AbstractClinical imaging including as PET, CT and MRI have revolutionised the detection and management of diseases such as cancer. When imaging agents are coupled onto nanosized carriers they provide information on the tumour location as well as provide an insight into their biodistribution. Therefore, these nanocarriers can be involved in integration of diagnosis and therapy in a single platform, which is called theranostics. Image Guided Focused Ultrasound drug delivery is a promising strategy for enabling both cancer diagnosis and treatment using the same nanocarrier delivery/diagnostic system. The aim of this project is to develop near infrared fluorescence (NIRF) and magnetic resonance imaging (MRI) labelled liposomes for targeted image guided drug delivery when combined with focused ultrasound (FUS). FUS can be applied for regional increase in temperature (hyperthermia) whereas MR guided FUS (MRgFUS) is a clinically used instrument that can provide this controlled hyperthermia.
Previous studies have shown that incorporation of chelated Gd3+ lipids into liposomal formulations empowered these nanoparticles with MRI contrast enhancement. Here, various spacers between the chelating ligand (head group) and the lipid tail were introduced, to investigate their effects on liposomes’ T1 relaxivities, a parameter used for measuring the contrast efficiency. Image guided thermosensitive PEGylated liposomes (iTSLs) were prepared with various Gd3+ chelated lipids that were made for the purpose of this study. In addition, a second, near infrared fluorescence (NIRF) label was also included in the liposomes for optical imaging. The prepared iTSLs were characterised by T1 relaxivities using a 400 MHz NMR and 9.4 T MRI. Gd3+ concentrations of liposome formulation were determined by Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) and Total Reflection X-Ray Fluorescence (TXRF). In addition, these two analytical methods were compared for reproducibility and accuracy for assessment of Gd3+ concentrations in liposomes. Moreover, the liposomal formulations incorporating with MRI and NIRF lipids were loaded with a chemotherapeutic agent (doxorubicin). In vivo, the tumours were monitored with doxorubicin when released via heat activation by FUS, which showed intrinsic drug fluorescence change. iTSLs accumulation in tumours at defined time points (post injection) in vivo were investigated with both imaging techniques (NIRF and MRI).
Both NMR and MRI relaxometries studies showed potential for MR contrast enhancement. T1-weighted images showed positive enhancement for all iTSLs, with longer spacers apparently having a stronger effect. In mice, administration of iTSLs have shown a time-dependent tumour contrast enhancement and the change in T1 was quantified over time. The studies on xenograft mice models provided evidence that mild FUS-induced hyperthermia greatly improves the iTSLs uptake in tumours and trigger rapid drug release which improves the overall therapeutic index.
|Date of Award||1 Mar 2021|
|Supervisor||Maya Thanou (Supervisor) & Po-Wah So (Supervisor)|