Design, Engineering and Biological Performance of Responsive Lipid Vesicles for Enhanced Drug Delivery by Mild Hyperthermia

The design of a delivery system that specifically delivers anticancer drug to the tumour site avoiding normal tissues damage has always been a challenge. In this thesis we describe the engineering and biological performance of novel temperature- sensitive liposomes (TSL) that have both a substantial in vivo stability and an efficient content-release by mild hyperthermia (HT).;The last chapter of this thesis explored the opportunities of increasing the therapeutic specificity of TSL by designing anti-MUC-1 targeted vesicles based on the traditional TSL (TTSL) to trigger drug release after specific uptake into cancer cells. We showed that TTSL liposomes maintain their physicochemical and thermal properties after conjugation to anti-MUC-1 antibody. Moreover, the system was further evaluated by studying the in vitro cellular binding, uptake and therapeutic efficacy. Taking this system a step further, its biodistribution and therapeutic potential were also examined. Different protocols were applied to explore the effect of HT on the accumulation of targeted TTSL into the tumour and their therapeutic efficacy.;In summary, this thesis explains the design, engineering and biological performance of novel temperature-responsive vesicles. Our studies demonstrate the critical factors to consider in the design of clinically relevant TSL and the importance of matching the heating protocol to their physicochemical and pharmacokinetic parameters to maximise therapeutic benefits.;First, we explain the development of novel lipid-peptide hybrids (Lp-Peptide) by anchoring leucine zipper temperature-sensitive peptide within the liposomal lipid bilayer. The dissociation of the self-assembled coiled-coil structure of the peptide by mild Hyperthermia (HT) is considered to be responsible for triggering drug release. We characterized this system by studying its physicochemical properties and the interaction of the peptide with the lipid bilayer. Then we examined its potential to retain and trigger the release of the anticancer drug, doxorubicin, in vitro at physiological temperatures and after exposure to mild HT. The hybrid system was further evaluated at the cellular level by studying its biocompatibility, cellular uptake and cytotoxic activity. In addition, the blood kinetics, tumour and other tissues accumulation were explored when we studied the system in vivo. Our data suggested that Lp-Peptide hybrids can increase both immediate and long-term drug accumulation in the tumour. Therefore, we studied their therapeutic activity comparing two different heating protocols to mimic intravascular and interstitial drug release.