Chemical and Biomolecular Engineering - Theses

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Start date: 2000 × End date: 2019 × Type: PhD thesis × Subject: drug delivery × Author: Dodds, Sarah ×

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    In vivo behaviour of polymer-based nanoengineered materials
    Dodds, Sarah ( 2016)
    Nanoengineered materials are attracting a great deal of interest as the basis for therapeutic delivery systems, due to their potential to prolong circulation half-lives, circumvent solubility problems and reduce toxicity through efficient targeting. The versatility of polymers and polymer-based materials makes them logical candidates in this area, where the ability to tailor particular functionalities is key to producing materials which have a place in the clinic. Specifically, capsules assembled using the layer-by-layer (LbL) technique offer unique control over material composition, size, shape and functionality. Additionally cylindrical polymer brushes (CPBs) offer unique properties, being single molecules which can offer particle-like dimensions through highly tuneable chemistry. Understanding the behaviour of such systems in vivo is critical to progressing materials beyond the laboratory. Achieving significant blood residence time is important for the ultimate bioavailability of potential encapsulated therapeutics. This thesis looks at the in vivo behaviour of both LbL assembled polymer capsules and cylindrical polymer brushes. Specifically this work aims to (i) investigate the behaviour of click-LbL capsule systems in vivo; (ii) extend the understanding of LbL capsule protein fouling behaviour, relating in vitro to in vivo findings; (iii) investigate the behaviour of cylindrical polymer brush materials in vivo. This will be demonstrated through the assembly of a range of click-LbL capsule systems including poly(methacrylic acid) (PMA), poly(N-vinyl pyrrolidone) (PVPON), and poly(2-diisopropylaminoethyl methacrylate) (PDPA), followed by tritium labelling and analysis using a rat model to establish capsule pharmacokinetics and biodistribution. The understanding of LbL capsule behaviour in vivo is then extended by applying poly(ethylene glycol) (PEG) functionalisation approaches to PVPON film and capsule modification. Capsules are functionalised using single PEG chains as well as densely grafted PEG CPBs. Methods used to assess film interaction with serum proteins in vitro are evaluated in light of in vivo performance. This leads to an in vivo study of CPBs to support their viability as drug delivery vehicles in their own right. CPB pharmacokinetics and biodistribution are shown to be dependent on both brush length and stiffness, with promising half-lives in the range reported for some stealth liposome systems. The fundamental in vivo data reported for both LbL capsules and CPBs are expected to form a valuable foundation for the further development of both systems.