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.

Abstract

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.

• Authors: A R Khokhar, S al-Baker, T Brown, R Perez-Soler
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 34 Issue 1 Pg. 325-9 (Jan 1991) ISSN: 0022-2623 [Print] United States
• PMID: 1992134 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Indicators and Reagents
• Liposomes
• Organoplatinum Compounds
• Phosphatidylglycerols
• bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II)
• dimyristoylphosphatidylglycerol
• Dimyristoylphosphatidylcholine

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemical synthesis, toxicity)
• Dimyristoylphosphatidylcholine
• Drug Carriers
• Indicators and Reagents
• Leukemia L1210 (drug therapy)
• Liposomes
• Mice
• Molecular Structure
• Organoplatinum Compounds (administration & dosage, chemical synthesis, therapeutic use, toxicity)
• Phosphatidylglycerols
• Structure-Activity Relationship