Liatsi-Douvitsa, Eva; (2019) Polyester-based Micelles and Vesicles for Pulmonary Administration. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text THESIS FINAL.pdf Download (238MB) | Preview

Abstract

Therapeutic biomacromolecules have gained a prominent place in the pharmaceutical industry in the last decade. This strong appeal stems directly from their highly specific function, which is allowing the eradication of previously untreatable diseases. However, their delicate supramolecular structure introduces serious obstacles to their effective delivery. This is where polymersomes represent ideal candidates as a nanodelivery platform as they can host (i.e. encapsulate), stabilize and protect sensitive cargo, assisting it to cross in vivo barriers and reaching its target. The polymeric systems developed and proposed in this study are built from FDA-approved materials and hence make more feasible a potential clinical translation. The systems are based on degradable polyesters, copolymerised with the biocompatible and antifouling PEG and self-assembled into vesicular morphologies that allow the encapsulation of the sensitive cargo into their enclosed cavity. The model encapsulant, the monoclonal antibody (MoAb), Omalizumab, employed in the treatment of allergic asthma and chronic idiopathic urticaria (CIU), is currently administered by subcutaneous injection which reduces its bioavailability in the target organ, the lung. The model MoAb was successfully encapsulated into PEG-polyester nanoplatforms without compromising the protein structure, using a biology-inspired technique, namely electroporation. The nanoplatforms were subjected to spray-drying to enable their absorption through the lungs and open this way the road to targeted lung delivery. The particle size distribution values suggest that the largest volume of particles falls within the optimal range for pulmonary delivery within the alveolar space, namely below 1 μm, while it was also demonstrated that the polymeric nanocarriers retained the physicochemical characteristics. The effect of nanoparticle shape on cell-uptake was also addressed by employing micellar morphologies. We found that spherical micelles displayed a more pronounced internalisation compared the equivalent anisotropic structures, suggesting a different uptake mechanism. The self-assembly of PEG-polyesters was studied employing both top-down (i.e. film hydration) and bottom up approaches (i. e. solvent displacement). The 4 content of the hydrophobic polyester block has been identified to have a crucial impact on the self-assembly process. We were able to finely control supramolecular polymer self-assembly, in terms of particles size and shape, by tuning the ration between the hydrophilic-to-hydrophobic ration of the polymer while attained platform exhibits characteristics that could fit different applications. A platform of enhanced softness, for instance can be an ideal candidate to cross lung barriers for an efficient MoAb delivery while a more rigid one could be employed for fast immune-cell targeting.

Download activity - last month

Export as JSONCSVXML

Download activity - last 12 months

Export as JSONXMLCSV

Downloads by country - last 12 months

Export as JSONCSVXML

Archive Staff Only

View Item