Solid lipid nanoparticles (SLN) have demonstrated good potential for oral peptide delivery. However, their hydrophobic nature generally accounts for low peptide entrapment efficiency (EE%). In this study, a new strategy was adopted to improve peptide EE% by incorporating a hydrophilic viscosity-enhancing agent (VA) within SLN cores to develop viscosity enhanced nanocarriers (VEN). Three agents namely, propylene glycol (PG), polyethylene glycol (PEG) 400 and PEG 600, were tested with human insulin serving as a model peptide drug. The effects of VA were both concentration- and type-dependent. 70% w/ w PG had achieved the highest EE% (54.5%), versus the two PEGs, compared to only 20.4% in unmodified SLN. PG based VEN had demonstrated good dispersion stability at gastrointestinal (GI) pHs and preferential uptake by intestinal Caco2 cells while showing low cytotoxicity. Additionally, they preserved the integrity of insulin and significantly protected it against GI enzymatic degradation. Freeze dried VEN had shown good stability upon storage at -20°C. Orally administered insulin-VEN had achieved good hypoglycemic effect in fasted rats with relative bioavailability of 5.1%. To conclude, an easily implementable technique to improve peptide entrapment within SLN has been validated, and the resulting VEN had proved promising efficacy for oral peptide delivery.

5-Fluorouracil (5-FU), an antimetabolite drug, is extensively used in the treatment solid tumors. However, its severe side effects limit its clinical benefits. To enhance 5-FU anticancer efficacy and reduce its side effects it was loaded onto gold nanoparticles (GNPs) using two thiol containing ligands, thioglycolic acid (TGA) and glutathione (GSH). The GNPs were prepared at different 5-FU/ligand molar ratios and evaluated using different techniques. Anticancer efficacy of 5-FU/GSH-GNPs was studied using flow cytometry in cancerous tissue obtained from patients having colorectal cancer. The GNPs were spherical in shape and had a size of ∼9–17 nm. Stability of the GNPs and drug release were studied as a function of salt concentration and solution pH. Maximum 5-FU loading was achieved at 5-FU/ligand molar ratio of 1:1 and 2:1 for TGA-GNPs and GSH-GNPs, respectively. GNPs coating with pluronic F127 improved their stability against salinity. 5-FU release from GNPs was slow and pH-dependent. 5-FU/GSH-GNPs induced apoptosis and stopped the cell cycle progression in colorectal cancer cells. They also had a 2-fold higher anticancer effect compared with free 5-FU. These results confirm the potential of GNPs to enhance 5-FU anticancer efficacy.

5-Fluorouracil (5-FU), an antimetabolite drug, is extensively used in the treatment solid tumors. However, its severe side effects limit its clinical benefits. To enhance 5-FU anticancer efficacy and reduce its side effects it was loaded onto gold nanoparticles (GNPs) using two thiol containing ligands, thioglycolic acid (TGA) and glutathione (GSH). The GNPs were prepared at different 5-FU/ligand molar ratios and evaluated using different techniques. Anticancer efficacy of 5-FU/GSH-GNPs was studied using flow cytometry in cancerous tissue obtained from patients having colorectal cancer. The GNPs were spherical in shape and had a size of ∼9–17 nm. Stability of the GNPs and drug release were studied as a function of salt concentration and solution pH. Maximum 5-FU loading was achieved at 5-FU/ligand molar ratio of 1:1 and 2:1 for TGA-GNPs and GSH-GNPs, respectively. GNPs coating with pluronic F127 improved their stability against salinity. 5-FU release from GNPs was slow and pH-dependent. 5-FU/GSH-GNPs induced apoptosis and stopped the cell cycle progression in colorectal cancer cells. They also had a 2-fold higher anticancer effect compared with free 5-FU. These results confirm the potential of GNPs to enhance 5-FU anticancer efficacy.

