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dc.contributor.advisorHouston, Todd
dc.contributor.authorMosaiab, Tamim
dc.date.accessioned2019-03-29T04:18:33Z
dc.date.available2019-03-29T04:18:33Z
dc.date.issued2018
dc.identifier.doi10.25904/1912/1147
dc.identifier.urihttp://hdl.handle.net/10072/382729
dc.description.abstractBacterial infection is still one of the leading causes of hospitalization and mortality, although antibiotics are used comprehensively to treat the infectious diseases. The clinical failure of antibiotic therapy is associated with low bioavailability, poor penetration capacity to bacterial infection sites, the side effect of antibiotics, and the antibiotic resistance properties of bacteria. Moreover, many deadly infectious diseases are produced by microorganisms that are able to survive in macrophages. The intracellular location of these pathogens protects them from the host defence systems and from some antibiotics with poor penetration into macrophages. Therefore, the use of non-viral nanoparticulate systems for the delivery of therapeutic agents is receiving considerable attention to improve the penetration of drugs into macrophages as well as the use of specific target molecules onto the nanocarrier systems that deliver these drugs directly to the target cell. These systems can be designed to meet specific physicochemical requirements, and they exhibit low toxic and immunogenic effects. This thesis attempts to rationally design and synthesise antibiotic-encapsulated glyconanoparticles (GNPs) and glyco-coated liposomes for active targeting of macrophages to treat a range of infectious diseases. Macrophages are a promising target for carbohydrate-based therapeutics as they express carbohydrate binding receptors which internalize bound material via receptor-mediated endocytosis. Therefore, we targeted the lectin receptors presented on the macrophage cell membrane by coupling many monomeric sugar moieties onto appropriate scaffolds such as polymers or liposomal systems to create multivalent targeting carriers and improve the activity, stability and lower cytotoxicity. The natural cationic polysaccharide chitosan was selected to conjugate specific carbohydrate sequences on the polymer backbone to target macrophages. Moreover, a variety of liposomal formulations with multivalent targeting ligands were considered as potential therapeutic carriers to macrophages. The hydrophobic antibacterial agents N-alkylsulphonylacetamide and hydrophilic aminoglycoside were loaded into the artificial nanocarrier system to explore their ability to inhibit bacterial growth. The antibiotic carrier was also modified via different monosaccharides including mannose and galactose to promote the interaction of the nanovehicle with macrophages and enhance drug concentration into the infected immune cells. Glycolipids from Mycobacterium tuberculosis have a profound impact on the innate immune response of the host. Macrophage inducible C-type Lectin (Mincle) is a pattern recognition receptor that has been shown to bind trehalose dimycolate (TDM) from the mycobacteria and instigate intracellular signaling in the immune cell. There are structural similarities between TDM and phosphatidyl inositol mannoside (PIM) structures and these latter structures may also bind Mincle. To test this, we have successfully synthesized and characterized a series of novel mannose derivatives modified with fatty esters at the 6-position to explore their ability to interact with macrophages. The results showed that the amount of two major cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 released from LPS stimulated U937 cells decreased significantly when compared to control upon treatment with the prepared glycolipids indicating the reduction of cytokines production by macrophages. (Chapter 2) Antibiotic loaded [amikacin and n-decanesulphonylacetamide (DSA)] cationic dimethyldioctadecylammonium bromide (DDAB) with fatty acyl and fatty amido α-D-benzylmannoside liposomes were prepared by the thin film hydration method and characterized via DLS (Chapter 3). The antibiotic loading efficiency and the release profile in the prepared glyco-coated liposomes were also determined. The efficiencies of the drug loaded liposomes were tested against S. aureus infected macrophages and results showed significant intracellular bacterial growth inhibition (Chapter 3). In Chapter 4, mannose precursors have been synthesized with carboxyl group at the anomeric position and fatty amides at the 6-position. The lactose and mannose derivatives were prepared after conjugating these sugar molecules onto the chitosan backbone to produce mannose and lactose grafted chitosan (Chitmannolac). The engineered chitosan derivatives were utilized to make GNPs via nanoprecipitation method and characterized using NMR spectroscopy, FT-IR spectroscopy, UV-vis spectroscopy, fluorescence spectroscopy and DLS. The intracellular bacterial killing efficiency was determined using the artificial GNPs and result showed promising antimicrobial inhibition upon incubating with these GNPs. Overall this PhD thesis implements modern synthetic strategies to discover novel drug carriers for biomedical application. This thesis work develops a macrophage targeted drug delivery system from the ground up through: (i) designing novel glycolipids that can mimic various naturally occurring glycolipids; (ii) providing step by step synthesis of glycolipids and their characterization; (iii) preparation of liposomes and micelles using the similar glycolipids moieties and compare their target ability to mammalian cells; and (iv) demonstrating the intracellular bacterial inhibition using liposomes and GNPs that encapsulate both hydrophobic and hydrophilic drugs in the same carrier.en_US
dc.languageEnglish
dc.language.isoen
dc.publisherGriffith University
dc.publisher.placeBrisbane
dc.subject.keywordsGlyconanoparticlesen_US
dc.subject.keywordsMacrophagesen_US
dc.subject.keywordsTherapeutic agentsen_US
dc.subject.keywordsBiomedical applicationen_US
dc.subject.keywordsLiposomesen_US
dc.titleGlyconanoparticles for targeting macrophages to deliver therapeutic agentsen_US
dc.typeGriffith thesisen_US
gro.facultyScience, Environment, Engineering and Technologyen_US
gro.rights.copyrightThe author owns the copyright in this thesis, unless stated otherwise.
gro.hasfulltextFull Text
dc.contributor.otheradvisorKiefel, Milton
gro.thesis.degreelevelThesis (PhD Doctorate)en_US
gro.thesis.degreeprogramDoctor of Philosophy (PhD)en_US
gro.departmentInstitute for Glycomicsen_US
gro.griffith.authorMosaiab, Tamim


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