Overcoming cisplatin resistance of ovarian cancer cells by targeted liposomes in vitro.
The clinical application of cisplatin to treat solid tumours is often limited by the development of tumour cell resistance against this cytostatic agent. Although liposomal carriers of cisplatin are currently in clinical development, approaches to functionally overcome cisplatin resistance by liposomes have hardly been reported. We prepared PEGylated cisplatin-containing liposomes with diameters of about 110 nm and targetability to transferrin receptors (TfR) to correlate cisplatin cell uptake with cytotoxicity in sensitive and cisplatin resistant ovarian cancer cells A2780 compared to the free drug. Whereas the cell entry of free cisplatin was reduced by factor 4 after 24h in resistant cells, liposomal uptake was similar in both cell lines and not affected by resistance. Cytotoxicity was clearly related to intracellular platinum levels, which were even higher for liposomal vs. free cisplatin in the resistant cells after 24, 48, and 72 h and slightly lower in the sensitive cells. However, TfR targeting was of less impact on activity in comparison to non-targeted liposomes. Detection of cellular ATP levels within 24h allowed postulations on the intracellular fate of the liposomes. Altogether, this study strongly supports approaches to overcome cisplatin resistance by a liposomal application of the drug.
Krieger
Michaela L
ML
Department of Pharmacy, University Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Eckstein
Niels
N
Schneider
Verena
V
Koch
Martin
M
Royer
Hans-Dieter
HD
Jaehde
Ulrich
U
Bendas
Gerd
G
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008081:Liposomes; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D011990:Receptors, Transferrin / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D011990:Receptors, Transferrin; D011092:Polyethylene Glycols; D002945:Cisplatin