Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.758309
Title: Lipid oil nanodroplets for hydrophobic drug delivery
Author: Charalambous, Antonia
ISNI:       0000 0004 7431 0829
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2018
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Abstract:
Delivery of anti-cancer drugs to tumours is a fundamental requirement for cancer treatment. However, failure of drugs to reach tumours at sufficient concentrations due to poor bioavailability, rapid metabolism and elimination compromises effective treatment. A substantial number of potent anti-cancer drugs, exhibit hydrophobic properties that hinder their clinical use. Therefore, there is an urgent need for the development of a hydrophobic drug delivery system (DDS) that aims to effectively deliver and controllably trigger the release of these agents. This may improve drug bioavailability, efficacy and reduce severe side effects. Lipid-Oil-NanoDroplets (LONDs) are nanosized nanoemulsions and are proposed as a novel hydrophobic DDS for colorectal cancer (CRC) treatment. LONDs were produced using a two-step high pressure homogenisation process, producing LONDs with size ranges between 100-300 nm. The hydrophobic vascular disrupting agent Combretastatin A4 (CA4) was encapsulated and used as a proof-of-concept for LOND evaluation in vitro and in vivo. CA4 was dispersed in triacetin or tripropionin oil to form the LOND core, stabilised by a phospholipid-shell. Using a microfluidic production platform, CA4 LONDs were attached on-chip to gas-filled, phospholipid-shelled therapeutic microbubbles (thMBs). CA4 thMBs were targeted to vascular endothelial growth factor receptor 2 (VEGFR-2) and used as LOND delivery vehicles. An external ultrasound (US) destruction pulse applied at the tumour site was used to trigger targeted release and enhance delivery. This project showed CA4 release and/or uptake from LONDs in both endothelial and human CRC cells by immunofluorescence and flow cytometry. Intratumoural delivery of CA4 LONDs was observed and quantified in CRC xenografts using liquid chromatography tandem mass spectrometry (LS-MS/MS). Administration of CA4 LONDs resulted in a modest tumour growth inhibition in vivo, while a reduction in tumour perfusion was observed with CA4 thMBs. Combination therapy of CA4 thMBs with a chemotherapeutic agent, irinotecan, further reduced tumour growth compared to irinotecan alone, potentially through reduction in tumour perfusion. These results suggest that LONDs may serve as a novel hydrophobic DDS, while thMBs could further enhance tumour specific delivery.
Supervisor: Markham, Alexander ; Coletta, Louise ; Bonthron, David ; Carr, Ian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.758309  DOI: Not available
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