الفهرس 
General introductionOnly 14 pages are availabe for public view
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Abstract
Apocynin (APO) is a bioactive phytochemical possessing a versatile pharmacological effect in treating a wide spectrum of diseases. Despite the potential pharmacological effects of APO have been previously reported in different intervention of disciplines such as : liver fibrosis, inflammatory and oxidative-based liver damage, alcoholic liver diseases, as well as hepatic carcinoma, no endeavor has been investigated, yet to fabricate a polymeric nanostructured delivery system for enhancing APO’s hepatoprotective or targeting its anti-hepatocarcinogenesis efficacy. Accordingly, the main objective of this thesis was to fabricate an oral nanoparticulate system of APO to scout its anticipated hepatoprotective efficacy and, additionally, to fabricate an auspicious targeted nanostructured delivery system to achieve the outmost anticipated effect of APO against hepatocellular carcinoma (HCC). Objectives : In this study, two polymeric nanoparticulate delivery systems (PNDSs) have been adopted to deliver APO. The premier approach is the use of chitosan (CS) coated polymeric nanoparticulate delivery system (PNDS) that has come to the forefront as a viable drug delivery strategy, presenting opportunities for controlled release, protecting active components from enzymatic or environmental degradation, conferring permeation enhancement characteristics, and enhancing the pharmacological activity of the encapsulated drug. Whilst the second one is the use of galactosylated chitosan (GC) tailored PNDS for asialoglycoprotein receptor (ASGPR) -targeting. Methods : To our knowledge, no research has been conducted to fabricate an oral mucoadhesive polymeric nanoparticulate system of APO to reconnoiter its anticipated hepatoprotective efficacy against lipopolysaccharide (LPS)/D-(+)-galactosamine hydrochloride (D-GalN)-induced fulminant hepatitis (FH) in BALB/c mice. Along these lines, this part was directed to fabricate, optimize, by adopting a randomized full 33 factorial design, and extensively evaluate a CS surface decorated polymeric NPs prepared by the double emulsion-solvent evaporation method. No endeavor has been accomplished yet to develop a nanostructured delivery system anticipated for targeting APO’s anticancer activity, precisely against HCC. Consequently, CS derivative with galactose groups namely ; GC, particularly recognized by the ASGPR “referred to as galactose receptor and mainly expressed on hepatocytes’ surface while minimally on extra-hepatic cells” was synthesized and its chemical structure was thoroughly characterized by substantial techniques. Afterwards, GC-coated nanoplatform for hepatocyte attachment “APO-loaded galactosylated chitosan-coated poly(d,l-lactide-co-glycolide) nanoparticles (APO-loaded GC-coated PLGA NPs)” was developed. Results: APO-loaded CS-coated PLGA NPs were successfully prepared by double emulsion-solvent evaporation technique (w1/o/w2). The SDE paradigm provided an efficient mean to optimize the DMAs of the w1/o/w2 method of preparation. The optimal APO-loaded CS-coated PLGA NPs formula (F19). Such formulation was surveyed elaborately and characterized supplementally regarding its mucoadhesion efficiency, morphology by transmission electron microscopy (TEM), solid state characterization via Fourier transform-infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) and X-ray Diffraction (XRD). Eventually, it’s in vitro release profile, kinetic analysis, and physical stability at refrigerated (4 ± 1°C) and ambient temperatures. The optimal APO-loaded CS-coated PLGA NPs formula (F19) evoked a prodigious in vivo hepatoprotective efficacy against LPS/D-GalN induced FH in BALB/c mice. GC was synthesized and its chemical structure was thoroughly characterized by substantial techniques. Afterwards, GC-coated nanoplatform for hepatocyte attachment “APO-loaded galactosylated chitosan-coated poly(d,l-lactide-co-glycolide) nanoparticles (APO-loaded GC-coated PLGA NPs)” was developed. The developed NPs were comprehensively appraised regarding their ; EE %, Z-average, ζP, morphology by TEM, and solid-state characterization via FT-IR spectroscopy, DSC as well as XRD. Eventually, these NPs were assessed for their in vitro release profile, kinetic analysis, and physical stability at refrigerated (4 ± 1°C) temperature. The investigated APO-loaded GC-coated PLGA NPs evoked a spectacular anticancer efficacy against the HepG2 cell line. Conclusion : APO-loaded CS-coated PLGA NPs and APO-loaded GC-coated PLGA NPs could be considered as a promising PNDS to open new prospects for therapeutic intervention in inflammatory based liver diseases and for designing nano-phytomedicines with high cellular delivery performance and an auspicious anticancer efficacy, respectively.