Title:
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Flexible polymersome delivery of macromolecules across human skin
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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.
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