Repurposing celecoxib for colorectal cancer targeting via pH-triggered ultra-elastic nanovesicles: Pronounced efficacy through up-regulation of Wnt/ß-catenin pathway in DMH-induced tumorigenesis.

Celecoxib (CLX), a selective inhibitor for cyclooxygenase 2 (COX-2), has manifested potential activity against diverse types of cancer. However, low bioavailability and cardiovascular side effects remain the major challenges that limit its exploitation. In this work, we developed ultra-elastic nanovesicles (UENVs) with pH-triggered surface charge reversal traits that could efficiently deliver CLX to colorectal segments for snowballed tumor targeting. CLX-UENVs were fabricated via a thin-film hydration approach. The impact of formulation factors (Span 80, Tween 80, and sonication time) on the nanovesicular features was evaluated using Box-Behnken design, and the optimal formulation was computed. The optimum formulation was positively coated with polyethyleneimine (CLX-PEI-UENVs) and then coated with Eudragit S100 (CLX-ES-PEI-UENVs). The activity of the optimized nano-cargo was explored in 1,2-dimethylhydrazine-induced colorectal cancer in Wistar rats. Levels of COX-2, Wnt-2 and ß-catenin were assessed in rats' colon. The diameter of the optimized CLX-ES-PEI-UENVs formulation was 253.62 nm, with a zeta potential of -23.24 mV, 85.64% entrapment, and 87.20% cumulative release (24 h). ES coating hindered the rapid release of CLX under acidic milieu (stomach and early small intestine) and showed extended release in the colon section. In colonic environments, the ES coating layer was removed due to high pH, and the charge on the nanovesicular corona was shifted from negative to positive. Besides, a pharmacokinetics study revealed that CLX-ES-PEI-UENVs had superior oral bioavailability by 2.13-fold compared with CLX suspension. Collectively, these findings implied that CLX-ES-PEI-UENVs could be a promising colorectal-targeted nanoplatform for effective tumor management through up-regulation of the Wnt/ß-catenin pathway.

Liver Targeting of Daclatasvir via Tailoring Sterically Stabilized Bilosomes: Fabrication, Comparative In Vitro/In Vivo Appraisal and Biodistribution Studies.

INTRODUCTION: Hepatitis C virus (HCV) is a significant public health concern that threatens millions of individuals worldwide. Daclatasvir (DAC) is a promising direct-acting antiviral approved for treating HCV infection around the world. The goal of this study was to encapsulate DAC into novel polyethylene glycol (PEG) decorated bilosomes (PEG-BILS) to achieve enhanced drug delivery to the liver. METHODS: DAC-loaded BILS were primed by a thin film hydrating technique. The study of the impact of various formulation variables on the properties of BILS and selection of the optimal formulation was generated using Design-Expert® software. The optimum preparation was then pegylated via the incorporation of PEG-6-stearate (5% w/w, with respect to the lipid phase). RESULTS: The optimum PEG-BILS formulation, containing PL:SDC ratio (5:1), 5 mg cholesterol, and 30 min sonication, yielded spherical vesicles in the nanoscale (200±15.2 nm), elevated percent of entrapment efficiency (95.5±7.77%), and a sustained release profile of DAC with 35.11±2.3% release. In vivo and drug distribution studies revealed an enhanced hepatocellular delivery of DAC-loaded PEG-BILS compared to DAC-unPEG-BILS and DAC suspension, where DAC-PEG-BILS achieved 1.19- and 1.54 times the AUC0-24 of DAC-unPEG-BILS and DAC suspension, respectively. Compared with DAC-unPEG-BILS and DAC suspension, DAC-PEG-BILS delivered about 2 and 3 times higher DAC into the liver, respectively. CONCLUSION: The innovative encapsulation of DAC-PEG-BILS has a great potential for liver targeting.

Loratadine bioavailability via buccal transferosomal gel: formulation, statistical optimization, in vitro/in vivo characterization, and pharmacokinetics in human volunteers.

Loratadine (LTD) is an antihistaminic drug that suffers limited solubility, poor oral bioavailability (owing to extensive first-pass metabolism), and highly variable oral absorption. This study was undertaken to develop and statistically optimize transfersomal gel for transbuccal delivery of LTD. Transfersomes bearing LTD were prepared by conventional thin film hydration method and optimized using sequential Quality-by-Design approach that involved Placket-Burman design for screening followed by constrained simplex-centroid design for optimization of a Tween-80/Span-60/Span-80 mixture. The transferosomes were characterized for entrapment efficiency, particle size, and shape. Optimized transferosomes were incorporated in a mucoadhesive gel. The gel was characterized for rheology, ex vivo permeation across chicken pouch buccal mucosa, in vitro release, and mucoadhesion. Pharmacokinetic behavior of LTD formulations was investigated in healthy volunteers following administration of a single 10-mg dose. Optimal transferosomes characterized by submicron size (380 nm), spherical shape and adequate loading capacity (60%) were obtained by using quasi-equal ratio surfactant mixture. In terms of amount permeated, percentage released, and mucoadhesion time, the transferosomal gel proved superior to control, transferosome-free gel. Bioavailability of the transferosomal gel was comparable to Claritin® oral tablets. However, inter-individual variability in Cmax and AUC was reduced by 76 and 90%, respectively, when the buccal gel was used. Linear Correlation of in vitro release with in vivo buccal absorption fractions was established with excellent correlation coefficient (R2>0.97). In summary, a novel buccal delivery system for LTD was developed. However, further clinical investigation is warranted to evaluate its therapeutic effectiveness and utility.