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

Abdul R. Khokhar, Salaam Al-Baker, Trellis Brown, Roman Perez-Soler

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

cw-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 >95% and stability in normal saline at 4 °C was >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.

Original languageEnglish (US)
Pages (from-to)325-329
Number of pages5
JournalJournal of Medicinal Chemistry
Volume34
Issue number1
DOIs
StatePublished - Jan 1 1991
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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