Chemical and Biomolecular Engineering - Theses

Permanent URI for this collection

Search Results

Now showing 1 - 2 of 2
  • Item
    Thumbnail Image
    Engineering Nanocapsules with Tunable Physiochemical Properties for Controlled Bio−Nano Interactions
    Li, Shiyao ( 2021)
    The rapid development of nanoparticle engineering has extended into a wide range of bio-medical applications. Metal-phenolic network (MPN) capsules, which are formed upon coordination of polyphenols with metal ions, have emerged as a promising class of particle-based drug delivery systems, due to their tunable physiochemical properties and drug-loading capability. For example, the use of poly(ethylene glycol) (PEG)-conjugated polyphenol to coordinate with metal ions affords PEG-MPN capsules that show reduced nonspecific cellular associations in vitro when compared with MPN capsules prepared from tannic acid (TA) as a polyphenol. However, to date, the literature studies on MPN capsules have generally focused on the preparation of MPN capsules on the micrometer scale, which is not within the optimal size range of nanoparticle-based drug delivery systems. It has been a challenge to engineer MPN capsules on the nanometer scale with controllable size. Therefore, engineering MPN nanocapsules with controllable physiochemical properties and subsequently studying the interactions between the nanocapsules and different biological systems are important towards effectively advancing MPN capsules in biomedical applications. In the present thesis, MPN nanocapsules with sizes between 50 to 150 nm were engineered through template-assisted self-assembly. The effects of capsule size on the bio-nano interactions between PEG-MPN nanocapsules and different biological systems were investigated through in vitro cell association assays, ex vivo blood assays, and in vivo circulation and biodistribution studies. The PEG-MPN nanocapsules of 50 nm showed reduced association with leukocytes (up to 70%) and longer circulation time in vivo (4 h vs. 1 h) than the 150 nm PEG-MPN nanocapsules. The PEG-MPN nanocapsules were then endowed with targeting capability to target tumor cells by functionalizing the nanocapsules with anti-PEG-anti-epidermal growth factor receptor (EGFR) bispecific antibodies. The obtained PEG-MPN-EGFR showed specific association with EGFR-overexpressed MDA-MB-468 human breast cancer cells in vitro. Although the targeting ability of PEG-MPN-EGFR was largely limited in the presence of human blood (particle association reduced to 1/9 of the in vitro results; that is from ~81 to ~9 nanocapsules per cell), it was restored in washed blood conditions (where the human plasma was removed from the blood). These results were comparable to that of the in vitro experiments, demonstrating the important role of human plasma in regulating the bio-nano interactions. Finally, the effect of different protein corona on immune cell-particle interactions was investigated. TA-based MPN nanocapsules were precoated with a protein corona composed of different serum proteins (bovine serum albumin, fetal bovine serum, and bovine serum), and the association between the precoated MPN nanocapsules with leukocytes in human blood was analyzed using mass cytometry. Precoating the nanocapsules with serum proteins effectively reduced association with leukocytes, in which precoating the nanocapsules with fetal bovine serum reduced the capsule association with neutrophils and monocytes up to 90% compared with nanocapsules without precoating. Proteomics analysis of the protein corona composition suggests that the enrichment of immunoglobulins is positively correlated with the increased leukocyte association of the nanocapsules. Overall, MPN nanocapsules with controlled physiochemical properties were engineered and the interactions between the nanocapsules with different biological systems were studied.
  • Item
    Thumbnail Image
    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.