Ribociclib Hybrid Lipid-Polymer Nanoparticle Preparation and Characterization for Cancer Treatment.

Ribociclib is a newly approved orally administered drug for breast cancer. This study aimed to prepare, characterize, and evaluate hybrid lipid-polymer nanoparticles (PLNs) of ribociclib to enhance its in vitro dissolution rate, pharmacokinetics, and anticancer efficacy. Ribociclib-loaded PLNs were prepared by solvent evaporation using the Box-Behnken design to optimize formulation variables. Particle size, entrapment efficiency, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), in vitro release cytotoxicity, molecular modeling, and pharmacokinetic studies were examined. The ribociclib-loaded PLN (formula 1, F1) was optimized in terms of particle size (266.9 ± 4.61 nm) and encapsulation efficiency (59.1 ± 2.57 mg/mL). DSC and thermogravimetric characterization showed the absence of a crystalline structure in the prepared PLNs, confirmed by FTIR, and showed no interactions between the components and the drug. AFM showed well-dispersed heterogeneously shaped nanoparticles. The in vitro release profile exhibited significant results for the optimized formula, reaching 100% at 600 and 90 min at pH 6.8 and 1.2, respectively. The low IC50 obtained by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay suggests that optimized PLN might serve as an effective delivery vehicle for cancer treatment, especially breast and lung cancer. Molecular modeling revealed several hydrogen bonds. A pharmacokinetic study in rats showed that the ribociclib formula had a 6.5-fold increase in maximum concentration (Cmax) and a 5.6-fold increase in area under the curve (AUC). Regarding the everted intestinal sac absorption, formula 1 increased ribociclib penetration relative to the physical combination and pure medication. In conclusion, optimized PLNs with enhanced physicochemical and cytotoxic properties and improved pharmacokinetic parameters were successfully prepared.

Esomeprazole and apixaban pharmacokinetic interactions in healthy rats.

Esomeprazole is used in various clinical settings where a decrease in gastric acid production is desired since it is a proton pump inhibitor. Apixaban, an anticoagulant, is used to reduce the risk of stroke in patients with certain cardiovascular diseases. This research aims to examine the effects of giving esomeprazole and apixaban to rats simultaneously, as well as to measure their pharmacokinetics and look for statistical differences or interactions. A method for the simultaneous determination of esomeprazole and apixaban in rat plasma was developed using HPLC/MS and validated by ICH guidelines. Five groups of Wistar rats were created, and the drugs were administered as follows: esomeprazole (5 mg/kg) intravenously, apixaban (125 mcg/Kg) intravenously, esomeprazole (5 mg/kg) orally, apixaban (250 mcg/kg) orally, and esomeprazole (5 mg/kg) and apixaban (250 mcg/kg) both orally. Both drugs' concentrations were measured in plasma samples collected on a predetermined schedule. The pharmacokinetics of both drugs were calculated and statistically analyzed using a 90% confidence interval and non-compartmental analysis. When the two drugs were combined, apixaban's Cmax and AUC increased while esomeprazole's Cmax and AUC decreased. On the other hand, Apixaban's Tmax decreased with an increase in esomeprazole's Tmax, indicating a possible interaction between the two drugs. When both drugs were taken together, their bioavailability was reduced, implying that less esomeprazole was absorbed over time.

Crosstalk of low density lipoprotein and liposome as a paradigm for targeting of 5-fluorouracil into hepatic cells: cytotoxicity and liver deposition.

This study aimed to utilize cholesterol conjugation of 5-fluorouracil (5-FUC) and liposomal formulas to enhance the partitioning of 5-FU into low density lipoprotein (LDL) to target hepatocellular carcinoma (HCC). Thus, 5-FU and 5-FUCwere loaded into liposomes. Later, the direct loading and transfer of 5-FU, and 5-FUC from liposomes into LDL were attained. The preparations were characterized in terms of particle size, zeta potential, morphology, entrapment efficiency, and cytotoxicity using the HepG2 cell line. Moreover, the drug deposition into the LDL and liver tissues was investigated. The present results revealed that liposomal preparations have a nanosize range (155 - 194 nm), negative zeta potential (- 0.82 to - 16 mV), entrapment efficiency of 69% for 5-FU, and 66% for 5-FUC. Moreover, LDL particles have a nanosize range (28-49 nm), negative zeta potential (- 17 to -27 mV), and the entrapment efficiency is 11% for 5-FU and 85% for 5-FUC. Furthermore, 5-FUC loaded liposomes displayed a sustained release profile (57%) at 24 h compared to fast release (92%) of 5-FU loaded liposomes. 5-FUC and liposomal formulas enhanced the transfer of 5-FUC into LDL compared to 5-FU. 5-FUC loaded liposomes and LDL have greater cytotoxicity against HepG2 cell lines compared to 5-FU and 5-FUC solutions. Moreover, the deposition of 5-FUC in LDL (26.87ng/mg) and liver tissues (534 ng/gm tissue) was significantly increased 5-FUC liposomes compared to 5-FU (11.7 ng/g tissue) liposomal formulation. In conclusion, 5-FUC is a promising strategy for hepatic targeting of 5-FU through LDL-mediated gateway.

Enhancing Oral Bioavailability of Apigenin Using a Bioactive Self-Nanoemulsifying Drug Delivery System (Bio-SNEDDS): In Vitro, In Vivo and Stability Evaluations.

