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Development of targeted nanoparticles for the treatment of Pulmonary Hypertension

Tsilova, Scheilly Liu; (2025) Development of targeted nanoparticles for the treatment of Pulmonary Hypertension. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Pulmonary arterial hypertension (PAH) is an ultimately fatal condition that arises due to over-proliferation and apoptosis resistance of pulmonary artery cells. Current treatments only alleviate symptoms and do not resolve cellular dysfunction. Imatinib, a tyrosine kinase inhibitor, was studied for PAH but abandoned in Phase 3 trials due to its lack of safety and efficacy following systemic delivery. Many drug delivery systems, including nanoparticles (NPs), were researched to address the problems of free drug administration, but the encapsulation methods used were inefficient, costly, and involved complex, multi-step processes, leading to issues such as toxicity, polydispersity, and low encapsulation efficiency. Additionally, when administered in vivo, NPs primarily relied on the leaky vasculature for delivery, lacking specific targeting. This work aimed to improve imatinib delivery by encapsulating it in poly(lactic-co-glycolic acid) (PLGA) NPs, produced by electrospray (ES), a more efficient one-step process that avoids surfactants, high temperatures, and significant waste. The NPs were functionalised with an antibody to target relevant cells for improved drug delivery. The NPs were optimised for size, shape, composition, and morphology, and characterised for drug encapsulation efficiency and release profile in vitro and tested on various cell lines. The NPs were functionalised by conjugating a model antibody via carbodiimide chemistry. ES enabled the production of PLGA NPs with controlled size and hydrophobicity, allowing for high encapsulation efficiency and controlled drug release. Imatinib-loaded NPs reduced cell viability in lung cancer cells, had effects similar to free drug on endothelial cells, and had enhanced antiproliferative effects on arterial smooth muscle cells, in both the absence and presence of mitogen stimulation. Two antibody conjugation methods were identified, and a standard protein assay proved unreliable for quantification due to interferences. This work developed efficient, targeted PLGA nanoparticles further to develop targeted pulmonary drug delivery strategies for PAH.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Development of targeted nanoparticles for the treatment of Pulmonary Hypertension
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2025. 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 > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics
URI: https://discovery.ucl.ac.uk/id/eprint/10207987
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