Ultrasound-mediated transport of nanoparticles and the influence of particle density
<p>Cancer therapeutics are limited in efficacy by poor penetration into tumour tissue. This doctoral thesis aims to explore how changing the density of a therapeutic could influence its ultrasound-mediated delivery and penetration depth, thereby testing the hypothesis that increasing particle...
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| Format: | Thesis |
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2018
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| _version_ | 1797074287291531264 |
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| author | Lea-Banks, H |
| author2 | Coussios, C |
| author_facet | Coussios, C Lea-Banks, H |
| author_sort | Lea-Banks, H |
| collection | OXFORD |
| description | <p>Cancer therapeutics are limited in efficacy by poor penetration into tumour tissue. This doctoral thesis aims to explore how changing the density of a therapeutic could influence its ultrasound-mediated delivery and penetration depth, thereby testing the hypothesis that increasing particle density increases penetration depth of nanoparticles under ultrasound exposure. Density-enhanced transport in the presence of ultrasound-induced cavitation is studied utilising a combination of numerical simulations, <em>in vitro</em> and <em>in vivo</em> experimental models.</p> <p>The penetration depth of nanoparticles of different densities was first predicted using a computational model to assess the magnitude of acoustic and fluid dynamic forces on a spherical nanoparticle in the presence or absence of a cavitating microbubble. This simulation showed that a denser particle will be transported further when exposed to ultrasound. Furthermore, cavitation was identified as fundamental for enhanced transport, with forcing due to microstreaming dominating the transport behaviour. These predictions were validated and supported experimentally using an <em>in vitro</em> model, where a fivefold increase in particle density resulted in a 43 % increase in peak particle penetration depth.</p> <p>To form a closer analogue to the tumour environment, a three-dimensional flow-vessel phantom was then implemented, where the penetration depths of three density-contrasting nanoparticles with unique fluorescent tags – co-delivered with either a micro- or a nano-scale cavitation agent – were studied. A trend between nanoparticle density and extravasation depth was again discernible, with the densest particles penetrating the furthest. However, the choice of cavitation agent often had a greater influence on particle transport.</p> <p>Finally, experiments were performed in a tumour-bearing mouse model, where the bio-distribution of fluorescent nanoparticles was assessed after ultrasound exposure. A bistatic HIFU setup was used to activate cavitation agents, and passive acoustic mapping was implemented to detect cavitation activity within the tumour site. Density-contrasting fluorescent nanoparticles were used as mock therapeutics, and were successfully detected in <em>ex vivo</em> tumours through IVIS imaging. However, due to experimental limitations, the influence of nanoparticle density on ultrasound-mediated drug delivery <em>in vivo</em> could not be determined, and so recommendations are made for how the hypothesis can be further validated.</p> |
| first_indexed | 2024-03-06T23:33:59Z |
| format | Thesis |
| id | oxford-uuid:6d03ee65-003f-4a33-bd9d-f1dc0cb517bf |
| institution | University of Oxford |
| last_indexed | 2024-03-06T23:33:59Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | oxford-uuid:6d03ee65-003f-4a33-bd9d-f1dc0cb517bf2022-03-26T19:14:55ZUltrasound-mediated transport of nanoparticles and the influence of particle densityThesishttp://purl.org/coar/resource_type/c_db06uuid:6d03ee65-003f-4a33-bd9d-f1dc0cb517bfORA Deposit2018Lea-Banks, HCoussios, CStride, E<p>Cancer therapeutics are limited in efficacy by poor penetration into tumour tissue. This doctoral thesis aims to explore how changing the density of a therapeutic could influence its ultrasound-mediated delivery and penetration depth, thereby testing the hypothesis that increasing particle density increases penetration depth of nanoparticles under ultrasound exposure. Density-enhanced transport in the presence of ultrasound-induced cavitation is studied utilising a combination of numerical simulations, <em>in vitro</em> and <em>in vivo</em> experimental models.</p> <p>The penetration depth of nanoparticles of different densities was first predicted using a computational model to assess the magnitude of acoustic and fluid dynamic forces on a spherical nanoparticle in the presence or absence of a cavitating microbubble. This simulation showed that a denser particle will be transported further when exposed to ultrasound. Furthermore, cavitation was identified as fundamental for enhanced transport, with forcing due to microstreaming dominating the transport behaviour. These predictions were validated and supported experimentally using an <em>in vitro</em> model, where a fivefold increase in particle density resulted in a 43 % increase in peak particle penetration depth.</p> <p>To form a closer analogue to the tumour environment, a three-dimensional flow-vessel phantom was then implemented, where the penetration depths of three density-contrasting nanoparticles with unique fluorescent tags – co-delivered with either a micro- or a nano-scale cavitation agent – were studied. A trend between nanoparticle density and extravasation depth was again discernible, with the densest particles penetrating the furthest. However, the choice of cavitation agent often had a greater influence on particle transport.</p> <p>Finally, experiments were performed in a tumour-bearing mouse model, where the bio-distribution of fluorescent nanoparticles was assessed after ultrasound exposure. A bistatic HIFU setup was used to activate cavitation agents, and passive acoustic mapping was implemented to detect cavitation activity within the tumour site. Density-contrasting fluorescent nanoparticles were used as mock therapeutics, and were successfully detected in <em>ex vivo</em> tumours through IVIS imaging. However, due to experimental limitations, the influence of nanoparticle density on ultrasound-mediated drug delivery <em>in vivo</em> could not be determined, and so recommendations are made for how the hypothesis can be further validated.</p> |
| spellingShingle | Lea-Banks, H Ultrasound-mediated transport of nanoparticles and the influence of particle density |
| title | Ultrasound-mediated transport of nanoparticles and the influence of particle density |
| title_full | Ultrasound-mediated transport of nanoparticles and the influence of particle density |
| title_fullStr | Ultrasound-mediated transport of nanoparticles and the influence of particle density |
| title_full_unstemmed | Ultrasound-mediated transport of nanoparticles and the influence of particle density |
| title_short | Ultrasound-mediated transport of nanoparticles and the influence of particle density |
| title_sort | ultrasound mediated transport of nanoparticles and the influence of particle density |
| work_keys_str_mv | AT leabanksh ultrasoundmediatedtransportofnanoparticlesandtheinfluenceofparticledensity |