The Engineering and Development of pH-Responsive Biopolymers for Drug Delivery Applications

This dissertation describes experimental studies to understand the structure of biocompatible pH responsive polymers and their interaction with the biological system in order to design more effective entities for biomedical applications. A systemic approach was used to study the structure and biological interaction of pH responsive biocompatible poly (L-lysine iso-phthalamide) (PLP) polymer and its derivatives. Poly (L-lysine isophalamide) is a unique polymer that contains pendant carboxylate group and modification with phenylalanine was able to enhance the intracellular delivery efficiency of the polymer. However, the exact structure and mechanism of action remains mostly unknown. In this study, a variety of modifiers was used to synthesise new PLP derivatives in order to elucidate their effect on the polymer structure and other functional characteristics. New characterisation methods including circular dichroism and small angle neutron scattering were introduced to provide more detailed information on the polymer structure and evidence to explain the polymer-membrane interaction. It was determined that PLP adopted a helical structure in solution and that the ability of the PLP- derivative to from a lamellar structure in solution would lead to enhanced intracellular delivery effectiveness. Chirality of the PLP components and modifiers were also examined. Three PLP enantiomers and four phenylalanine modified PLP were synthesised and characterised. The polymers were determined to be chemically identical and had comparable functionalities. However, it was proven again that the ability for polymer to form lamellar structure would result in enhanced intracellular delivery efficiency. The structural and functional information was later used to better design a drug delivery system for the cryopreservation of mammalian cells. The approach was successful, as the resulting vitamin E modified polymer was able to achieve similar cryosurvival rate with trehalose as cryoprotectant compared the gold standard DMSO protocol. The success marked the importance of application-specific design and understanding of drug delivery systems.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2019

Author dc:creator

• Chen, Alexander

Advisor dc:contributor.advisor

• Slater, Nigel

• pH-responsive polymers
• Intracellular Delivery
• Polymer synthesis

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/32310d22-83a9-4ef2-9c0c-08c29744c545/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.45789

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/298733