Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.788949
Title: Synthesis and characterisation of stimuli-responsive amino acid-based polymeric materials for drug delivery
Author: Wang, Shiqi
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Abstract:
The delivery of cell-targeted therapeutics, particularly macrodrugs such as proteins and nucleic acids, is of great importance for modern therapy. However, there are many different barriers in the complex bio-environment, which significantly limit the drug availability and efficacy. Herein, this thesis presents the work on development of smart amino acid-based polymeric materials for drug delivery. Specifically, drug delivery vehicles at different length scales with different stimuli-responsive behaviour have been systematically investigated. A library of anionic, cell penetrating peptide-mimicking, lysine-based hyperbranched polymers have been developed for intracellular drug delivery. Results showed that these polymers destabilised membranes significantly at late endosomal pH, but remained non-lytic at physiological pH. The multivalency effect of the hyperbranched structure further effectively promoted the membrane interactions. Further investigation into endosomal release showed that the hyperbranched polymers could facilitate intracellular payload delivery in Hela cells. A series of amphiphilic hydrogels have been developed for oral drug delivery. The effects of crosslinking ratio, solid contents and molecular weights of crosslinkers on hydrogels' behaviour were investigated. Also, the in vitro model drug loading and release was evaluated. Results suggested that hydrophobic payloads could be successfully incorporated into the hydrogels, and the release in biorelevant buffers was triggered by pH stimulus. Furthermore, by using disulfide-bond containing crosslinkers, the hydrogels responded to the redox trigger in the colon, which led to a faster and more efficient release. For intracellular drug delivery via an oral route, nanogels were prepared using membrane-active polymers by either physical or chemical crosslinking. The physically crosslinked nanogels were designed to have pH-responsive dissociation. So they could retain model drugs in the acidic gastric fluid, but release them in the neutral intestinal fluid. After dissociation, the polymers were membrane-lytic at slight acidic pH (5.5), which could probably permeabilise cell membranes for intracellular delivery.
Supervisor: Chen, Rongjun Sponsor: European Commission
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.788949  DOI:
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