5-Fluorouracil (5-FU), an antimetabolite drug, is extensively used in the treatment solid tumors. However, its severe side effects limit its clinical benefits. To enhance 5-FU anticancer efficacy and reduce its side effects it was loaded onto gold nanoparticles (GNPs) using two thiol containing ligands, thioglycolic acid (TGA) and glutathione (GSH). The GNPs were prepared at different 5-FU/ligand molar ratios and evaluated using different techniques. Anticancer efficacy of 5-FU/GSH-GNPs was studied using flow cytometry in cancerous tissue obtained from patients having colorectal cancer. The GNPs were spherical in shape and had a size of ∼9–17 nm. Stability of the GNPs and drug release were studied as a function of salt concentration and solution pH. Maximum 5-FU loading was achieved at 5-FU/ligand molar ratio of 1:1 and 2:1 for TGA-GNPs and GSH-GNPs, respectively. GNPs coating with pluronic F127 improved their stability against salinity. 5-FU release from GNPs was slow and pH-dependent. 5-FU/GSH-GNPs induced apoptosis and stopped the cell cycle progression in colorectal cancer cells. They also had a 2-fold higher anticancer effect compared with free 5-FU. These results confirm the potential of GNPs to enhance 5-FU anticancer efficacy.

An innovative strategy dedicated to quality-by-design (QbD) principles has been comprehensively applied in the set-up of a vortex aided salting-out-assisted liquid–liquid microextraction (VA-SALLME) combined with a core–shell chromatographic method for the simultaneous analysis of two anti-glaucoma drugs, dorzolamide hydrochloride (DOR) and timolol maleate (TIM), in rabbit plasma. Each step of the QbD workflow has been implemented, starting from using the design of experiments with a Plackett–Burman design for screening and a Box–Behnken design for response surface methodology up to using Monte Carlo simulations for error propagation. The optimal chromatographic conditions were: a core–shell Kinetex XB C18 column with ACN: 45.56 mmol L-1 phosphate buffer at pH 3.76 (18.17 : 81.83%, v/v) as the mobile phase at a 1 mL min-1 flow rate, using hydrochlorothiazide as an internal standard and detection at 254 and 295 nm for DOR and TIM, respectively. Incorporating QbD principles in the method development allowed the visualization of two definite design spaces for the VA-SALLME and the HPLC methods, providing assurance of the quality in accordance with ICH guideline Q8(R2). Linearity was found over the concentration ranges of 0.9–50 and 1.5–50 ng mL-1 with quantitation limits of 0.87 and 1.40 ng mL-1 for DOR and TIM, respectively. As a consequence of the obtained unprecedented chromatographic separation and sensitivity, it was possible to carry out simultaneous pharmacokinetic studies of the two anti-glaucoma drugs after their single instillation.

An innovative strategy dedicated to quality-by-design (QbD) principles has been comprehensively applied in the set-up of a vortex aided salting-out-assisted liquid–liquid microextraction (VA-SALLME) combined with a core–shell chromatographic method for the simultaneous analysis of two anti-glaucoma drugs, dorzolamide hydrochloride (DOR) and timolol maleate (TIM), in rabbit plasma. Each step of the QbD workflow has been implemented, starting from using the design of experiments with a Plackett–Burman design for screening and a Box–Behnken design for response surface methodology up to using Monte Carlo simulations for error propagation. The optimal chromatographic conditions were: a core–shell Kinetex XB C18 column with ACN: 45.56 mmol L-1 phosphate buffer at pH 3.76 (18.17 : 81.83%, v/v) as the mobile phase at a 1 mL min-1 flow rate, using hydrochlorothiazide as an internal standard and detection at 254 and 295 nm for DOR and TIM, respectively. Incorporating QbD principles in the method development allowed the visualization of two definite design spaces for the VA-SALLME and the HPLC methods, providing assurance of the quality in accordance with ICH guideline Q8(R2). Linearity was found over the concentration ranges of 0.9–50 and 1.5–50 ng mL-1 with quantitation limits of 0.87 and 1.40 ng mL-1 for DOR and TIM, respectively. As a consequence of the obtained unprecedented chromatographic separation and sensitivity, it was possible to carry out simultaneous pharmacokinetic studies of the two anti-glaucoma drugs after their single instillation.

The progestational potency and selectivity of synthetic steroidal agonists can be enhanced by even larger chemical moieties at 17a-position of the steroid backbones. Hereby a series 5a-c and 6a-c of novel 17a-[1-(substituted phenyl)-1,2,3-triazol-4-yl]-19-nortestosterone-17b-yl acetates were designed and synthesized using click chemistry approach searching progestogenic derivatives with potential anticancer activity. Compounds 5a,b and 6a,c have affected to different extents the three histopathological parameters considered for evaluation of their progestational activity. The compounds 5a,b and 6a,c showed modifications in rat uterus at 35.7e34.8 nM levels with privileged endometrial thickening effect and least change of uterine weight relative to NEA at 52.9 nM level. Up to 40 mg/kg dose compounds 5b and 6c were non-toxic. Molecular docking of the ligands in PR showed in the majority of cases a conformational fitting into the active site different from that of the reference steroid NEA. Compound 6b revealed about 46.4% growth inhibition of CNS cancer SNB-75 cell line, 56% growth inhibition of renal cancer A498 cell line and 56.7% growth inhibition of prostate cancer PC-3 cell line which was mediated by cell cycle arrest. Drugability of the screened compounds showed tolerated results after being challenged to diverse physicochemical parameters.