Apigenin (APG) is a very well-known flavonoid for its anti-inflammatory and anticancer properties. The purpose of this study is to improve the solubility and bioavailability of APG using a stable bioactive self-nanoemulsifying drug delivery system (Bio-SNEDDS). APG was incorporated in an oil phase comprising coconut oil fatty acid, Imwitor 988, Transcutol P, and HCO30 to form a Bio-SNEDDS. This preparation was characterized for morphology, particle size, and transmission electron microscopy (TEM). The APG performance was investigated in terms of loading, precipitation, release and stability tests from the optimal Bio-SNEDDS. An antimicrobial test was performed to investigate the activity of the Bio-SNEDDS against the selected strains. Bioavailability of the Bio-SNEDDS was evaluated using Wister rats against the commercial oral product and the pure drug. The results demonstrated the formation of an efficient nanosized (57 nm) Bio-SNEDDS with a drug loading of 12.50 mg/gm which is around 500-fold higher than free APG. TEM analysis revealed the formation of spherical and homogeneous nanodroplets of less than 60 nm. The dissolution rate was faster than the commercial product and was able to maintain 90% APG in gastro intestinal solution for more than 4 h. A stability study demonstrated that the Bio-SNEDDS is stable at a harsh condition. The in vivo pharmacokinetics parameters of the Bio-SNEDDS formulation in comparison to the pure drug showed a significant increase in maximum concentration (Cmax) and area under the curve (AUC (0-t)) of 105.05% and 91.32%, respectively. Moreover, the antimicrobial study revealed moderate inhibition in the bacterial growth rate. The APG-Bio-SNEDDS could serve as potential carrier aimed at improving the clinical application of APG.

Phytochemical profiling, antioxidant and anticancer activities of Gastrocotyle hispida growing in Saudi Arabia.

The present study aimed at isolation the phytocompounds from the aerial parts of Gastrocotyle hispida and to evaluate its antioxidant and anticancer potential using in vitro assay. Gastrocotyle hispida is belonging to the family Boraginaceae used as a refreshing drink like tea. The decoction of the leaves is diuretic and is used in the treatment of rheumatism. Phytochemical study of a methanol extract yielded five known compounds viz: ß-sitosterol (GH-1), ß-sitosterol 3-glucoside (GH-2), 1-O-ß-glucopyranosyl-1,4-dihydroxy-2-prenylbenzene (GH-3), 6-Hydroxy-2,2-dimethyl-3-chrom (GH-4) and rosmarinic acid (GH-5). Total phenolic and flavonoid contents were calculated for the extract and fractions, the methanolic extract contained the highest content of total flavonoids (178 mg/g, expressed as quercetin equivalents) and total polyphenol (98.4 mg/g, expressed as gallic acid equivalent). Compounds were isolated by using column chromatography. In vitro, antioxidant activity of the extract and isolated compounds was investigated by DPPH and ABTS radical scavenging assays. The four different cell lines HepG2 (Liver), HEK-293 (Kidney) MCF-7 (Breast) and MDA-MB 231 (Breast) were used against the compounds. The isolated compounds showed dose-dependent free radical scavenging property in all tested models with the IC50 values of 10.2 µg/mL rosmarinic acid (GH-5), 52.1 µg/mL ß-sitosterol (GH-1) and 85 µg/mL for ß-sitosterol 3-glucoside (GH-2). The ß-sitosterol (GH-1) showed significant activity against HepG2 and HEK 293 cell lines. Rosmarinic acid (GH-5) possesses potent anticancer activity against breast cancer cells (MCF7) with the IC50 value of 4.2 µg/mL. It can be concluded that Gastrocotyle hispida has potential antioxidant, anticancer activities and further used as an anticancer agent.

Hepatoprotective Effect of Eriobotrya japonica Leaf Extract and Its Various Fractions against Carbon Tetra Chloride Induced Hepatotoxicity in Rats.

Eriobotrya japonica is traditionally used as an antipyretic, digestive, and diuretic agent. Its flowers possess free radical-scavenging, antioxidative, and hepatoprotective effects. We investigated the hepatoprotective potential of E. japonica leaf extract and its various fractions against hepatotoxicity in rats. Liver injury was stimulated by the oral administration of carbon tetrachloride (CCl4; 2.5 mL/kg b.wt.). Male albino rats (n = 55) were distributed arbitrarily into 11 groups: Group I, normal control group; Group II, CCl4 (positive control group); Group III, CCl4 + silymarin; Groups IV and V, CCl4 + two doses of 250 and 500 mg/kg of the 80% methanolic extract of E. japonica leaves, respectively; Groups VI and VII, CCl4 + 250 mg/kg and 500 mg/kg of the ethyl acetate fraction, respectively; Groups VIII and IX, CCl4 + 250 and 500 mg/kg of the butanol fraction, respectively; and Groups X and XI, CCl4 + 250 and 500 mg/kg of the aqueous fraction of E. Japonica leaves, respectively. CCl4-treated rats that were given 250 or 500 mg/kg of the methanol extract of E. Japonica leaves, or its ethyl acetate, butanol, or aqueous fractions, had significantly lower levels of biochemical parameters such as alanine aminotransferase, aspartate transaminase, alkaline phosphate, total protein, gamma-glutamyl transferase, and bilirubin levels than those of the CCl4 positive group. However, the extract and fractions did not significantly affect lipid profiles. Thus, we conclude that Eriobotrya leaf extract and its fractions have a hepatoprotective effect against CCl4-induced hepatotoxicity in rats.