Thermosensitive Liposome Formulation of Cisplatin for Cancer Treatment

Cisplatin (CDDP) is a platinum-based antineoplastic drug that is approved by the U.S. Food and Drug Administration (FDA) and Health Canada for treatment of many cancers. However, CDDP is associated with severe toxicities, including nephrotoxicity, gastrointestinal toxicity, and neurological toxicity. A number of advanced drug delivery platforms, including liposomes, have been investigated in order to reduce the systemic toxicity associated with this drug. SPI-77 and LipoplatinTM are liposome formulations of CDDP that have been successfully developed and moved forward into clinical evaluation. These liposome formulations demonstrated significantly increased tumor drug accumulation relative to free drug, yet, there was lack of improvement in therapeutic efficacy over free drug as a result of limited release of drug from carriers at the tumor site. This thesis aims (1) to develop a heat-activated thermosensitive liposome formulation of CDDP (HTLC) to overcome the limited drug release of conventional liposome formulations of CDDP, (2) to assess the therapeutic efficacy of the HTLC formulation in combination with local hyperthermia (HT) in comparison to free drug and LipoplatinTM, (3) to evaluate the impact of tumor microenvironment (TME) of cervical cancer on treatment response to the HTLC formulation to identify potential prognostic markers, and (4) to investigate the short-term (i.e. 24 hr) effect of local HT on tumor morphology, microvessel density (MVD), and innate inflammatory response in non-small-cell lung cancer (NSCLC). Overall, this work demonstrated successful development of the HTLC formulation, which revealed superior therapeutic benefit in combination with local HT relative to free drug and LipoplatinTM in mouse xenograft models of cervical carcinoma and NSCLC, including four distinct patient-derived xenograft (PDX) models. TME parameters, in particular elevated levels of both tumor-associated stroma and hypoxia were shown to be overriding factors that limit drug efficacy in cervical cancer. Furthermore, local HT resulted in a significant change in the TME of NSCLC at 24 hr post-treatment, including widespread necrosis, reduction of MVD, and activation of the innate immune system.Ph.D.2019-11-03 00:00:0