The progestational potency and selectivity of synthetic steroidal agonists can be enhanced by even larger chemical moieties at 17a-position of the steroid backbones. Hereby a series 5a-c and 6a-c of novel 17a-[1-(substituted phenyl)-1,2,3-triazol-4-yl]-19-nortestosterone-17b-yl acetates were designed and synthesized using click chemistry approach searching progestogenic derivatives with potential anticancer activity. Compounds 5a,b and 6a,c have affected to different extents the three histopathological parameters considered for evaluation of their progestational activity. The compounds 5a,b and 6a,c showed modifications in rat uterus at 35.7e34.8 nM levels with privileged endometrial thickening effect and least change of uterine weight relative to NEA at 52.9 nM level. Up to 40 mg/kg dose compounds 5b and 6c were non-toxic. Molecular docking of the ligands in PR showed in the majority of cases a conformational fitting into the active site different from that of the reference steroid NEA. Compound 6b revealed about 46.4% growth inhibition of CNS cancer SNB-75 cell line, 56% growth inhibition of renal cancer A498 cell line and 56.7% growth inhibition of prostate cancer PC-3 cell line which was mediated by cell cycle arrest. Drugability of the screened compounds showed tolerated results after being challenged to diverse physicochemical parameters.

The progestational potency and selectivity of synthetic steroidal agonists can be enhanced by even larger chemical moieties at 17a-position of the steroid backbones. Hereby a series 5a-c and 6a-c of novel 17a-[1-(substituted phenyl)-1,2,3-triazol-4-yl]-19-nortestosterone-17b-yl acetates were designed and synthesized using click chemistry approach searching progestogenic derivatives with potential anticancer activity. Compounds 5a,b and 6a,c have affected to different extents the three histopathological parameters considered for evaluation of their progestational activity. The compounds 5a,b and 6a,c showed modifications in rat uterus at 35.7e34.8 nM levels with privileged endometrial thickening effect and least change of uterine weight relative to NEA at 52.9 nM level. Up to 40 mg/kg dose compounds 5b and 6c were non-toxic. Molecular docking of the ligands in PR showed in the majority of cases a conformational fitting into the active site different from that of the reference steroid NEA. Compound 6b revealed about 46.4% growth inhibition of CNS cancer SNB-75 cell line, 56% growth inhibition of renal cancer A498 cell line and 56.7% growth inhibition of prostate cancer PC-3 cell line which was mediated by cell cycle arrest. Drugability of the screened compounds showed tolerated results after being challenged to diverse physicochemical parameters.

The progestational potency and selectivity of synthetic steroidal agonists can be enhanced by even larger chemical moieties at 17a-position of the steroid backbones. Hereby a series 5a-c and 6a-c of novel 17a-[1-(substituted phenyl)-1,2,3-triazol-4-yl]-19-nortestosterone-17b-yl acetates were designed and synthesized using click chemistry approach searching progestogenic derivatives with potential anticancer activity. Compounds 5a,b and 6a,c have affected to different extents the three histopathological parameters considered for evaluation of their progestational activity. The compounds 5a,b and 6a,c showed modifications in rat uterus at 35.7e34.8 nM levels with privileged endometrial thickening effect and least change of uterine weight relative to NEA at 52.9 nM level. Up to 40 mg/kg dose compounds 5b and 6c were non-toxic. Molecular docking of the ligands in PR showed in the majority of cases a conformational fitting into the active site different from that of the reference steroid NEA. Compound 6b revealed about 46.4% growth inhibition of CNS cancer SNB-75 cell line, 56% growth inhibition of renal cancer A498 cell line and 56.7% growth inhibition of prostate cancer PC-3 cell line which was mediated by cell cycle arrest. Drugability of the screened compounds showed tolerated results after being challenged to diverse physicochemical parameters.