Exploring the Potentials and Limitations of Solid Tumor Treatment by Thermosensitive Liposomes and Hyperthermia

Traditional chemotherapy for solid tumors is often associated with undesired side effects in treated patients. Furthermore, infused drugs are rapidly cleared from the circulation which largely hinders accumulation in the target tissue. An emerging therapeutic strategy consists in the encapsulation of chemotherapeutic drugs inside liposomes in order to prevent side effects and rapid clearance. Throughout the last decades of research, there has been an increasing interest in liposomes that are able to locally release their contents at the site of solid tumors. This has led to the initiation of clinical trials for the evaluation of thermosensitive liposomes (TSLs), which are drug-loaded nanoparticles that rapidly release the drug within mildly heated tissue (40-43 °C). However, these liposomes are relatively unstable in circulation during the tumor heating period, which may lead to sub-optimal drug delivery to the tumor.
This thesis first describes the improved design of TSLs for enhanced cancer therapy, as well as a comprehensive characterization of such formulations in a pre-clinical setting. Subsequently, a comparative study was conducted to assess the influence of varying delivery strategies, which focused either on intravascular drug release of TSLs or their prior accumulation in the tumor tissue, in generating a therapeutic response. Furthermore, the relationship between variation in tumor biology, drug delivery kinetics, and therapeutic response was investigated. Lastly, a feasibility study on magnetic nanoparticle entrapment into liposomes was performed for potential applications in image-guided drug delivery.
The present findings contribute to the improvement of existing therapies using TSLs, provide an improved understanding of the mechanism of their delivery, and of cancer types that are more likely to respond to TSL-based therapy.