPGS using an emulsion and solvent-evaporation method. The resulting TPGS-modified MZF nanoparticles exhibited a dual-contrast ability, with a longitudinal relaxivity (35.22 s⁻¹ mM Fe⁻¹) and transverse relaxivity (237.94 s⁻¹ mM Fe⁻¹) that were both higher than Resovist^®. Furthermore, the TPGS-assisted MZF formulation can be used for hyperthermia treatment to successfully suppress cell viability and tumor growth after applying an alternating current (AC) electromagnetic field at lower amplitude. Thus, the TPGS-assisted MZF theranostics can not only be applied as a potential contrast agent for MRI but also has potential for use in hyperthermia treatments. Full article

Pancreatic cancer is one of the highest causes of mortality throughout the world; thus, it requires an effective treatment strategy. Some chemotherapeutic agents used in the clinics or under clinical trials are hydrophobic and have poor aqueous solubility; consequently, they also have minimal systemic bioavailability. Nanoparticle-based drug delivery tactics have the potential for overcoming these limitations and enhancing their therapeutic efficacy. Herein, a glutathione (GSH)-sensitive micelle (PAH-SS-PLGA) was synthesized for the combined delivery of alpha-tocopheryl succinate (TOS) and curcumin to improve its therapeutic efficacy. The chemical structures of PAH-SS-PLGA were analyzed using Proton Nuclear Magnetic Resonance (¹H-NMR) and Fourier Transform Infrared (FTIR) spectroscopy, whereas the particle size, zeta potential, and surface morphology were observed using dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release results revealed that more TOS and curcumin were released in the presence of GSH (5 mM) than the physiological pH value. Fluorescence microscopy images revealed that nanoformulated curcumin/rhodamine was uptaken by PAN02 pancreatic cancer cells. In vitro cytotoxicity assays showed higher cytotoxicity for nanoformulated TOS and/or curcumin than free TOS and/or curcumin. In addition, higher cytotoxicity was observed for combination drugs than free drugs alone. Most interestingly, at all tested concentrations of nanoformulated drugs (PAH-SS-PLGA, TOS, and curcumin), the calculated combination index (CI) value was less than one, which shows that TOS and curcumin have a synergistic effect on cellular proliferation inhibition. Overall, synthesized co-polymers are the best carriers for combination drugs, TOS, and curcumin, because they enhance the therapeutic efficacy and improve pancreatic cancer treatments. Full article

Most prostate cancer patients develop resistance to anti-androgen therapy. This is referred to as castration-resistant prostate cancer (CRPC). Docetaxel (DTX) is the mainstay treatment against CRPC. However, over time patients eventually develop DTX resistance, which is the cause of the cancer-related mortality. Curcumin (CUR) as a natural compound has been shown to have very broad pharmacological activities, e.g., anti-inflammatory and antioxidant properties. However, CUR is very hydrophobic. The objective of this study was to develop CUR nanoparticles (NPs) and evaluate their cytotoxicity in DTX-resistant CRPC cells for the treatment of DTX-resistant CRPC. We tested solubility of CUR in different lipids and surfactants. Finally, Miglyol 812 and D-alpha-tocopheryl poly (ethylene glycol) succinate 1000 (TPGS) were chosen to prepare lipid-based NPs for CUR. We fully characterized CUR NPs that had particle size < 150 nm, high drug loading (7.5%), and entrapment efficiency (90%). Moreover, the CUR NPs were successfully lyophilized without using cryoprotectants. We tested the cytotoxicity of blank NPs, free CUR, and CUR NPs in sensitive DU145 and PC3 cells as well as their matching docetaxel-resistant cells. Cytotoxicity studies showed that blank NPs were very safe for all tested prostate cancer cell lines. Free CUR overcame the resistance in PC3 cells, but not in DU145 cells. In contrast, CUR NPs significantly increased CUR potency in all tested cell lines. Importantly, CUR NPs completely restored CUR potency in both resistant DU145 and PC3 cells. These results demonstrate that the CUR NPs have potential to overcome DTX resistance in CRPC. Full article

Recent studies show that alpha-tocopheryl succinate (TS) exhibits selective toxicity against cancer cells. In this study, we investigated the effect of TS’s presence on the physico-chemical and structural properties of DPPC liposomes using fluorescence parameters (intensity, lifetime, and position of emission maximum) of 1-anilino-8-naphtalene sulphonate (ANS), differential scanning calorimetry (DSC) and zeta potential methods. Increasing the TS presence in the DPPC gel phase produced ANS fluorescence enhancement with a hypsochromic shift of the maximum. The zeta potential measurements show an increase in the negative surface charge and confirmed that this process is connected with the hydrophobic properties of dye, which becomes located deeper into the interphase region with a progressing membrane disorder. Temperature dependence studies showed that an increase in temperature increases the ANS fluorescence and shifts the ANS maximum emission from 464 to 475 nm indicating a shift from hydrophobic to a more aqueous environment. In the liquid crystalline phase, the quenching of ANS fluorescence occurs due to the increased accessibility of water to the ANS located in the glycerol region. The DSC results revealed that increasing the presence of TS led to the formation of multicomponent DSC traces, indicating the formation of intermediate structures during melting. The present results confirmed that TS embedded into the DPPC membrane led to its disruption due to destabilisation of its structure, which confirmed the measured biophysical parameters of the membrane. Full article

The rapid release of poorly water-soluble drugs from amorphous solid dispersion (ASD) is often associated with the generation of supersaturated solution, which provides a strong driving force for precipitation and results in reduced absorption. Precipitation inhibitors, such as polymers and surfactants, are usually used to stabilize the supersaturated solution by blocking the way of kinetic or thermodynamic crystal growth. To evaluate the combined effect of polymers and surfactants on maintaining the supersaturated state of itraconazole (ITZ), various surfactants were integrated with enteric polymer hydroxypropyl methylcellulose acetate succinate (HPMC AS) to develop polymer–surfactant based solid dispersion. The supersaturation stability was investigated by in vitro supersaturation dissolution test and nucleation induction time measurement. Compared to the ASD prepared with HPMC AS alone, the addition of d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) exhibited a synergistic effect on precipitation inhibition. The results indicated that the TPGS not only significantly reduced the degree of supersaturation which is the driving force for precipitation, but also provided steric hindrance to delay crystal growth by absorbing onto the surface of small particles. Subsequently, the formulations were evaluated in vivo in beagle dogs. Compared with commercial product Sporanox^®, the formulation prepared with HPMC AS/TPGS exhibited a 1.8-fold increase in the AUC (0–24 h) of ITZ and a 1.43-fold increase of hydroxyitraconazole (OH-ITZ) in the plasma. Similarly, the extent of absorption was increased by more than 40% when compared to the formulation prepared with HPMC AS alone. The results of this study demonstrated that the ASD based on polymer–surfactant system could obviously inhibit drug precipitation in vitro and in vivo, which provides a new access for the development of ASD for poorly water-soluble drug. Full article