title: Cationic lipid complexed camptothecin (EndoTAG-2) improves antitumoral efficacy by tumor vascular targeting.
abstract: Neo-vascular targeting by cationic colloidal carriers enables to realize an innovative approach for tumor therapy. EndoTag-2 is a novel vascular targeting agent, comprising the mammalian topoisomerase I inhibitor camptothecin in its carboxylate form complexed to cationic lipid (cationic lipid complexed camptothecin). Here we studied tumor vascular targeting properties, antitumoral effects and mode of action of EndoTag-2. Tumor vascular targeting properties of fluorescently labelled EndoTag-2 were investigated by in vivo microscopy using A-MEL-3 tumors grown in the dorsal skinfold chamber preparation and by fluorescence histology of s.c. LLC-1 carcinomas. Therapeutic effects have been investigated in the s.c. LLC-1 carcinoma model and the L3.6pl human pancreatic cancer model implanted orthotopically in athymic nude mice. Antivascular effects have been studied by histological investigation of tumor microvessel density and non invasive investigation of tumor blood flow by dynamic contrast enhanced MRI imaging (DCE-MRI). EndoTag-2 selectively targeted tumor microvessels as confirmed by quantitative fluorescence microscopy. Compared to controls EndoTag-2 revealed remarkable antitumoral efficiency in s.c. LLC-1 carcinomas implanted in C57/Bl6 mice. Growth and metastasis of orthotopic L3.6pl human pancreatic tumors was significantly inhibited by EndoTag-2 treatment. Quantitative analysis of tumor microvessel density revealed significant reduction of microvessel density in lewis lung carcinomas up to 50%. DCE-MRI confirmed significant reduction of intratumoral vascular volume as well as tumor perfusion upon EndoTag-2 treatment. In conclusion this study shows that cationic lipid complexed camptothecin (EndoTag-2) is a markedly active antitumor agent based on an innovative vascular targeting approach.
authors.affiliation: Department of Surgery and Institute for Surgical Research, Klinikum Grosshadern, University of Munich, Munich, Germany. martin.eichhorn@med.uni-muenchen.de
authors.forename: M E
authors.initials: ME
authors.lastname: Eichhorn
authors.forename: S
authors.initials: S
authors.lastname: Luedemann
authors.forename: S
authors.initials: S
authors.lastname: Strieth
authors.forename: A
authors.initials: A
authors.lastname: Papyan
authors.forename: H
authors.initials: H
authors.lastname: Ruhstorfer
authors.forename: H
authors.initials: H
authors.lastname: Haas
authors.forename: U
authors.initials: U
authors.lastname: Michaelis
authors.forename: B
authors.initials: B
authors.lastname: Sauer
authors.forename: M
authors.initials: M
authors.lastname: Teifel
authors.forename: G
authors.initials: G
authors.lastname: Enders
authors.forename: G
authors.initials: G
authors.lastname: Brix
authors.forename: K-W
authors.initials: KW
authors.lastname: Jauch
authors.forename: C J
authors.initials: CJ
authors.lastname: Bruns
authors.forename: M
authors.initials: M
authors.lastname: Dellian
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology*; D002412:Cations; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002412:Cations; D002166:Camptothecin