Liposomal Nanomedicine with Short Chain Sphingolipids Modulate Tumor Cell Membrane Permeability Modulate Tumor Cell Membrane Permeability and Improve Chemotherapy

Abstract

Chapter 6 discusses the significance of the results described in this thesis and future perspectives.
The main goal of the thesis was the application of SCS enriched liposomes to improve chemotherapy outcome, by enhancing drug bioavailability in target tumor cells. Development of SCS (C8-GluCer or C8-GalCer) enriched liposomes containing Dox and MTO was successfully achieved with optimal characteristics from a pharmaceutical point of view, for use in vitro and vivo studies and to advance pharmaceutical development of such formulations toward clinical application, which is currently ongoing for C8-GluCer-Dox-liposomes. In vitro studies revealed that the SCS drug uptake enhancing and cytotoxic properties were displayed preferentially in tumor cells. Mechanistic studies demonstrated that this was related to preferential accumulation of SCS in tumor cell membranes. Intravital microscopic imaging proved that intratumoral bioavailable drug levels for SCS-liposomal treatment exceeded standard liposomal treatment in a MDA MB-231 tumor model. Therapeutic studies in an orthotopic breast cancer model demonstrated improved therapeutic efficacy of C8-GluCer enriched MTO-liposomes compared to standard MTO-liposomes. SCS-enriched liposomal chemotherapy represents a novel attractive drug delivery approach, which combines the benefits of reduced toxicity and improved tumor accumulation of drugs through nanoliposomal encapsulation with enhanced intracellular drug delivery by SCS-mediated tumor cell membrane permeabilization. In these studies we’ve broadened the application using different glycosphingolipids to formulate two chemotherapeutic drugs. Given their proven therapeutic potential, the performed pharmaceutical optimization of formulations will contribute to ultimate near future clinical application. Next to a translational direction, future studies will aim at further broadening of this drug delivery platform to include novel chemotherapeutic drugs, new SCS lipids and the search for optimal SCS – drug combinations for improved drug delivery. A further understanding of the working mechanism, especially in relation to the tumor cell membrane lipid composition will help to find efficient tumor cell-specific drug delivery routes for various chemotherapeutic drugs.