title: Targeted and heat-triggered doxorubicin delivery to tumors by dual targeted cationic thermosensitive liposomes.
abstract: Liposomal nanoparticles can circumvent toxicity of encapsulated chemotherapeutic drugs, but fall short in tumor-specific and efficient intracellular drug delivery. To overcome these shortcomings, we designed a multifunctional dual targeted, heat-responsive nanocarrier encapsulating doxorubicin (Dox) as a chemotherapeutic content. Dox-loaded cationic thermosensitive liposomes (Dox-CTSL) carry targeting functions addressing tumor cells and tumor vasculature and have a heat-responsive lipid bilayer. Targeted Dox-CTSL demonstrated superior uptake by and toxicity to different tumor cell lines and endothelial cells compared to non-targeted TSL. Heat triggered intracellular Dox release in acidic cell compartments was visualized as fluorescent Dox nanobursts by live cell confocal microscopy. In vivo, using high resolution intravital microscopy, we demonstrated that Dox-CTSL upon an external heat-trigger delivered 3-fold higher Dox quantity to tumors than TSL. Dox-CTSL bound specifically to tumor vasculature, which in combination with the heat-triggered drug release caused significant tumor vessel damage, which was not observed when non-targeted TSL were administered. Therefore, Dox-CTSL have strong potency to increase drug efficacy due to targeted delivery and heat-triggered drug release in tumors.
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Bilyana M
authors.initials: BM
authors.lastname: Dicheva
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Timo L M
authors.initials: TL
authors.lastname: ten Hagen
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Debby
authors.initials: D
authors.lastname: Schipper
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Ann L B
authors.initials: AL
authors.lastname: Seynhaeve
authors.affiliation: Unit Hyperthermia, Department Radiotherapy, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Gerard C
authors.initials: GC
authors.lastname: van Rhoon
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Institut Gustave Roussy, Villejuif, 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, The Netherlands. Electronic address: g.koning@erasmusmc.nl.
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006358:Hot Temperature; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000008:administration & dosage
chemical_list: D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Cancer chemotherapy; Cationic thermosensitive liposomes; Cytotoxicity; Hyperthermia; Triggered drug release