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    Modulation of inflammatory responses at mucosal surfaces by nanoparticle-based siRNA delivery

    Frede, Annika

    [Thesis]. Manchester, UK: The University of Manchester; 2016.

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    Abstract

    In this thesis nanoparticles consisting of a calcium phosphate core encapsulated by poly(lactic-co-glycolic) acid and polyethylenimine were developed for the delivery of siRNA in vivo. The nanoparticles were efficiently endocytosed by different cell types in vitro without exhibiting cytotoxic characteristics. Without possessing endogenous immune response activating properties, the nanoparticles had a highly preferable composition for the delivery of siRNA and subsequent gene knockdown. The delivery of siRNA with nanoparticles was tested in two different murine disease models: DSS-induced colitis as model for human IBD and a TH1-induced lung inflammation as model for COPD. In IBD and COPD chemokines and cytokines are predominant players in the progression of the inflammatory response. The local interference of cytokine signalling mediated by siRNA-loaded nanoparticles might therefore be a promising new therapeutic approach. In both murine models, the aim was to deliver siRNA directed against inflammation related cytokines by nanoparticles for the local treatment of mucosal inflammation.The local administration of nanoparticles loaded with siRNA to mice suffering from intestinal or lung inflammation led to significantly decreased target gene expression on mRNA as well as protein level in biopsies from the target tissues. Furthermore, reduced cytokine levels were accompanied by diminished inflammatory pathologies and augmented clinical signs of sickness. The results of this thesis indicate that a specific and local modulation of inflammatory responses by nanoparticle-based siRNA delivery is feasible and demonstrates a major therapeutic potential.

    Bibliographic metadata

    Type of resource:
    Content type:
    Form of thesis:
    Type of submission:
    Degree type:
    Doctor of Philosophy
    Degree programme:
    PhD Immunology
    Publication date:
    Location:
    Manchester, UK
    Total pages:
    176
    Abstract:
    In this thesis nanoparticles consisting of a calcium phosphate core encapsulated by poly(lactic-co-glycolic) acid and polyethylenimine were developed for the delivery of siRNA in vivo. The nanoparticles were efficiently endocytosed by different cell types in vitro without exhibiting cytotoxic characteristics. Without possessing endogenous immune response activating properties, the nanoparticles had a highly preferable composition for the delivery of siRNA and subsequent gene knockdown. The delivery of siRNA with nanoparticles was tested in two different murine disease models: DSS-induced colitis as model for human IBD and a TH1-induced lung inflammation as model for COPD. In IBD and COPD chemokines and cytokines are predominant players in the progression of the inflammatory response. The local interference of cytokine signalling mediated by siRNA-loaded nanoparticles might therefore be a promising new therapeutic approach. In both murine models, the aim was to deliver siRNA directed against inflammation related cytokines by nanoparticles for the local treatment of mucosal inflammation.The local administration of nanoparticles loaded with siRNA to mice suffering from intestinal or lung inflammation led to significantly decreased target gene expression on mRNA as well as protein level in biopsies from the target tissues. Furthermore, reduced cytokine levels were accompanied by diminished inflammatory pathologies and augmented clinical signs of sickness. The results of this thesis indicate that a specific and local modulation of inflammatory responses by nanoparticle-based siRNA delivery is feasible and demonstrates a major therapeutic potential.
    Thesis main supervisor(s):
    Thesis co-supervisor(s):
    Language:
    en

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    Academic department(s):

    Record metadata

    Manchester eScholar ID:
    uk-ac-man-scw:301897
    Created by:
    Frede, Annika
    Created:
    29th June, 2016, 16:01:58
    Last modified by:
    Frede, Annika
    Last modified:
    9th January, 2019, 09:51:48

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