Singh, Latavia2015-09-082015-09-082015-09-08http://hdl.handle.net/10539/18542A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfillment of the requirements for the degree of Master of Pharmacy Johannesburg 2015Viruses boast a highly skilled mode of entry into the cells of all living organisms. This occurs due to the intelligent make-up of these biological systems. A drug delivery system was designed to mimic viruses ordinarily, hence taking advantage of cell entry ease that these viruses parade and ultimately, as a result, ensuring intracellular antiviral transmittal to targeted sites in the body. The Hepatitis B Virus (HBV) was used as a representative virus with representative antiviral drug being Lamivudine (LMV). An architecturally-configured nanoparticulate system (ACNS) was formed by a novel graft copolymerization of hydrophobic epsilon-Caprolactam (ECL) onto the backbone of hydrophilic Hyaluronic acid (HA) (HA-g-ECL). HA-g-ECL showed competence in forming amphiphilic micelles broadening areas of its application in drug delivery. A Box-Behnken experimental design strategy generated formulations thoroughly screened in terms of variables (copolymer, surfactant and solvent) affecting responses (size, drug entrapment efficiency and mean dissolution time). ACNS particles were created with sizes varying from 32.03nm to 132.95 nm holding a negative surface charge. LMV content ranged from 18.52 – 47.77 %. Sustained drug release with an initial burst release was attained. A single optimal formulation was computed by way of statistical variable response optimization. Commendable desirability percentages were achieved for measurement outcomes. A cryoprotectant screening evaluation determined 20 % mannitol to be optimal in maintaining ACNS size. Optimal ACNS was surface-modified with a viral-mimicry targeting ligand for liver concentration. Linoleic acid (LA) was graft copolymerized to chitosan synthesizing chitosan-linolate (C-LA) employed as a coat (C-LA ACNS). Tests to assess response data deviation of C-LA ACNS from optimal ACNS were carried out with positive outcomes. Ex vivo internalization via fluorescent microscopy and imaging studies in liver HepG2 cells showed positive uptake in both optimal ACNS and C-LA ACNS with exemplary findings for C-LA ACNS due to an augmented intracellular receipt. In vivo appraisal proceeded in a rodent animal model dispensing C-LA ACNS intraportally. Ultrasound imaging confirmed echogenic C-LA ACNS robust in the hepatic area. Ultra Performance Liquid Chromatography was executed on blood plasma and hepatic tissue samples for LMV detection and quantification. C-LA ACNS proved an impressive hepato-targeting ability with LMV Cmax = 91.723 μg/mL in liver tissue against LMV Cmax = 8.947 μg/mL in blood plasma at equivalent time points. ACNS demonstrated significant liver targeting ability on the grounds that a fatty acid be incorporated into its structure. Evolution of this mechanism will lead to favorably high levels of antiviral drugs within sites in the body that are laden with viral disease and will assist in destruction of the virus. This system will prove particularly beneficial in the treatment of opportunistic infections associated with HIV/AIDS and HBV.enThesis