title: Plasma membrane targeting by short chain sphingolipids inserted in liposomes improves anti-tumor activity of mitoxantrone in an orthotopic breast carcinoma xenograft model.
abstract: Mitoxantrone (MTO) is clinically used for treatment of various types of cancers providing an alternative for similarly active, but more toxic chemotherapeutic drugs such as anthracyclines. To further decrease its toxicity MTO was encapsulated into liposomes. Although liposomal drugs can accumulate in target tumor tissue, they still face the plasma membrane barrier for effective intracellular delivery. Aiming to improve MTO tumor cell availability, we used short chain lipids to target and modulate the tumor cell membrane, promoting MTO plasma membrane traversal. MTO was encapsulated in liposomes containing the short chain sphingolipid (SCS), C8-Glucosylceramide (C8-GluCer) or C8-Galactosylceramide (C8-GalCer) in their bilayer. These new SCS-liposomes containing MTO (SCS-MTOL) were tested in vivo for tolerability, pharmacokinetics, biodistribution, tumor drug delivery by intravital microscopy and efficacy, and compared to standard MTO liposomes (MTOL) and free MTO. Liposomal encapsulation decreased MTO toxicity and allowed administration of higher drug doses. SCS-MTOL displayed increased clearance and lower skin accumulation compared to standard MTOL. Intratumoral liposomal drug delivery was heterogeneous and rather limited in hypoxic tumor areas, yet SCS-MTOL improved intracellular drug uptake in comparison with MTOL. The increased MTO availability correlated well with the improved antitumor activity of SCS-MTOL in a MDAMB-231 breast carcinoma model. Multiple dosing of liposomal MTO strongly delayed tumor growth compared to free MTO and prolonged mouse survival, whereas among the liposomal MTO treatments, C8-GluCer-MTOL was most effective. Targeting plasma membranes with SCS improved MTO tumor availability and thereby therapeutic activity and represents a promising approach to improve MTO-based chemotherapy.
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam 3000 CA, The Netherlands. Electronic address: l.cordeiropedrosa@erasmusmc.nl.
authors.forename: Lília R
authors.initials: LR
authors.lastname: Cordeiro Pedrosa
authors.affiliation: Department of Diagnostic Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam 1066 CX, The Netherlands.
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam 3000 CA, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Soullié
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam 3000 CA, The Netherlands.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Seynhaeve
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam 3000 CA, The Netherlands; Institut de Cancerologie Gustave Roussy, Villejuif, Paris 94800, France.
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam 3000 CA, The Netherlands.
authors.forename: Timo L M
authors.initials: TL
authors.lastname: Ten Hagen
authors.affiliation: Department of Radiotherapy, Division of Biological Stress Response, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam 1066 CX, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam 3000 CA, The Netherlands. Electronic address: g.koning@erasmusmc.nl.
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D008081:Liposomes; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D020714:Maximum Tolerated Dose; D008819:Mice, Nude; D008942:Mitoxantrone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013107:Sphingolipids / Q000737:chemistry*; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D013107:Sphingolipids; D008942:Mitoxantrone
keywords: Chemotherapy; Mitoxantrone; Nanoliposomes; Short chain sphingolipids; Targeting tumor cell membrane; Tumor-cell membrane-permeability modulation