Biomembrane Interactions with Amphiphilic Polymer Drug Delivery Devices

Abstract

The aim of this thesis is to investigate the interactions of the class of PEO-PPO-PEO amphiphilic block copolymers with lipid biomembranes. In particular, we attempted to understand the molecular interactions underpinning the biological activity of PEO-PPO-PEO block copolymers and to define the structure, the dynamics and the behaviour of the lipid membrane in response to contact with these copolymers. PEO-PPO-PEO block copolymers are an important class of non-ionic, self-assembling surfactants, sold under the trademark name Pluronics®, which are considered promising candidates for drug delivery applications. The work initially focussed on the interaction of three Pluronic® block copolymers, PEO11-PPO16-PEO11, PEO13-PPO30-PEO13 and PEO19-PPO69-PEO19 (Pluronics® L35, L64 and P123, respectively) with lipid monolayers at the air-water interface. A link between the structural and the molecular characteristics of the copolymers and their ability to penetrate interact and associate with the lipid monolayer was established, through isothermal studies. The hydrophobic content of the copolymer in combination with its hydrophilic: hydrophobic ratio, were found to define its surface activity and penetration and incorporation ability. Subsequently, we investigated the interaction of Pluronic® L64 block copolymer with lipid monolayers and hybrid lipid/copolymer monolayers. The copolymer displayed a clear effect on the isothermal, rheological and morphological behaviour of the system. The presence of the copolymer seemed to induce a viscous dominant behaviour of the system and increased monolayer fluidisation. To further explore and clarify the mechanism of the copolymer interaction with the lipid membrane and its effect on the properties and the behaviour of the membrane, we subsequently studied the interaction of PEO13-PPO30-PEO13 (Pluronic® L64) with lipid vesicles. The interaction of the copolymer with both the lipid hydrophilic head groups and the hydrophobic alkyl chains was established. The initial adsorption of the copolymer at the interfacial head group region of the lipid bilayer was followed by its incorporation in the bilayer interior. The interaction of the copolymer with the lipid vesicle membrane induced strong structural, viscoelastic, morphological and phase behaviour changes of the membrane. Increased Pluronic® L64 incorporation resulted in membrane disorganisation, fluidisation and disruption Finally, the self-assembly ability of PEO13-PPO30-PEO13 block copolymer (Pluronic® L64) into lamellar vesicular structures was evaluated. Furthermore, the ability of these copolymer and hybrid copolymer/lipid vesicles to effectively carry and release a drug load was further explored. The produced copolymer and hybrid copolymer/lipid vesicles were found to possess favourable physicochemical and morphological characteristics for drug delivery.

Date of Award	31 Dec 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Aline Saiani (Supervisor) & Paola Carbone (Supervisor)