Development of New Nanoniosome Carriers for Vorinostat: Evaluation of Anticancer Efficacy In Vitro.

Vorinostat (VST) is a chemotherapeutic agent administrated for various types of cancers. However, it suffers from side effects and chemoresistance that reduce its application. Different nanoniosomes comprised Span 20, 60, 65 and 80 were prepared by the thin film hydration method and loaded with VST. The nanoniosomes were physicochemically characterized using particle size analysis and field emission scanning electron microscopy. The best formulation that was prepared using Span 65 (VST-NN-S65) included vesicle size of 127 nm with a narrow size distribution. VST-NN-S65 had an entrapment efficiency and loading capacity of 81.3 ± 5.1 and 32.0 ± 3.9 %, respectively. Drug release rate measurements showed that 90 % of VST was liberated within 1 h. Cytotoxicity assessments of VST-NN-S65 in HeLa and MCF7 cells indicated significant improvement in the effectiveness of VST, compared to the VST suspension. For VST-NN-S65, IC50 values of 26.3 and 6.6 µg mL-1 were obtained for HeLa and MCF7 cell lines, respectively. In situ apoptosis detection by the TUNEL assay revealed that apoptosis mainly occurred in the cell lines.

Capecitabine-loaded nanoniosomes and evaluation of anticancer efficacy.

Capecitabine (CAP) is an FDA-approved and frequently used chemotherapeutic agent for the treatment of various cancers. However, there are some side effects and chemoresistance limiting its use. Nanotechnological approaches can enhance the efficacy of anticancer drugs. In this study, CAP-loaded nanoniosomes were prepared. Nanoniosomes were prepared by the method of thin film hydration wherein CAP was loaded into the nanoniosomes. Nanoniosomes were then characterized by field emission scanning electron microscopy and (particle) vesicle size analysis. The cytotoxicity effect of the nanoniosomes were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. CAP was loaded into the nanoniosomes and loading capacity and entrapment efficiency were determined. The vesicle size of the nanoniosomes was obtained in the nanometer scale, and CAP release profiles from the nanoniosomes were also obtained. Finally, the cytotoxicity effect of CAP and CAP-loaded nanoniosomes were evaluated toward MCF7 and PANC1 cell lines. The nanoniosomes with an amphipathic structure can penetrate into the cells with an enhanced release rate. These caused the toxicity of drug in the nanoniosomes to be higher than the free drug.

Evaluation of a self-nanoemulsifying docetaxel delivery system.

A self-nanoemulsifying drug delivery system (SNEDDS) was developed as a novel route to enhance the efficacy of docetaxel lipophilic drug. SNEDDS comprised ethyl oleate, Tween 80 and poly(ethylene glycol) 600, as oil, surfactant and co-surfactant, and formed stabilized monodispersed oil nanodroplets upon dilution in water. SNEDDS represented encapsulation efficiency and loading capacity of 21.4 and 52.7%, respectively. The docetaxel release profile from the drug-loaded SNEDDS was recorded, its effectiveness against MCF-7 cell line was investigated, and an IC50 value of 0.98 ± 0.05 µg mL-1 was attained. The drug-loaded SNEDDS was administrated in rats, and the pharmacokinetic parameters of maximum concentration of 22.2 ± 0.8 µg mL-1, time to attain this maximum concentration of 230 min, and area under the curve of 1.71 ± 0.18 µg min mL-1 were obtained. The developed SNEDDS formulation can be represented as an alternative to docetaxel administration.

A novel self-nanoemulsifying formulation for sunitinib: Evaluation of anticancer efficacy.

Breast cancer is the top cancer and a main cause of death among women. The incidence of this cancer is increasing in the world. Sunitinib maleate is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor that inhibits tumor cell proliferation and angiogenesis, and has been administrated as an anticancer drug. Self-nanoemulsifying drug delivery system (SNEDDS) is an isotopic mixture of an oil, a surfactant and usually a co-surfactant, which can spontaneously form fine oil-in-water nanoemulsion in aqueous media. Here, a SNEDDS composed of 15% ethyl oleate (as an oil phase), 30% tween 80 (as a surfactant), and 55% PEG 600 (as a co-surfactant) was prepared and developed as a carrier for sunitinib. The average droplet size of sunitinib-loaded SNEDDS was 29.5±6.3nm with a stability of more than one month. Sunitinib release from SNEDDS was enhanced accompanied by a controlled dissolution of the drug. Cytotoxicity studies on 4T1 and MCF-7 cell lines indicated a toxicity enhancement in sunitinib by SNEDDS. To inspect the bioavailability of the drug-loaded SNEDDS after oral administration with a dose of 50mgkg-1, the maximum plasma concentration and the mean area under the plasma concentration-time curve were measured. It was found that these parameters were increased 1.45- and 1.24-times respectively, compared to a drug suspension.

Erlotinib-loaded albumin nanoparticles: A novel injectable form of erlotinib and its in vivo efficacy against pancreatic adenocarcinoma ASPC-1 and PANC-1 cell lines.

Erlotinib was loaded on albumin nanoparticles for the first time and the cytotoxic effect of the resulting nanoparticles against ASPC-1 and PANC-1 pancreatic adenocarcinoma cell lines was evaluated. The carrier (albumin nanoparticles, ANPs) was synthesized by desolvation method using a mixed solvent followed by thermal crosslinking for stabilization. ANPs and the drug-loaded ANPs were characterized by field emission scanning and transmission electron microscopies, particle size analysis and Fourier transform infrared spectroscopy. The nanoformulation had a size of <14nm with a good monodispersity. Drug loading and encapsulation efficiencies were evaluated as 27 and 44%. Cytotoxicity assays after 72h revealed the potential of ANPs to improve erlotinib toxicity (54% against 34% of free drug toward ASPC-1 cell line, and 52% against 30% toward PANC-1 cell line). Values of IC50 were obtained for both cell lines and indicated significant reduction in the erlotinib dose necessary for killing the cells, while, ANPs were completely safe. The results demonstrated that erlotinib-loaded ANPs had a remarkable potential for pancreatic cancer drug delivery.

