Sustained release donepezil loaded PLGA microspheres for injection:Preparation,in vitro and in vivo study

The purpose of this study was to develop a PLGA microspheres-based donepezil(DP)formulation which was expected to sustain release of DP for one week with high encapsulation efficiency(EE).DP derived from donepezil hydrochloride was encapsulated in PLGA microspheres by the O/W emulsion-solvent evaporation method.The optimized formulation which avoided the crushing of microspheres during the preparation process was characterized in terms of particle size,morphology,drug loading and EE,physical state of DP in the matrix and in vitro and in vivo release behavior.DP microspheres were prepared successfully with average diameter of 30m,drug loading of 15.92±0.31%and EE up to 78.79±2.56%.Scanning electron microscope image showed it has integrated spherical shape with no drug crystal and porous on its surface.Differential scanning calorimetry and X-ray diffraction results suggested DP was in amorphous state or molecularly dispersed in microspheres.The Tg of PLGA was increased with the addition of DP.The release profile in vitro was characterized with slow but continuous release that lasted for about one week and fitted well with first-order model,which suggested the diffusion governing release mechanism.After single-dose administration of DP microspheres via subcutaneous injection in rats,the plasma concentration of DP reached peak concentration at 0.50 d,and then declined gradually,but was still detectable at 15 d.A good correlation between in vitro and in vivo data was obtained.The results suggest the potential use of DP microspheres for treatment of Alzheimer’s disease over long periods.

Multi-omic characterization of genome-wide abnormal DNA methylation reveals diagnostic and prognostic markers for esophageal squamous-cell carcinoma

This study investigates aberrant DNA methylations as potential diagnosis and prognosis markers for esophageal squamous-cell carcinoma(ESCC),which if diagnosed at advanced stages has<30%five-year survival rate.Comparing genome-wide methylation sites of 91 ESCC and matched adjacent normal tissues,we identified 35,577 differentially methylated CpG sites(DMCs)and characterized their distribution patterns.

VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance

Radiotherapy remains the mainstay for treatment of various types of human cancer;however,the clinical efficacy is often limited by radioresistance,in which the underlying mechanism is largely unknown.Here,using esophageal squamous cell carcinoma(ESCC)as a model,we demonstrate that guanine nucleotide exchange factor 2(VAV2),which is overexpressed in most human cancers,plays an important role in primary and secondary radioresistance.We have discovered for the first time that VAV2 is required for the Ku70/Ku80 complex formation and participates in non-homologous end joining repair of DNA damages caused by ionizing radiation.