Chierico, L; (2015) Polymersomes mediated intracellular delivery of antibodies: implication in anticancer therapy. Doctoral thesis , UCL (University College London).

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Abstract

Cancer is one of the leading causes of death in the developed world. Nevertheless, many pharmaceutical products available in the clinic lack of tissue specificity, and often have severe side effects. Nowadays, advances in molecular biology and biotechnology have allowed the development of biological therapeutic approaches aimed to give a step forward on cancer treatment. Biotherapy involves the use of biomolecules such as antibodies that have the potential to increase the specificity of anticancer treatments, thus limiting the side effects. Unfortunately, the effectiveness of such biomolecules is hindered by their pharmacokinetics, and their translation into patient care is heavily restricted by low solubility in water, instability / degradation in vivo and low efficiency. Besides that, such biomolecules require appropriate delivery strategies to penetrate cellular barriers, thus being able to interfere with pathways that can be involved in cancer development. This research project aims to bridge the lack of technology regarding the development of an effective and biocompatible delivery system. The pH sensitive PMPC-PDPA ((poly(2-(methacryloyloxy)ethyl phosphorylcholine) - poly(2-(diisopropylamino)ethyl methacrylate)) polymersome was employed as candidate for the intracellular delivery of functional therapeutic antibodies in live cells. The PMPC-PDPA diblock copolymer combines the ability to release the loaded cargo upon acidification within the endosomes with an overall biocompatibility. First, the antifouling proprieties of polymersomes were investigated, and then compared to micelles. Subsequently, electroporation was exploited as reliable technique to effectively encapsulate antibodies within polymersomes. The delivery of antibodies in live cells was assessed using anti γ-tubulin antibody as a model system. Finally, Ki-67 was explored as a possible target for anticancer therapy. Interestingly, relevant differences in the biological functions of this marker were revealed between cancerous and non-cancerous cells. Furthermore, antibodies against Ki-67 were delivered in live cells, and their activity was tested to explore the potential of Ki-67 as a target for anticancer therapy.

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