AbstractThe main aim of the work undertaken in this thesis was to investigate the potential of ultrasound-targeted microbubble destruction (UTMD) mediated chemo-sonodynamic therapy (chemo-SDT) for the treatment of prostate cancer (PCa). Chapter 1 provides an introductory overview to the challenges associated with PCa, current treatments / limitations, SDT and the potential for combining SDT with UTMD. Chapter 2 details the methods used in chapters 3-6. Chapter 3 (the first results chapter) describes how the sonosensitiser Rose Bengal (RB) can be loaded onto microbubbles (MBs) using the avidin-biotin interaction with docetaxel (DTX) incorporated in the core to produce DTX-MB-RB that were subsequently tested for UTMD mediated efficacy in 3D spheroid and murine models PCa. This treatment produced improved efficacy when compared to standard DTX monotherapy. Chapter 4 aimed to address some of the shortcomings associated with the preparation of DTX-MB-RB in chapter 3. In particular, the requirement for the avidin-biotin linkage was eliminated and RB loading was achieved by synthesising a RB modified lipid which was used as a constituent lipid of the MB shell. This approach enabled the preparation of DTX-MB-RB in a single step from a pre-MB suspension following activation for 45 sec using a VialMix® shaker. The pre-MB suspension displayed good stability when stored for 3 months at 5 oC and these DTX-MB-RB were used in the efficacy experiments undertaken in Chapter 5. This involved testing the DTX-MB-RB in DU145 and LNCaP 3D spheroid models as well as PC3 (androgen resistant) and 22Rv1 (androgen dependent) murine models of PCa. The results demonstrated the effectiveness of UTMD mediated chemo-SDT in all the models tested and was more effective than UTMD mediated DTX-MB or MB-RB treatment in the 3D spheroid models and DTX monotherapy in the murine models. Chapter 6 involved the preparation of two new drug functionalised lipids: one functionalised with 5-fluoruridine (5-FUR) and the second with irinotecan (IRIN). These lipids were used to manufacture MBs carrying the drug payloads which were investigated for efficacy in 3D DU145 3D spheroid model of PCa. While these chemotherapies are not normally used in the treatment of PCa, the results demonstrated the potential of UTMD mediated 5FUR-MB-IRIN as the
cell viability was reduced by 91.32%. Final conclusions and a future outlook are provided in Chapter 7.
|Date of Award||Jan 2023|
|Sponsors||Department for the Economy|
|Supervisor||Anthony McHale (Supervisor), John Callan (Supervisor) & Bridgeen Callan (Supervisor)|
- Prostate cancer