Chemical and biological studies on a series of lipid-soluble (trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) complexes incorporated in liposomes.
cis-Bis(neodecanoato)(trans-(R,R)-1,2-diaminocyclohexane)platinum( II) [L-NDDP] is a liposome incorporated lipophilic cisplatin analogue that has shown promising antitumor activity against tumors resistant to cisplatin and liver metastases in mice. L-NDDP is currently under clinical evaluation. However, NDDP is an isomeric mixture of different species having various isomeric neodecanoic moities as liganded leaving groups. A series of new highly lipid-soluble cis-bis(neodecanoato)(trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) [Pt] complexes, using single isomers of neodecanoic acid, were synthesized and characterized by analytical and spectroscopic techniques (infrared and 195Pt NMR). Multilamellar vesicles (MLVs) composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) at a molar ratio of 7:3 were used as carriers of the Pt complexes. The efficiency of incorporation of the liposomal-platinum (L-Pt) preparations was greater than 95% and stability in normal saline at 4 degrees C was greater than 95% at day 14 in each case. The iv LD50 values of all L-Pt preparations tested were in the range of 62.3 to 104 mg/kg. The % T/C obtained after a single ip injection of the optimal dose of L-Pt preparations against L1210 leukemia was in the range of 150 to 253 (160 for cisplatin). When a multiple ip injection schedule was used (on days 1, 5, and 9) the L-Pt preparations of R,R complexes (1, 7, and 9) were more active than cisplatin at the optimal dose (% T/C = 257 for each vs 220 for cisplatin). The L-Pt preparations of R,R complexes were also markedly active against L1210 leukemia resistant to cisplatin (% T/C 355, 231, and 185 respectively vs 112 for cisplatin). These studies show that the single isomers of NDDP are comparable to the original isomeric mixture in terms of toxicity and biological activity.
Khokhar
A R
AR
Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
al-Baker
S
S
Brown
T
T
Perez-Soler
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000633:toxicity; D004134:Dimyristoylphosphatidylcholine; D004337:Drug Carriers; D007202:Indicators and Reagents; D007939:Leukemia L1210 / Q000188:drug therapy*; D008081:Liposomes; D051379:Mice; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D010715:Phosphatidylglycerols; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004337:Drug Carriers; D007202:Indicators and Reagents; D008081:Liposomes; D009944:Organoplatinum Compounds; D010715:Phosphatidylglycerols; C054367:bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II); C002773:dimyristoylphosphatidylglycerol; D004134:Dimyristoylphosphatidylcholine