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Combinatorial Low-Binding Affinity Polymersomes for Targeting Dendritic Cells: Towards Cancer Vaccine Development

Cursi, Chiara; (2023) Combinatorial Low-Binding Affinity Polymersomes for Targeting Dendritic Cells: Towards Cancer Vaccine Development. Doctoral thesis (Eng.D), UCL (University College London). Green open access

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Abstract

Conventional DNA cancer vaccines fail to adequately stimulate the adaptive immune system and to establish proper immunisation. This is reflected in clinical practice, where only a handful of them have been approved by the FDA. Within this project the use of the pH-sensitive polymer Poly (2-(methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylamino-ethyl methacrylate) (PMPC-PDPA) has been investigated for DNA antigen encapsulation and intracellular delivery. By implementing a dendritic cellular model (DC2.4), it was demonstrated the expression and surface presentation of the antigen model (SIINFEKL). Furthermore, exploratory experiments highlighted the inflammatory power of the immunomodulator cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) in in vitro settings, with potential implications for in vivo cancer vaccines. Moreover, current strategies of design for active targeting nanoparticles (NPs) are suboptimal and characterised by off-target binding and side effects. In this work, it was demonstrated a paradigm shift in the design of active targeting nanoparticles based on the concepts of the ‘range selectivity’ theory. Specific Ligands for the phenotypic targeting of dendritic cells (DCs) were selected (PMPC, mUNO and PEP4) and conjugated to the respective polymer, such as PMPC-PDPA or polyethylene glycol-poly (lactic acid) (PEG- PLA). Multivalent and multiplexing POs were prepared and tested in vitro, proving experimentally the validity of computational hypotheses. Multivalent and combinatorial POs were also intradermally injected into animal models to further corroborate in vitro experimental evidence. It was envisioned that the implementation of empirical observation combined with in silico simulation would help to define the optimal range of the number of ligands on a vesicle for the phenotypic targeting of DCs, ultimately improving the intracellular co-delivery of antigen and adjuvant for the development of a cancer vaccine.

Type: Thesis (Doctoral)
Qualification: Eng.D
Title: Combinatorial Low-Binding Affinity Polymersomes for Targeting Dendritic Cells: Towards Cancer Vaccine Development
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10166406
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