title: Antitumor activity and biodistribution of cisplatin nanocapsules in nude mice bearing human ovarian carcinoma xenografts.
abstract: Cisplatin nanocapsules represent a novel lipid formulation of the anticancer drug cis-diamminedichloridoplatinum(II) (cisplatin), characterized by an unprecedented cisplatin-to-lipid molar ratio, and exhibiting strongly increased in-vitro cytotoxicity compared with the free drug. In this study, antitumor efficacy and biodistribution of PEGylated cisplatin nanocapsules were compared with those of the free drug in a mouse tumor model. Nude mice bearing human ovarian carcinoma OVCAR-3 xenografts were treated twice with a 1-week interval by intravenous administration of cisplatin nanocapsules or cisplatin in solution, and the growth inhibitory effects were determined by measurement of tumor volumes. At a dose of 3 mg cisplatin/kg, corresponding to the maximum tolerated dose of cisplatin nanocapsules, cisplatin nanocapsules and cisplatin in solution exhibited similar therapeutic effectiveness, reducing tumor growth by 90% at day 20 after first injection. The platinum biodistribution was assayed by analyzing plasma and tissues for total platinum content by nonflame atomic absorption spectroscopy. Plasma and tumor concentrations of platinum were similar for both formulations. During the first hour after injection of cisplatin nanocapsules, the platinum content of the kidney was 40% less than that after administering the free drug. Platinum from nanocapsules showed rapid and 4.5-fold higher accumulation in the liver compared with free cisplatin, and, at a slower rate, accumulation to a high concentration in the spleen. We conclude that the formulation of cisplatin nanocapsules inhibits the growth of OVCAR-3 xenografts in nude mice, albeit to a similar extent as free cisplatin. The results suggest that the antitumor efficacy of the nanocapsules could be improved by preventing rapid clearance from circulation.
authors.affiliation: Department of Biochemistry of Membranes, Bijvoet Institute, Utrecht University, Utrecht, The Netherlands.
authors.forename: Rutger W H M
authors.initials: RW
authors.lastname: Staffhorst
authors.forename: Kasper
authors.initials: K
authors.lastname: van der Born
authors.forename: Caroline A M
authors.initials: CA
authors.lastname: Erkelens
authors.forename: Irene H L
authors.initials: IH
authors.lastname: Hamelers
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.forename: Epie
authors.initials: E
authors.lastname: Boven
authors.forename: Anton I P M
authors.initials: AI
authors.lastname: de Kroon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D053769:Nanocapsules; D002945:Cisplatin