Unilateral and bilateral dental transpositions in the maxilla-dental and skeletal findings in 63 individuals.

AIM: This was to elucidate dental and skeletal findings in individuals with unilateral and bilateral maxillary dental transpositions. MATERIAL AND METHODS: The sample comprised of radiographic materials from 63 individuals with maxillary dental transpositions from the Departments of Odontology at the Universities of Copenhagen and Aarhus and by the Danish municipal orthodontic service. The cases were divided into three groups: unilateral transposition of the canine and first premolar (Type 1U), bilateral transposition of canine and first premolar (Type 1B), and unilateral transposition of canine and lateral incisor (Type 2). The dentitions were analysed regarding agenesis and dental morphological anomalies on panoramic radiographs, and craniofacial aspects were cephalometrically analysed on profile images The results were statistically evaluated. RESULTS: All groups demonstrated increased occurrences of agenesis (Type 1U and Type 1B: 31 agenesis in 15 patients; and Type 2 three agenesis in three patients). Taurodontic root morphology was most dominant in Type 1U. Peg-shaped lateral incisors showed an increased occurrence, though not in Type 1U. Skeletally, Type 1B and Type 1U demonstrated maxillary retrognathia (more pronounced in Type 1B). Type 2 showed a significant posterior inclination of the maxilla. CONCLUSION: Transpositions of maxillary canines involve dental and skeletal deviations. Dental deviations were predominantly taurodontic root morphology and agenesis. Regarding skeletal deviations, bilateral transpositions of the canines and the first premolars are associated with skeletal changes. Unilateral transpositions are possibly a localised deviation with minor or no skeletal involvements. The results indicate a possible difference in the aetiologies of unilateral and bilateral transpositions.

Electrocatalytic oxidation and determination of deferasirox and deferiprone on a nickel oxyhydroxide-modified electrode.

The electrocatalytic oxidation of two orally administered iron chelator drugs (deferiprone, CP20, and deferasirox, ICL670) was investigated on a nickel oxyhydroxide-modified nickel electrode in alkaline solution. The oxidation process involved and its kinetics were investigated using cyclic voltammetry, chronoamperometry, and electrochemical impedance spectroscopy techniques, as well as steady-state polarization measurements. Voltammetric studies indicated that in the presence of the drugs under study, the anodic peak current of low-valence nickel species increased, followed by a decrease in the corresponding cathodic current. This result indicates that the drugs were oxidized via oxyhydroxide species immobilized on the electrode surface via an EC' mechanism. A mechanism based on the electrochemical generation of Ni(III) active sites and their subsequent consumption by the drugs in question was also investigated. The corresponding rate law under the control of charge transfer was developed, and kinetic parameters were derived. In this context, the charge-transfer resistance accessible both theoretically and through impedancemetry was used as a criterion. The rate constants of the catalytic oxidation of the drugs and the electron-transfer coefficients are reported. A sensitive, simple, and time-saving amperometric procedure was developed for the analysis of deferasirox and deferiprone, with detection limits of 28 and 19 microM, respectively. The electrode was used for the direct assay of deferasirox and deferiprone tablets.

Comparative genotoxicity of 2,3'-O-cyclocytidine, beta-xylocytidine and 1-beta-D-arabinofuranosylcytosine in human tumor cell lines.

We have investigated the genotoxicity of two 3'-derivatives of cytidine, 2,3'-O-cyclocytidine (3'-cycloC) and beta-xylocytidine (xyloC), in human leukemia and solid tumor cell lines. Both derivatives were found to be cytotoxic at micromolar concentrations. For example, in the alveolar tumor cell line A549 which was included in all experiments as a reference, drug concentrations required to induce 50% inhibition of cell growth (D50 values) equalled 55 microM for 3'-cycloC and 80 microM for xyloC. Compared with the response of this reference cell line, none of the solid tumor cell lines tested--representing five different malignancies--displayed significant hypersensitivity to these drugs, while the acute lymphoblastic leukemia cell lines proved to be hypersensitive (range of D50 values, 5-13 microM). To gain insight into the modes of cytotoxic action of xyloC and 3'-cycloC, we compared the effect on DNA metabolism of these compounds with that of 1-beta-D-arabinofuranosylcytosine (araC), a potent inhibitor of semi-conservative DNA replication and long-patch excision repair. As seen with araC, the xylo compound strongly inhibited both DNA replicative synthesis and the repair of DNA damage induced by UV light and 60Co gamma-radiation. In gamma-irradiated A549 cells, the extent of repair inhibition by 1 mM xyloC was approximately 40% of that inhibited by araC, and concomitant exposure of the irradiated cultures to xyloC plus araC gave rise to a synergistic response. Since araC was employed at a concentration (0.1 mM) which produced a maximal effect on DNA repair when applied alone, the observed synergistic response implies that the mode of action of xyloC on DNA repair is different from that of araC. In contrast to that observed with xyloC, 3'-cycloC proved to be a very weak inhibitor of DNA replication and repair, strongly suggesting that the genotoxic action of the latter analog may be through a mechanism other than inhibition of DNA synthesis.