Intraliposomal chemical activation patterns of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP)-a potential antitumour agent.
L-NDDP is a liposome-entrapped platinum compound currently in phase 2 clinical trials that has been shown to undergo intraliposomal activation. The degradation/activation kinetics of liposome entrapped cis-bis-neodecanoato-trans-R,R-1,2-diamminocyclohexane platinum (II) [L-NDDP] at different conditions of pH, and temperature is presented. Liposomes were reconstituted in a solution of 0.9% sodium chloride (NaCl) in water (pH 5) at room temperature (formulation conditions currently used in the ongoing clinical trials). In the temperature experiments, L-NDDP 0.9% sodium chloride liposomes were incubated in a water-bath at 40, 60, and 80 degrees C. In the pH experiments, these solutions were compared to water, phosphate with and without chloride ion present, phosphate buffer without chloride ion at pH 3.1, 5.0, and 7.4, and glycine buffer with and without chloride ion. In 0.9% sodium chloride at room temperature, the chemical degradation/activation of liposome-bound NDDP was biphasic, with most of the degradation (approximately 45% conversion) occurring during the first hour after formation of the liposome suspension. NDDP degradation was pH dependent: when using pH 3 phosphate buffer as a reconstituting solution, liposome-bound NDDP degraded rapidly, whereas in pH 7.4 phosphate buffer it was stable for > 72 h. NDDP degradation was also temperature-dependent, the 50% point decreasing from 12 h at 25 degrees C to 9.5 h at 40 degrees C, 3.8 h at 60 degrees C, and 0.3 h at 80 degrees C when using 0.9% NaCl in water as a reconstituting solution. Using glycine buffer solution with and without NaCl at room temperature, no NDDP degradation over a 72 h period was observed at 25 degrees C; however, at 40 degrees C, only 68% NDDP remained intact at 72 h. Atomic absorption spectrophotometry (AAS) analysis of the eluting fractions after injection of L-NDDP samples reconstituted in chloride-containing and non chloride-containing solutions clearly indicated that the formation of DACH-Pt-Cl2 was only observed when chloride-containing solutions were used and was first detected at 3 h when using 0.9% NaCl in water as a reconstituting solution. These results indicate that pH and temperature, and not the presence of chloride ion, are the main factors leading to the activation of NDDP. Since 45% of NDDP is already degraded at 1 h in the same conditions, it is concluded that (1) the first active intermediates of L-NDDP formed within the liposomes are the DACH-Pt chloro-aquo and diaquo intermediates, and (2) the in vivo, antitumour activity of L-NDDP is most likely mediated by direct intracellular delivery of the active species.
Maclean
D S
DS
Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
Khokhar
A R
AR
Tyle
P
P
Perez-Soler
R
R
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D002021:Buffers; D002712:Chlorides / Q000737:chemistry; D004337:Drug Carriers; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008081:Liposomes; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000737:chemistry*; D010984:Platinum / Q000032:analysis; D011208:Powders; D013056:Spectrophotometry, Ultraviolet; D013535:Suspensions; D013696:Temperature
D000970:Antineoplastic Agents; D002021:Buffers; D002712:Chlorides; D004337:Drug Carriers; D008081:Liposomes; D009944:Organoplatinum Compounds; D011208:Powders; D013535:Suspensions; C054367:bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II); D010984:Platinum