Rehal, Jasvinder Singh; (2004) Poly-(ϵcaprolactone) nano- and microparticles as vaccine delivery systems. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The development of novel and easy administrable vaccine delivery systems against infectious diseases is of major importance. Mucosal vaccine delivery systems would potentially save millions of lives, especially in the developing world. This thesis describes the optimisation and investigation of PCL nano- and microparticles as vaccine delivery systems, both in vivo and in vitro. The effect of co-solvents on the loading efficiency of ovalbumin in polymeric PLGA and PCL nanoparticles was investigated using the w/o/w solvent evaporation method. Acetone and ethyl-acetate in combination with DCM reduced the loading efficiency of ovalbumin in the nanoparticles when compared to DCM in the organic phase alone, whereas methanol, iso-propanol and benzyl-alcohol in combination with DCM increased the loading efficiency of ovalbumin in the nanoparticles, when compared to DCM in the organic phase alone. Diphtheria-toxoid encapsulated in PCL nanoparticles using DCM/benzyl-alcohol in the organic phase, lead to similar IgG antibody titres compared to when DCM was used in the organic phase. Following i.m. and i.n. administration of diphtheria-toxoid loaded PCL, PLGA and PLGA-PCL co-polymer or PLGA-PCL blend nanoparticles, PCL nanoparticles induced IgG antibody titres significantly higher than PLGA nanoparticles or free diphtheria- toxoid administered, while the uptake of polymeric nanoparticles by Caco-2 cells, was in the order of: PCL>PLGA-PCL co-polymer>PLGA-PCL blend>PLGA. The addition of alum in the internal aqueous phase or the organic phase was investigated in relation to the effect on diphtheria-toxoid loading efficiency and IgG immune response. The addition of alum in the internal aqueous phase resulted in the highest loading efficiencies, and also resulted in the highest diphtheria-toxoid specific IgG antibody titres following i.m. administration. PCL nanoparticles induced higher diphtheria-toxoid specific IgG antibody titres than PCL microparticles, following i.m. administration. The production of IL-6 and IFN-γ cytokines following boosting with diphtheria-toxoid was determined and indicated that Diphtheria-toxoid loaded nanoparticles induced a mainly Th2 type immune response, whereas diphtheria-toxoid microparticles induced a mainly Th1 type immune response.

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