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Title: Design and characterisation of targeting drug-loaded polymeric nanoparticles
Author: Marouf, W. M. Y.
ISNI:       0000 0001 3619 2022
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2008
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The aim of this work was the design and characterisation of drug-loaded, polymeric targeting nanoparticles (NP). Poly(lactide-co-glycoIide) (PLGA), a well known biodegradable and biocompatible polymer, was used for NP preparation. NP were formulated using controllable diffusion and emulsification combinations. This procedure was able to produce NP with narrow particle size distribution, high drug entrapment efficiency and ability to sustain drug release. To achieve drug targeting, ligand was conjugated to the NP surface using carbodiimide chemistry. The density of reactive carboxyl groups on the surface of PLGA NP was modulated by combining high molecular weight, end-capped PLGA, RG 505 S with a low molecular weight, non end-capped PLGA, RG 502 H. Such apprC?ach was able to conjugate protein-type targeting ligand onto NP surface along with modulation of drug release profile. Increasing the RG 502 H proportion in PLGA blend was found to increase the amount of ligand conjugation to NP surface as well as rate of drug release. Anti-Siglec-7 polyclonal antibody directed toward an endocytotic receptor was conjugated to the NP surface. Confocal laser scanning microscopy images obtained with Nile Red-loaded NP and fluorescence. microscopy images obtained with Acridine Orange-loaded NP, suggested selective binding of anti-Siglec- 7 conjugated NP to cells expressing Siglec-7 receptor with possible intracellular uptake. The ability of cytotoxic drug-loaded targeting NP to improve cytotoxicity was evaluated by encapsulating camptothecin, topoisomerase-I inhibitor, into PLGA NP with different densities of surface carboxylic acid, which was then conjugated with IgG anti-Fas monoclonal antibody. In vitro antitumour activity, evaluated using human colorectal cancer cell lines (HCT116), indicated that PLGA NP were able to improve CPT anti-tumour activity compared with CPT solution. Conjugating anti-Fas mAb onto the surface of CPT-loaded NP resulted in improved potency compared to corresponding naked NP, and was able to synergise with CPT.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available