Orally administered therapeutic agents need to cross the mucosal epithelial membrane in the intestine to reach the systemic circulation. This intestinal epithelial membrane is covered by a biopolymer barrier, namely, mucus which protects the underlying layer through trapping or degrading of foreign particles and macromolecules. Thus, mucus can restrict the systemic absorption of some therapeutic agents such as peptides by enzymatic degradation. Nanoparticles (NPs) could serve as a carrier for these peptides to protect them from environmental conditions in the mucus and to increase their bioavailability. However, these NPs can be trapped themselves by the mucus, hence, a proper nano-strategy should be selected to deliver these peptides orally. NPs delivery through intestinal mucus barrier has been studied extensively, where various in vitro tests and mucus models were investigated to mimic the in vivo test. In this thesis, two mucus models were assessed for their suitability as intestinal mucus barrier through which NPs diffusion can be studied. Also, multiple particle tracking (MPT) technique was exploited to study the diffusion and interaction of nanoparticles through pig intestinal mucus barrier. This technique (MPT) was used to understand the factors affecting the diffusion through mucus of NPs representing various nano-strategies such as PEGylated NPs and mucolytic NPs. Based on data obtained for the diffusion of NPs, we adopted a nano-strategy mimicking the capsid shell virus in which the NPs surfaces are densely covered with oppositely charged groups but with overall neutral charge. To do so, polyelectrolyte (PEC) NPs based on the self-assembly of (+) chitosan and (-) polyacrylic acid (PAA) were synthesized and the diffusion of these densely charged NPs was studied. After proving the concept, RAFT technique was used to synthesize zwitterionic densely charged NPs in which butyl methcrylate (BMA) was used as the lipophilic core and sulfobetaine as the shell of NPs. Native mucus prepared by our group was found to be a proper model to study NPs diffusion through it by the MPT technique. Study of diffusion of NPs representing various nano-strategies through mucus revealed the impact of various properties of these NPs on their diffusion. For example, particle size, zeta potential, type and molecular weight of the polymer, type and concentration of the diffusion enhancer and method of synthesis of NPs were detected to affect the diffusion of these NPs. For PEC NPs, the data obtained showed a relation between the zeta potential of NPs and their diffusivities through the mucus, where the highest diffusivity was obtained for the neutrally charged PEC NPs. Accordingly, sulfobetaine NPs were highly efficient NPs in term of their stability, charge density, particle size and importantly their diffusivities through the mucus barrier which was significantly higher as compared with all other tested NPs and related to the ratio of the sulfobetaine polymer in the NPs. This indicates that densely charged viral like NPs can be promising carriers to improve the mucus permeation of some therapeutic agents.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:685479 |
| Date | January 2015 |
| Creators | Albaldawi, Muthanna |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/90289/ |
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