PhD defence W. (Wenqiu) Huang

Below is a brief summary of the dissertation:

The studies discuss the challenges and potential solutions associated with the use of the anticancer drug doxorubicin (DXR). DXR is effective against various cancers but has limited clinical application due to off-target toxicity and fast clearances. To overcome these limitations, researchers have developed nanoparticles (NPs), specifically liposomes, for targeted drug delivery. PEGylated liposomal doxorubicin, known as Doxil or Caelyx, has shown improved pharmacokinetics and passive targeting capabilities. However, its clinical efficacy has been limited due to tumor heterogeneity and the need for active targeting strategies. Another limitation is the slow release of DXR from NPs, which reduces intracellular drug concentration. Mild hyperthermia, applied at temperatures between 41-45°C, has been explored as a strategy to enhance drug delivery and release. The use of thermosensitive liposomes (TSLs) has shown promising results, as their composition allows for temperature-triggered release. However, TSLs require further optimization for successful clinical translation. The study also discusses the importance of accurately evaluating the pharmacokinetics of lipophilic NPs and drugs in vitro and in vivo, highlighting the instability of lipophilic fluorescent markers in biological conditions. Furthermore, the study explores the interaction between DXR and DNA, as well as the intracellular kinetics of drug distribution and its interaction with cellular compounds and structures in live cells using fluorescent lifetime imaging microscopy (FLIM), revealing the binding process and shedding light on mechanisms of drug resistance, as well as potential drug-related modifications to enhance drug activity.