Cancer Nanomedicine: Quantitative Visualisation and Efficacy of Nanoparticle Delivery

dc.contributor.advisor Kavallaris, Maria
dc.contributor.advisor Davis, Thomas
dc.contributor.advisor McGhee, John Ahmed-Cox, Aria 2022-06-15T03:27:19Z 2022-06-15T03:27:19Z 2022 2022-06-14T01:00:47Z
dc.description.abstract Cancer persists as a major public health concern with poor survival rates for aggressive tumours. Nanotechnology offers opportunities to develop delivery vehicles (nanoparticles) which can improve drug efficacy in cancer cells while reducing collateral toxicity caused by many current therapies. A key challenge in the clinical translation of therapeutic nanoparticles stems from the complexities of drug delivery; namely a need for greater understanding of how the biophysical characteristics of nanoparticles affects their tumour penetration and cell uptake. This thesis sought to address this challenge, developing advanced imaging and analysis methodologies to evaluate nanoparticle uptake and efficacy in quantitative cell models. We initially investigated the capability of rapid fluorescence lifetime imaging microscopy to measure nanoparticle cellular uptake. Results showcased the ability of this emerging quantitative imaging approach to track and quantify changes in nanoparticle dynamics on a second time scale, localising significant changes in nanoparticle lifetime with uptake across extracellular and nuclear boundaries in live cells. Broadening our study into tumour models which recapitulate key elements of the tumour microenvironment, glioblastoma, neuroblastoma and non-small cell lung cancer cells were grown as 3D spheroids and used to study the penetration kinetics of nanoparticles with confocal microscopy. The development of rigorous analysis methods enabled direct evaluation of nanoparticle kinetics. Subsequent study by lightsheet microscopy and real-time force imaging cytometry identified that nanoparticle uptake was influenced not only by nanoparticle size but also the stiffness and density of the cell model. Applying these analyses to functionalised nanoparticles for brain cancer delivery, we identified that lactoferrin coated nanoparticles (Lf-NP) had enhanced penetration kinetics. Low-density lipoprotein receptor (LRP1), for which lactoferrin is a key ligand, was shown to be highly expressed on the blood-brain barrier (BBB) and in glioblastoma. Following, in vitro models identified that Lf-NP could cross the BBB, and drug-loaded iterations of these nanoparticles were revealed to have elevated efficacy against glioblastoma cells. Collectively, these findings showcase methods to systematically visualise and quantify nanoparticle tumour cell uptake and highlight functionalised drug-loaded nanoparticles for further investigation in brain cancer.
dc.language English
dc.language.iso en
dc.publisher UNSW, Sydney
dc.rights CC BY 4.0
dc.subject.other Nanomedicine
dc.subject.other Cancer cell biology
dc.subject.other Fluorescence microscopy
dc.subject.other Quantitative imaging
dc.subject.other Mathematical modelling
dc.subject.other Glioblastoma
dc.subject.other Neuroblastoma
dc.subject.other Non-small cell lung cancer
dc.subject.other 3D spheroid
dc.subject.other Organoid
dc.subject.other Lightsheet microscopy
dc.subject.other Fluorescence lifetime imaging microscopy
dc.subject.other Nanoparticle
dc.subject.other Drug delivery
dc.subject.other Blood-brain barrier
dc.title Cancer Nanomedicine: Quantitative Visualisation and Efficacy of Nanoparticle Delivery
dc.type Thesis
dcterms.accessRights embargoed access
dcterms.rightsHolder Ahmed-Cox, Aria Maree
dspace.entity.type Publication
unsw.accessRights.uri 2024-06-15 2022-06-15
unsw.description.embargoNote Embargoed until 2024-06-15
unsw.relation.faculty Medicine & Health
unsw.relation.faculty Arts Design & Architecture School of Women's & Children's Health School of Art and Design School of Women's & Children's Health School of Women's & Children's Health
unsw.subject.fieldofresearchcode 320604 Nanomedicine
unsw.thesis.degreetype PhD Doctorate
Resource type