Metallomics in drug development: characterization of a liposomal cisplatin drug formulation in human plasma by CE-ICP-MS.
A capillary electrophoresis inductively coupled plasma mass spectrometry method for separation of free cisplatin from liposome-encapsulated cisplatin and protein-bound cisplatin was developed. A liposomal formulation of cisplatin based on PEGylated liposomes was used as model drug formulation. The effect of human plasma matrix on the analysis of liposome-encapsulated cisplatin and intact cisplatin was studied. The presence of 1 % of dextran and 4 mM of sodium dodecyl sulfate in HEPES buffer was demonstrated to be effective in improving the separation of liposomes and cisplatin bound to proteins in plasma. A detection limit of 41 ng/mL of platinum and a precision of 2.1 % (for 10 μg/mL of cisplatin standard) were obtained. Simultaneous measurements of phosphorous and platinum allows the simultaneous monitoring of the liposomes, liposome-encapsulated cisplatin, free cisplatin and cisplatin bound to plasma constituents in plasma samples. It was demonstrated that this approach is suitable for studies of the stability of liposome formulations as leakage of active drug from the liposomes and subsequent binding to biomolecules in plasma can be monitored. This methodology has not been reported before and will improve characterization of liposomal drugs during drug development and in studies on kinetics.
Department of Pharmacy Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Tam T T N
TT
Nguyen
Jesper
J
Østergaard
Stefan
S
Stürup
Bente
B
Gammelgaard
D000970:Antineoplastic Agents / Q000097:blood*; D001798:Blood Proteins / Q000737:chemistry*; D002945:Cisplatin / Q000097:blood* / Q000737:chemistry; D004339:Drug Compounding; D015195:Drug Design; D004355:Drug Stability; D019075:Electrophoresis, Capillary; D006801:Humans; D057230:Limit of Detection; D008081:Liposomes / Q000097:blood* / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry; D010758:Phosphorus / Q000097:blood*; D010984:Platinum / Q000097:blood*; D011485:Protein Binding; D013054:Spectrophotometry, Atomic
D000970:Antineoplastic Agents; D001798:Blood Proteins; D008081:Liposomes; D010743:Phospholipids; D010758:Phosphorus; D010984:Platinum; D002945:Cisplatin