Mohamed, Ahmed Moustafa Aly; (2006) Development of particulate carriers for delivery and targeting of biotherapeutics. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A progressive interest has arisen for applying biodegradable polymers to the delivery of biotherapeutics. Any polymer that is going to be used in the human body should have propensities for high biocompatibility as well as modulated biodegradability. The group of polymers most extensively studied so far in this regard is polyester polymers, like poly (lactic acid) (PLA), poly (glycolic acid) (PLGA), and polycaprolactone (PCL), and natural polymers like chitosan. This thesis describes a way to modulate the physicochemical properties of biodegradable nanoparticles by using selected hydrophilic polymers. Poly (ethylene glycol) (PEG) was utilised to improve the loading efficiency of the encapsulated protein antigens as well as to modulate their release profiles from PLGA and PCL nanoparticles, whereas poly- [N-(2-hydroxypropyl) methacrylamide] (pHPMA) was employed to modify the surface characteristics of chitosan/DNA nanoparticles. In addition, both hydrophilic polymers were utilised for the covalent attachment of targeting moieties, so that, the delivery of the encapsulated antigen or DNA plasmid to their targeting site could be improved. The effect of PEG on the loading efficiency of ovalbumin (OVA) in polymeric PLGA and PCL nanoparticles prepared by using a modified w/o/w solvent evaporation method was investigated. PEG with higher molecular mass improved OVA loading, and also OVA release was found to be dependant on the PEG content of the nanoparticles. PEG was also employed as an anchor for the two sugars, galactose and mannose to PCL nanoparticles encapsulating tetanus toxoid (TT) as vaccine delivery systems. Following their intranasal administration, tetanus toxoid loaded PCL-PEG-galactose or PCL-PEG-mannose nanoparticles induced IgG antibody titres higher than PCL nanoparticles or free tetanus toxoid administered. However, this was not the case following the intramuscular administration. Covalent attachment of either the monovalent PEG or the multivalent (pHPMA) to chitosan/DNA nanoparticles stabilised the surface of particles with a stealth-like shield as manifested in improvement in resistance to albumin binding. Moreover, the covalent attachment of transferrin as a targeting ligand to pHPMA showed an improved gene expression in prostate cancer cell line transfected by chitosan/DNA particles. When tested in vivo, pHPMA-coated chitosan/DNA nanoparticles were successful in eliciting an immune response.

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