Sipin, Miguel Luis Carale;
(2023)
Design of Polymeric Nanoparticles for Phenotypic Targeting.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
A key problem in healthcare today lies in our ability to target specific cells, particularly those within the brain. The problem arises from both inadequacies to target specific cells without targeting other cells and the difficulty in crossing the blood brain barrier (BBB). For this problem, the first barrier to overcome is to specifically target the blood brain barrier to enable the crossing of the BBB. Several targeting theories have arisen from the use of multivalent interactions yet are limited as they consider targeting only one receptor type. We herein investigate a more accurate targeting mechanism, phenotypic targeting (the targeting of a cell phenotype) and the variables that influence it. In this thesis, brain endothelial cells (bEnd3) were used as the target cell, the main cells for targeting the BBB. Nanoparticles were designed with AP2 or Glucose ligands, to target LRP-1 or Glut1 respectively, varying both the number of ligands and ligand insertion parameters (how embedded a ligand is within a polymer brush). When performing binding assays on three different cell lines (for endothelial cells (bEnd3), astrocytes (C8-D1A) and glioblastoma (T98G), we observed that inserting a ligand within a polymer brush alters the number of ligands required for a strong bind, which we postulate is due to a novel steric repulsion between nanoparticles. We observed no specific binding towards bEnd3 when compared with the other two cell lines; however, we postulate that this is due to difference in the glycocalyx of the three cell lines and that receptor conformation could change depending on the glycocalyx density. Crossing studies were then conducted, and we observed that embedding the ligand within a polymer brush could allow us to both ensure the endocytosis of nanoparticles into the BBB and the transcytosis across the BBB.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Design of Polymeric Nanoparticles for Phenotypic Targeting |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. 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-pp.ucl.ac.uk/id/eprint/10181040 |
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