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Title: Flexible polymersome delivery of macromolecules across human skin
Author: Pegoraro, Carla
ISNI:       0000 0004 2739 0125
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2011
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Transdermal drug delivery (TOO) can be defined as a continuous administration of therapeutic compounds across skin. It has many advantages compared to oral or intravenous administration routes but it has to compensate for the innate impermeability of the skin layer. In the past various delivery-enhancing techniques have been developed (e.g. microneedles, electrophoresis, etc.) but these have often caused temporary ski n irritation. In recent years lipid based vesicle systems, liposomes, have been used with varying levels of success as drug delivery vehicles. They have often been found to deliver only in the top layers of skin due to mechanical rupture. However liposomes that have demonstrated the ability to deform and squeeze between the very tight gaps in skin have been seen to enhance delivery. During this project mechanically strong and flexible polymeric vesicles, polymersomes, were developed for transdermal applications. The block copolymer nature of these structures renders them very tough and able to resist rupture more easily than liposomes. Polycarbonate porous membranes were used to model permeation across skin and various block-copolymer formulation were studied. Experiments were performed in a designed perfusion chamber that allowed the manipulation of the hydration and concentration gradients across the barrier so as to determine their influence on the transport process. Results showed the importance of surface chemistry and the vesicles size dependence of permeation across a porous structure without rupture. Human ex vivo skin was used to determine polymersome ability to cross the biological barrier. Permeation was quantified via fluorescence and imaged using Confocal Laser Scanning Microscopy (CLSM). Dextran, a high molecular weight molecule that has been seen not to cross the biological barrier, was chosen to determine whether or not polymersomes were able to deliver as well as cross skin. Results showed that polymersomes were able to efficiently penetrate human skin and deliver their payload. Tissue engineered melanoma skin models were used as a model clinical application for TDD using polymersomes. Polymersome uptake and permeation was studied for melanoma monolayers and 3D tissue models. The model anti-cancer drug chosen was doxorubicin for its natural fluorescence. Permeation and delivery were studied using fluorescence, fluorescence activated cell sorting (FACS), high-performance liquid chromatography (HPLC) and Confocal Laser Scanning Microscopy (CLSM) analysis. The drug uptake for all the cell types was seen to increase when encapsulated within polymersomes. Delivery across the TE skin models was also improved. The results obtained demonstrated an interesting potential for the development of needle free drug delivery systems based on block copolymer vesicles.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available